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International Journal of Clinical and Experimental Pathology logoLink to International Journal of Clinical and Experimental Pathology
. 2015 Jul 1;8(7):8311–8335.

Papillary renal cell carcinoma: a clinicopathological and whole-genome exon sequencing study

Kunpeng Liu 1,*, Yuan Ren 1,*, Lijuan Pang 1, Yan Qi 1, Wei Jia 1, Lin Tao 1, Zhengyan Hu 1, Jin Zhao 1, Haijun Zhang 2, Li Li 2, Haifeng Yue 3, Juan Han 3, Weihua Liang 4, Jianming Hu 1, Hong Zou 1,*, Xianglin Yuan 3, Feng Li 1,*
PMCID: PMC4555730  PMID: 26339402

Abstract

Papillary renal cell carcinoma (PRCC) represents the second most common histological subtype of RCC, and comprises 2 subtypes. Prognosis for type 1 PRCC is relatively good, whereas type 2 PRCC is associated with poor clinical outcomes. The aim of the present study was to evaluate the clinicopathological and mutations characteristics of PRCC. Hence, we reported on 13 cases of PRCC analyzed using whole-exome sequencing. Histologically, type 2 PRCC showed a higher nuclear grade and lymphovascular invasion rate versus type 1 PRCC (P < 0.05). Immunostaining revealed type 1 PRCC had higher CK7 and lower Top IIα expression rates (P < 0.05). Whole-exome sequencing data analysis revealed that the mutational statuses of 373 genes (287 missense, 69 silent, 6 nonsense, and 11 synonymous mutations) differed significantly between PRCC and normal renal tissues (P < 0.05). Functional enrichment analysis was used to classify the 287 missense-mutated genes into 11 biological process clusters (comprised of 61 biological processes) and 5 pathways, involved in cell adhesion, microtubule-based movement, the cell cycle, polysaccharide biosynthesis, muscle cell development and differentiation, cell death, and negative regulation. Associated pathways included the ATP-binding cassette transporter, extracellular matrix-receptor interaction, lysosome, complement and coagulation cascades, and glyoxylate and dicarboxylate metabolism pathways. The missense mutation status of 19 genes differed significantly between the groups (P < 0.05), and alterations in the EEF1D, RFNG, GPR142, and RAB37 genes were located in different chromosomal regions in type 1 and 2 PRCC. These mutations may contribute to future studies on pathogenic mechanisms and targeted therapy of PRCC.

Keywords: Papillary renal cell carcinoma, whole-exome sequencing, gene mutation

Introduction

Renal cell carcinoma (RCC) accounts for approximately 90% of all renal malignancies. Papillary RCC (PRCC), the second most common RCC subtype, accounting for approximately 10% of all cases, is a renal parenchyma malignant tumor with papillary or tubulopapillary architecture that presents as type 1 or 2 PRCC; type 1 PRCC is composed of single layered small cell and scanty cytoplasm, type 2 PRCC is characterized by pseudostratified large cells and eosinophilic cytoplasm is a renal parenchyma malignant tumor with papillary or tubulopapillary architecture [1]. Based on the cytologic and histologic features, PRCC can be divided into two subtypes, types 1 and 2 [2]. Type 1 PRCC is generally considered to have a better prognosis than type 2 PRCC, although no consensus regarding the standard treatment for metastatic PRCC exists [3-7].

Molecular genetic studies are highly important in diagnosis and prognosis evaluation, and may provide treatment directions. MET locates at 7q, and its mutation relates to susceptibility to PRCC [8]. Mutations of MET have been identified to cause hereditary PRCC, and occur in a small proportion of sporadic PRCC and a greater number show somatic copy number gains involving chromosome 7q [8,9]. In addition, leucine-rich repeat kinase 2 (LRRK2) is overexpressed and amplified in PRCC. MET and LRRK2 have a synergistic effect during tumor growth via the mTOR and STAT3 pathway [10]. The exome BeadChip can not only identify gene mutations, but also identify diagnostic and therapeutic oncogenes and tumor suppressor genes. Although the pathologic and immunophenotypic of PRCC have been investigated, whole-genome exon sequencing reports are limited. Therefore, we here examined the clinicopathological and gene mutation characteristics of PRCC by a combination of immunohistochemistry and exon chip analyses.

Materials and methods

Specimens

The study contained 13 paraffin-embedded PRCCs and 18 normal kidney tissues. 13 tumors consisted of 6 case of type 1 and 7 case of type 2 PRCC. All tissues were obtained from the archives of the Department of Pathology, School of Medicine, Shihezi University. After asked for the view of the patients and the Institutional Research Ethics Committee, we make a collection of the clinicopathological data for these cases in the patients’ medical records. All specimens were observed by two independent pathologists. Nuclear grading was done according to the Fuhrman nuclear grade system. Tumor stages were according to the 2010 TNM (T = Tumor, N = Node, M = Metastases) classification of the American Joint Committee on Cancer.

Immunohistochemistry (IHC)

IHC staining was performed on 4 μm thick formalin-fixed, paraffin-embedded tissue sections by the 2-step Envision technique (Dako, Denmark). The primary antibodies included cluster of differentiation (CD) 10 (GT200410, 1:100), cytokeratin (CK) (AE1/AE3, 1:100), vimentin (Vim3B4, 1:100), CD117 (1:300), alpha-methylacyl-CoA racemase (AMACR), Top IIα, MDM2, p53, (13H4, 1:100), and CK7 (OV-TL12/30, 1:50), and purchased from Dako company. Negative or positive control was set up on the basis of antibodies.

DNA extraction

Total DNA was isolated from the 13 cases of PRCC and 18 cases of normal kidney tissue samples by using a standard phenol/chloroform extraction method. The quantity of DNA was measured by reading A260/280 ratios by spectrophotometer. When A260/280 ratios located range 1.8 to 2.0, DNA was available. Extractions were stored at -80°C until they were labeled by nick translation.

Whole-exome sequencing

A total of 1 μg of DNA from each of the 13 PRCC tissues and 18 normal kidney tissues were labeled with Illumina reagents and hybridized to Human Exome BeadChips (Illumina, USA). The quality assessment was performed by Illumina Expression Console software. Compared with normal renal tissues, the mutative genes were identified the mutated genes by significance analysis of microarrays (SAM) algorithm in PRCC tissues. The mutative genes associated with cell cycle regulation and other biological functions were determined by Gene Ontology biological process (Gene Ontology BP) enrichment of the classification analysis. The pathways associated with PRCC were confirmed by the Kyoto Encyclopedia of Genes and Genomes database (KEGG).

Statistical analysis

All statistical calculations were done using SPSS 17.0. Difference of measurement data was compared with single factor analysis of variance. Count data were analyzed using Fisher’s exact test. Classification enrichment of gene function and pathway were used to analyze gene function (Gene Ontology of Biological Processes, Molecular function) by DAVID database and KEGG Database. P value < 0.05 was a difference in statistics.

Results

Clinical features

The clinical characteristics of type 1 and type 2 PRCC are summarized in Table 1. In this cohort, 7 patients were men and 6 were women (1.2 male/female ratio); mean age was 53.9 (range from 26 to 74); the average age of the patients was 61.5 (range from 48 to 74) with type 1 PRCC, 47.4 (range from 26 to 63) with type 2 PRCC. The male-to-female ratio, the mean age of the patients, and metastasis were not significantly different between the two groups. In the 13 cases, 3 were asymptomatic, 6 were presented with osphyalgia, and 4 were presented with hematuria. Ultrasonic examination and Computed tomography (CT) showed inhomogeneous mass, as the tumor mass often had hemorrhage, necrosis, or cystic degeneration. Follow-up found the tumor related survival rate was 82.7% (5/6) for the patients with type 1 and 28.6% (2/7) for those with type 2 PRCC. According to 2010 AJCC staging criteria, 6 neoplasms presented at stage 1, 4 at stage 2, 3 at stage 3, 0 at stage 4.

Table 1.

Distribution of analyzed clinicopathologic features and outcome of type 1 and type 2 PRCC

Characteristics Type 1 Type 2 P value
No. of patients 6 7
Age of patients Mean ± SD 61.5 ± 11.8 47.4 ± 13.7 0.075
Range 48-74 26-63
Sex of patients Male 3 4
Female 3 3 0.617
Metastasis Positive 0 1 0.538
Tumor size (cm) Mean ± SD 6.92 ± 3.06 7.27 ± 3.10 0.840
Range 3.5-11 3.9-13
Fuhrman grade Low (1-2) 6 2
High (3) 0 5 0.049
Lymphovascular invasion Negative 6 3
Positive 0 4 0.049
stage I-II 6 4
III -IV 0 3 0.122
Outcome Dead 5 (5/6)
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P value: type 1 PRCC vs. type 2 PRCC; Fisher’s exact test.

Histopathology

The differences of histopathology between the two types were described in Table 1. All tumors were located in unilateral renal parenchyma; Mean tumor size, calculated on the maximum diameter, was 7.11 cm (range from 3.5 to 13 cm); it was no difference between the two types. Tumor color are gray, gray yellow, gray red, or colorful; necrosis and hemorrhage could be observed in 4 cases grossly. Microscopically, the tumor was mainly composed of the different proportion of papillary and tubular structure. They were composed of cells arranged on a delicate fibrovascular core. The cytoplasm may be basophilic, eosinophilic, or sometimes partially clear. 6 (6/13) cases were diagnosed as type 1 (Figure 1A) and 7 (7/13) cases were type 2 PRCC (Figure 1B) by their appearance under a microscope. Type 2 PRCC had higher nuclear grade (P = 0.049) and Lymphovascular invasion in relative to type 1 (P = 0.049).

Figure 1.

Figure 1

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Microscopic and immunohistochemical findings in PRCC. A. Type 1 PRCC was papillae covered by small tumor cells with scanty and basophilic cytoplasm and round nucleus, arranged in a single layer on papillary basement membrane. (H&E, × 200); B. Type 2 PRCC was pseudostratified ciliated columnar epithelium on papillary cores, often with abundant and eosinophilic cytoplasm, large nuclei and prominent nucleoli (H&E, × 200); C. Immunohistochemically, PRCC showed diffuse intense plasma membrane staining for AMACR. (× 200).

Immunohistochemistry

Results of immunohistochemical staining were summarized in Table 2. All PRCC expressed AMACR (Figure 1C), CK7 positive expression rate of type 1 PRCC (6/6) was higher in compared with type 2 (2/7) (P = 0.016). In contrast, Top IIα immunoreactivity was negative (0/6) in type 1 PRCC, while the majority of type 2 PRCC (4/7) were positive for Top IIα (P = 0.049).

Table 2.

Immunohistochemical analyses of CK, CD10, Vimentin, AMACR, CK7, CD117, Top IIα, MDM2, and p53 in PRCC

Antigen PRCC Type 1 Type 2 P value
% (n) % (n) % (n) % (n)
CK 84.6 (11/13) 83.3 (5/6) 85.7 (6/7)
CD10 30.8 (4/13) 50 (3/6) 14.3 (1/7)
Vimentin 30.8 (4/13) 33.3 (2/6) 28.6 (2/7)
AMACR 100 (13/13) 100 (6/6) 100 (7/7)
CK7 61.5 (8/13) 100 (6/6) 28.6 (2/7) 0.016
CD117 30.8 (4/13) 33.3 (2/6) 28.6 (2/7)
Top IIα 30.8 (4/13) 0 (0/6) 57.1 (4/7) 0.049
MDM2 0 (0/13) 0 (0/6) 0 (0/7)
P53 30.8 (4/13) 7.7 (1/6) 42.9 (3/7)
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P value: type 1 PRCC vs. type 2 PRCC; Fisher’s exact test.

Whole-exome sequencing

In the whole-exome sequencing data analysis, the mutational status of 373 genes was found to be significantly different (P < 0.05) between PRCC and normal renal tissues. In PRCC tissues, 287 missense, 69 silent, 6 nonsense, and 11 synonymous mutations were detected (Table 3). In the functional enrichment analysis, the 287 missense-mutated genes were classified into 11 biological process clusters (comprised of 61 biological progresses) and 5 pathways (P < 0.05) (Table 4; Figure 2A). Mutated genes in PRCC tissues were mainly involved in cell adhesion, microtubule-based movement, cell cycle process, polysaccharide biosynthetic process, tissue morphogenesis, muscle cell development, cell death, differentiation maintenance of organ identity, negative regulation, fertilization, synapsis. Associated pathways included ABC transporters (ATP-binding cassette transporter), ECM (extracellular matrix)-receptor interaction, Lysosome, Complement and coagulation cascades, and Glyoxylate and dicarboxylate metabolism.

Table 3.

The 287 genes containing missense mutations detected in the PRCC tissues (p < 0.05)**

Chr SNP_name Alleles Gene p Mutation(s)
1 exm112317 [T/C] CD1C 0.039215686 Missense_A118V
1 exm103938 [T/C] UBAP2L 0.027634131 Missense_A642V, Missense_A642V
1 exm134287 [A/C] ASPM 0.049773756 Missense_A663S, Missense_A663S
1 exm112233 [C/G] CD1A 0.033333333 Missense_C68W
1 exm135632 [A/G] CAMSAP2 0.032967033 Missense_D257N
1 exm124480 [T/C] CENPL 0.045454545 Missense_D285G, Missense_D285G, Missense_D331G
1 exm131535 [A/G] HMCN1, MIR548F1 0.016983017 Missense_E2893G, Silent
1 exm113728 [C/G] MNDA 0.018181818 Missense_E41Q
1 exm131223 [A/G] HMCN1 0.022977023 Missense_E494K
1 exm127218 [C/G] AXDND1 0.014705882 Missense_E991Q
1 exm140251 [A/G] ZC3H11A 0.032967033 Missense_G233S
1 exm100981 [T/C] CRNN 0.047385621 Missense_G480S
1 exm131714 [T/C] HMCN1, MIR548F1 0.047619048 Missense_H4084Y, Silent
1 exm121615 [T/C] C1orf114 0.047619048 Missense_I37V
1 exm112921 [A/G] OR10X1 0.030969031 Missense_I60T
1 exm100957 [T/A] FLG2 0.009960474 Missense_L168F
1 exm139949 [T/C] OPTC 0.013931889 Missense_L268P
1 exm142351 [A/G] LEMD1 0.044117647 Missense_P25S, Missense_P25S, Missense_P25S, Silent, Missense_P25S
1 exm113801 [T/C] MNDA 0.028571429 Missense_P403L
1 exm138568 [A/C] LGR6 0.045454545 Missense_P920T, Missense_P868T, Missense_P781T
1 exm118835 [T/C] C1orf111 0.047619048 Missense_R217H
1 exm131074 [T/C] SWT1 0.030701754 Missense_R656C, Missense_R656C
1 exm101773 [T/C] SPRR4 0.033333333 Missense_R8W
1 exm1164 [T/C] AGRN 0.008333333 Missense_T1044M
1 exm127753 [T/C] CEP350 0.044117647 Missense_T1131I
1 exm131226 [T/C] HMCN1 0.047619048 Missense_T512I
1 exm111790 [A/C] FCRL3 0.027472527 Missense_V93G
1 exm118460 [C/G] FCRLB 0.045454545 Missense_X427S
1 exm117119 [A/C] KLHDC9 0.03250774 Silent, Silent, Missense_S171R, Missense_S171R
12 exm1053356 [A/G] GALNT9 0.047619048 Missense_A152V, Missense_A518V
12 exm1025298 [A/C] CEP290 0.029411765 Missense_D2396Y
12 exm1006156 [T/C] KRT2 0.027472527 Missense_E376K
12 exm1054454 [T/C] GOLGA3 0.028571429 Missense_G644D, Missense_G644D
12 exm1023832 [G/C] OTOGL 0.010989011 Missense_H1239D
12 exm1002135 [T/G] CERS5 0.030701754 Missense_I122L
12 exm1040411 [T/A] RBM19 0.013986014 Missense_K351N, Missense_K351N, Missense_K351N
12 exm1038106 [T/C] NAA25 0.024242424 Missense_K876R
12 exm1049484 [A/G] NCOR2 0.047619048 Missense_P2215L, Missense_P2215L, Missense_P2225L
12 exm1049813 [A/G] NCOR2 0.032967033 Missense_P535L, Missense_P535L, Missense_P536L
12 exm1024575 [C/G] TMTC2 0.026315789 Missense_R139G
12 exm1006431 [T/C] KRT77 0.045454545 Missense_R183Q
12 exm1034626 [A/G] USP30 0.026315789 Missense_R206H
12 exm1042014 [A/G] SRRM4 0.010989011 Missense_R223H
12 exm1036192 [A/G] TCHP 0.047619048 Missense_R444H, Missense_R444H
12 exm1037483 [A/G] SH2B3 0.034965035 Missense_R566Q
12 exm1029879 [A/G] UTP20 0.015151515 Missense_R869K
12 exm1003394 [T/C] GALNT6 0.008333333 Missense_S32N
12 exm1054936 [A/T] ZNF268 0.022222222 Missense_S383T, Silent, Silent, Silent, Silent, Silent, Silent, Missense_S383T, Missense_S300T
12 exm1016108 [A/C] INHBC 0.010989011 Missense_T166P
12 exm1053798 [T/C] POLE 0.04743083 Missense_V1512I
12 exm1020377 [T/C] MDM1 0.047619048 Missense_V348I, Missense_V383I
12 exm1050732 [A/G] TMEM132C 0.004761905 Missense_V444I
12 exm1006093 [T/C] KRT73 0.036521739 Missense_V61M
12 exm1013940 [T/C] BAZ2A 0.045454545 Missense_V950I
12 exm1000913 [A/G] FAM186B 0.028571429 Silent, Missense_P822S
12 exm1004123 [A/G] KRT80 0.038461538 Silent, Missense_S445L
12 exm1042629 [T/C] RAB35 0.012254902 Silent, Missense_V155I
12 exm1026178 [T/C] CLLU1OS, CLLU1 0.047619048 Silent, Silent, Silent, Missense_T106M
13 exm1055958 [T/C] N6AMT2 0.030701754 Missense_A140T
13 exm1060952 [A/G] USPL1 0.045454545 Missense_E1010K
13 exm1074843 [A/C] ABCC4 0.022222222 Missense_G187W, Missense_G187W
13 exm1062037 [A/C] BRCA2 0.043956044 Missense_H2074N
13 exm1065617 [T/C] NAA16 0.038461538 Missense_I547T
13 exm1057999 [T/C] PARP4 0.027777778 Missense_I81V
13 exm1068871 [A/T] SETDB2 0.01010101 Missense_K408I, Missense_K396I
13 exm1065317 [T/C] ELF1 0.029411765 Missense_N58S, Missense_N58S
13 exm1065781 [A/G] KIAA0564 0.035714286 Missense_P1173L
13 exm1070562 [A/C] CKAP2 0.024242424 Missense_P127T, Missense_P128T
13 exm1061900 [G/C] BRCA2 0.004761905 Missense_P655R
13 exm1064366 [A/G] FREM2 0.022977023 Missense_R1668H
13 exm1069663 [T/C] WDFY2 0.004995005 Missense_R168W
13 exm1062043 [A/G] BRCA2 0.027634131 Missense_R2108H
13 exm1075739 [A/G] FARP1 0.027472527 Missense_R411Q
13 exm1078359 [A/C] SLC10A2 0.027777778 Missense_S171A
13 exm1081805 [A/G] GRTP1 0.038461538 Missense_T227M
13 exm1079428 [C/G] COL4A1 0.044117647 Missense_V7L
13 exm1082605 [A/G] GAS6 0.015151515 Silent, Missense_S204L
14 exm1101474 [A/G] FRMD6 0.032967033 Missense_A207T, Missense_A207T
14 exm1102020 [C/G] TXNDC16 0.047619048 Missense_A398G, Missense_A403G
14 exm1107555 [A/G] SYNE2 0.012383901 Missense_A6671T, Missense_A6648T, Missense_A305T, Missense_A179T
14 exm1129474 [A/G] CDC42BPB 0.035714286 Missense_A983V
14 exm1098207 [C/G] MIA2 0.043956044 Missense_D547H
14 exm1096768 [A/C] FAM177A1 0.027777778 Missense_E64D, Missense_E87D
14 exm1115955 [T/A] MLH3 0.021978022 Missense_F390I, Missense_F390I
14 exm1083818 [T/A] OR4K13 0.049773756 Missense_I270N
14 exm1099035 [C/G] FANCM 0.038461538 Missense_L526V
14 exm1098233 [T/C] CTAGE5 0.036363636 Missense_P28S, Missense_P11S, Missense_P11S, Silent, Missense_P40S, Missense_P40S, Missense_P40S
14 exm1092597 [G/C] REC8 0.022268908 Missense_P294R, Missense_P294R
14 exm1115047 [A/G] LTBP2 0.045454545 Missense_P317L
14 exm1107750 [T/C] MTHFD1 0.025641026 Missense_P328L
14 exm1125535 [T/C] BDKRB2 0.027777778 Missense_R14C
14 exm1094536 [T/C] CMA1 0.028571429 Missense_R151K
14 exm1084549 [T/C] TEP1 0.045454545 Missense_R1772Q
14 exm1102594 [T/C] CGRRF1 0.040959041 Missense_R185W
14 exm1090676 [T/C] MYH6 0.038461538 Missense_R204H
14 exm1098547 [T/C] FSCB 0.030969031 Missense_R385Q
14 exm1117477 [T/C] POMT2 0.036363636 Missense_R421Q
14 exm1099301 [T/C] MIS18BP1 0.038461538 Missense_R510Q
14 exm1129681 [T/C] EXOC3L4 0.043956044 Missense_R560C
14 exm1122333 [T/C] RIN3 0.032967033 Missense_R79W
14 exm1091339 [A/G] DHRS2 0.035714286 Missense_R7Q, Missense_R7Q
14 exm1123266 [G/C] UNC79 0.029411765 Missense_S1194C
14 exm1122077 [C/G] ATXN3 0.012820513 ##############################################
14 exm1098992 [T/C] FANCM 0.047619048 Missense_S175F
14 exm1120581 [T/G] C14orf102 0.045454545 Missense_S35Y
14 exm1129309 [T/C] AMN 0.047619048 Missense_S92L
14 exm1109913 [A/G] ZFYVE26 0.008791209 Missense_T2352I
14 exm1121606 [A/G] CATSPERB 0.045454545 Missense_T250M
14 exm1122447 [T/C] RIN3 0.045454545 Missense_T638M
14 exm1104386 [A/G] ARID4A 0.029411765 Missense_T779A, Missense_T779A, Missense_T779A
14 exm1100138 [T/C] C14orf183 0.042105263 Missense_V263I
14 exm1134928 [A/G] MTA1 0.022222222 Missense_V372I, Missense_V372I
14 exm1086223 [A/G] ZNF219, C14orf176 0.028571429 Silent, Missense_E208K
15 exm1171367 [C/G] TIPIN 0.034502262 Missense_A111G
15 exm1183486 [G/C] FSD2 0.034965035 Missense_A129P
15 exm1156585 [A/G] PPIP5K1 0.021708683 Missense_A1372V, Missense_A1374V, Missense_A1374V, Missense_A1399V
15 exm1169486 [T/C] ANKDD1A 0.045454545 Missense_A141V
15 exm1154945 [G/C] TTBK2 0.021978022 Missense_A519P
15 exm1147190 [T/C] ATPBD4 0.044117647 Missense_D46N, Missense_D46N
15 exm1148492 [T/C] PLCB2 0.011904762 Missense_E1110K
15 exm1152491 [T/C] SPTBN5 0.035714286 Missense_E2614K
15 exm1148014 [A/G] EIF2AK4 0.017857143 Missense_E556G
15 exm1194142 [A/G] LRRK1 0.018181818 Missense_G1938D
15 exm1155304 [T/G] TMEM62 0.017857143 Missense_G496V
15 exm1152787 [T/C] SPTBN5 0.038461538 Missense_G800E
15 exm1179035 [C/G] C15orf27 0.018181818 Missense_I141M
15 exm1152778 [T/C] SPTBN5 0.027777778 Missense_K879E
15 exm1178328 [G/C] IMP3 0.008791209 Missense_L182V
15 exm1171637 [G/C] ZWILCH 0.044117647 Missense_L569V, Silent
15 exm1190716 [A/G] UNC45A 0.010989011 Missense_M249I, Missense_M264I
15 exm1156124 [A/G] TP53BP1 0.045454545 Missense_P1341S, Missense_P1341S, Missense_P1336S
15 exm1146914 [A/G] AQR 0.045454545 Missense_P1481L
15 exm1160701 [T/G] ATP8B4 0.028571429 Missense_P371H
15 exm1147780 [G/C] FSIP1 0.042105263 Missense_P541A
15 exm1157351 [G/C] CASC4 0.041501976 Missense_Q113H, Missense_Q113H
15 exm1164516 [A/T] MNS1 0.047619048 Missense_Q151L
15 exm1191113 [T/C] VPS33B 0.015151515 Missense_R107Q
15 exm1192792 [A/G] LRRC28 0.045454545 Missense_R109H
15 exm1158689 [A/G] DUOX1 0.028571429 Missense_R1481Q, Missense_R1481Q
15 exm1181151 [T/C] ADAMTS7 0.045454545 Missense_R218H
15 exm1182530 [A/G] IL16 0.035714286 Missense_R319H, Missense_R319H
15 exm1153234 [A/G] PLA2G4D 0.005546956 Missense_R333W
15 exm1183163 [A/G] FAM154B 0.047619048 Missense_R389H
15 exm1186633 [A/G] ACAN 0.027472527 Missense_R394Q, Missense_R394Q
15 exm1173050 [A/G] PAQR5 0.045454545 Missense_S11N, Missense_S11N
15 exm1171891 [A/G] AAGAB 0.003611971 Missense_S220P
15 exm1176284 [A/G] STRA6 0.024242424 Missense_S58L, Missense_S73L, Missense_S95L, Missense_S58L, Missense_S58L, Missense_S58L, Missense_S97L, Missense_S58L
15 exm1184631 [A/G] ZNF592 0.046800826 Missense_S926N
15 exm1173024 [A/G] GLCE 0.024509804 Missense_T453A
15 exm1148275 [T/C] BUB1B 0.027667984 Missense_T648I
15 exm1172534 [A/G] ITGA11 0.042105263 Missense_T960I
15 exm1185057 [A/G] SLC28A1 0.035714286 Missense_V189I
15 exm1188412 [T/C] PLIN1 0.035714286 Missense_V272M, Missense_V272M
15 exm1178993 [T/A] FBXO22, FBXO22-AS1 0.030701754 Missense_X404Y, Silent, Silent
15 exm1153448 [T/C] PLA2G4F 0.008791209 Silent, Missense_V247M
16 exm1229096 [T/C] KIAA0556 0.035714286 Missense_A1240V
16 exm1200654 [T/C] CACNA1H 0.044117647 Missense_A1942V, Missense_A1936V
16 exm1198320 [T/C] WDR24 0.047619048 Missense_A390T
16 exm1217326 [T/C] CIITA 0.018181818 Missense_A506V
16 exm1244992 [T/C] CNGB1 0.020979021 Missense_D402N
16 exm1243334 [G/C] CPNE2 0.035714286 Missense_D82E
16 exm1259888 [C/G] KARS 0.032967033 Missense_E120Q, Missense_E92Q
16 exm1216939 [T/C] EMP2 0.047619048 Missense_E121K
16 exm1227991 [A/G] AQP8 0.045454545 Missense_E150K
16 exm1261087 [A/T] CENPN 0.022727273 Missense_E84D, Missense_E84D, Missense_E84D
16 exm1234219 [A/G] PHKG2 0.049122807 Missense_G86S, Missense_G86S
16 exm1202974 [T/C] CRAMP1L 0.045454545 Missense_I1183T
16 exm1246300 [A/C] CDH11 0.006993007 Missense_I433M
16 exm1256594 [T/C] PKD1L3 0.029411765 Missense_K274E
16 exm1263840 [A/G] DNAAF1 0.017404938 Missense_K393R
16 exm1224564 [T/C] ZP2 0.013986014 Missense_M133V
16 exm1200229 [A/G] CACNA1H 0.043956044 Missense_M313V, Missense_M313V
16 exm1267532 [T/C] ZNF469 0.010989011 Missense_P1668L
16 exm1196373 [A/G] TMEM8A 0.015151515 Missense_P201S
16 exm1213609 [A/G] NMRAL1 0.020979021 Missense_P252L
16 exm1220429 [T/C] ABCC1 0.043956044 Missense_R1066W, Missense_R1007W, Missense_R951W, Missense_R1010W, Missense_R1066W
16 exm1200424 [A/G] CACNA1H 0.047385621 Missense_R1069Q, Missense_R1069Q
16 exm1221023 [T/C] XYLT1 0.000333 Missense_R147Q
16 exm1250942 [T/C] DPEP3 0.047619048 Missense_R154K, Missense_R154K
16 exm1259635 [G/C] TMEM231 0.024509804 Missense_R266T, Missense_R237T, Missense_R121T
16 exm1263012 [A/G] MLYCD 0.035714286 Missense_R392Q
16 exm1247857 [T/C] KIAA0895L 0.026923077 Missense_R459Q
16 exm1254754 [A/G] HYDIN 0.026923077 Missense_R4952W
16 exm1233884 [A/G] SRCAP 0.045454545 Missense_R966Q
16 exm1262654 [G/C] SDR42E1 0.010882822 Missense_S10T
16 exm1265329 [A/C] CRISPLD2 0.043956044 Missense_S144R
16 exm1261567 [T/G] PKD1L2 0.017857143 Missense_S1665Y
16 exm1247524 [A/C] CES4A 0.035714286 Missense_S258R, Missense_S160R, Missense_S164R
16 exm1251225 [A/T] NFATC3 0.045454545 Missense_S269T, Missense_S269T, Missense_S269T
16 exm1236325 [A/G] ITGAX 0.029411765 Missense_T123A
16 exm1243998 [A/G] GPR114 0.017857143 Missense_T20A
16 exm1207604 [A/C] CCNF 0.032967033 Missense_T327K
16 exm1247343 [T/C] CES2 0.012820513 Missense_T336M, Missense_T336M, Silent
16 exm1215572 [A/G] NAGPA 0.025641026 Missense_T465I
16 exm1268951 [A/G] PIEZO1 0.045454545 Missense_T563M
16 exm1225201 [T/C] VWA3A 0.022242889 Missense_T657I
16 exm1256018 [T/C] PHLPP2 0.045454545 Missense_V1282I
16 exm1252046 [A/G] CDH3 0.032967033 Missense_V561M
16 exm1210668 [A/T] MEFV 0.045454545 Silent, Missense_D424E
16 exm1199791 [C/G] LMF1 0.044117647 Silent, Missense_P562R, Silent
16 exm1199880 [T/C] LMF1 0.047619048 Silent, Missense_R230Q, Silent
17 exm1301651 [A/G] TBC1D28 0.026315789 Missense_A105V
17 exm1294762 [T/C] MYH2 0.024242424 Missense_A1444T, Missense_A1444T
17 exm1280149 [A/G] SPNS3 0.047619048 Missense_A269T
17 exm1290905 [T/G] ALOXE3 0.047619048 Missense_A282D, Missense_A150D
17 exm1350119 [A/G] SLC39A11 0.007936508 Missense_A287V, Missense_A280V
17 exm1273436 [T/C] GEMIN4 0.037409701 Missense_D929N
17 exm1283034 [T/C] ZNF232 0.018181818 Missense_E36K
17 exm1314605 [T/C] SYNRG 0.018181818 Missense_E717K, Missense_E717K, Missense_E716K, Missense_E795K, Missense_E717K, Missense_E717K, Missense_E634K
17 exm1353827 [G/C] GGA3 0.047619048 Missense_E97Q, Silent, Missense_E186Q, Missense_E147Q, Missense_E219Q
17 exm1294342 [T/C] MYH4 0.040559441 Missense_G256D
17 exm1363303 [A/G] GAA 0.047619048 Missense_G576S, Missense_G576S, Missense_G576S
17 exm1338149 [T/C] TOM1L1 0.045454545 Missense_L348F
17 exm1349475 [A/G] ABCA10 0.029411765 Missense_L663S
17 exm1361017 [T/C] DNAH17 0.04743083 Missense_M1986V
17 exm1296641 [T/C] COX10 0.034965035 Missense_P104L
17 exm1317248 [T/C] ERBB2 0.045454545 Missense_P1177L, Missense_P1207L
17 exm1365385 [A/G] AATK 0.045454545 Missense_P1192S, Missense_P1089S
17 exm1369369 [A/G] FASN 0.027777778 Missense_P617L
17 exm1303396 [A/G] ALDH3A1 0.038461538 Missense_P79L, Missense_P79L, Missense_P79L
17 exm1369510 [T/G] CCDC57 0.040959041 Missense_Q810K
17 exm1321241 [A/C] KRT31 0.021978022 Missense_R208L
17 exm1286100 [A/G] DVL2 0.028571429 Missense_R237W
17 exm1342903 [A/G] BRIP1 0.018181818 Missense_R264W
17 exm1327656 [T/C] G6PC3 0.028571429 Missense_R274C, Silent, Silent
17 exm1284328 [T/C] WSCD1 0.035714286 Missense_R303W
17 exm1295950 [A/G] DNAH9 0.047619048 Missense_R3726Q, Missense_R38Q
17 exm1331597 [A/G] GOSR2 0.046034203 Missense_R67K, Missense_R67K, Missense_R67K
17 exm1304297 [A/G] KCNJ12, KCNJ18 0.040959041 Missense_R6Q, Missense_R6Q
17 exm1354940 [T/C] RECQL5 0.021978022 Missense_R770Q
17 exm1311887 [T/C] UNC45B 0.031857032 Missense_R776W, Missense_R778W
17 exm1321356 [A/T] KRT37 0.033333333 Missense_S73C
17 exm1295567 [A/G] DNAH9 0.031620553 Missense_T1221A
17 exm1322017 [A/G] KRT19 0.036119711 Missense_T327M
17 exm1337873 [T/C] UTP18 0.038461538 Missense_T480I
17 exm1358363 [T/C] AANAT 0.028571429 Missense_T76I, Missense_T31I
17 exm1356970 [A/G] EVPL 0.034965035 Missense_T835I
17 exm1326778 [C/G] NBR1 0.016640867 Missense_V182L, Missense_V182L, Missense_V182L
17 exm1364681 [A/G] RNF213, LOC100294362 0.036363636 Missense_V4453I, Silent
17 exm1290479 [A/G] GUCY2D 0.038461538 Missense_V662M
17 exm1363356 [A/G] GAA 0.002262443 Missense_V780I, Missense_V780I, Missense_V780I
17 exm1345904 [T/C] TEX2 0.038461538 Missense_V881M
17 exm1296979 [A/T] FAM18B2-CDRT4, CDRT4 0.013986014 Silent, Silent, Missense_N163Y
17 exm1288528 [A/G] SHBG 0.043956044 Silent, Silent, Synonymous_K286K, Missense_D356N, Missense_D241N, Missense_D338N
18 exm1378989 [A/G] LAMA3 0.006993007 Missense_A2146T, Missense_A2090T, Missense_A481T, Missense_A537T
18 exm1392259 [A/G] RTTN 0.024242424 Missense_A240V
18 exm1379174 [T/C] TTC39C 0.024509804 Missense_A388V, Missense_A449V
18 exm1378848 [T/G] LAMA3 0.011904762 Missense_D1372Y, Missense_D1372Y
18 exm1371494 [A/G] CLUL1 0.001262626 Missense_E173K, Missense_E173K
18 exm1371832 [C/G] METTL4 0.045454545 Missense_E239Q
18 exm1387358 [A/G] SMAD4 0.026923077 Missense_E374K
18 exm1377011 [C/G] MC5R 0.024242424 Missense_F209L
18 exm1381158 [A/G] DSG2 0.018181818 Missense_H74R
18 exm1374780 [A/G] ANKRD12 0.001262626 Missense_K906R, Missense_K883R, Missense_K883R
18 exm1378769 [T/C] LAMA3 0.031857032 Missense_L937F, Missense_L937F
18 exm1378441 [T/C] NPC1 0.040559441 Missense_N961S
18 exm1374337 [T/C] CCDC165 0.024242424 Missense_R253W
18 exm1383557 [A/G] TPGS2 0.034502262 Missense_R47C
18 exm1381499 [T/C] TRAPPC8 0.044117647 Missense_R609H
18 exm1382923 [A/G] SLC39A6 0.049773756 Missense_R752C
18 exm1385694 [A/G] KATNAL2 0.018181818 Missense_R85H
18 exm1381420 [G/C] TRAPPC8 0.006993007 Missense_T1223R
18 exm1382877 [A/G] C18orf21 0.027472527 Missense_T44A, Missense_T44A, Silent, Missense_T132A
18 exm1381205 [A/G] DSG2 0.027634131 Missense_V515I
18 exm1375025 [A/G] RALBP1 0.030701754 Missense_V625I
18 exm1394601 [C/G] NFATC1 0.019230769 Silent, Missense_K398N, Missense_K398N, Missense_K385N, Missense_K385N
18 exm1388566 [G/C] LOC100505549, ATP8B1 0.020979021 Silent, Missense_T1242S
19 exm1420350 [T/C] MUC16 0.013931889 Missense_A12925T
19 exm1422477 [A/G] OR7G3 0.035714286 Missense_A237V
19 exm1404924 [A/G] ZNF556 0.020639835 Missense_A248T
19 exm1396451 [T/C] POLRMT 0.013986014 Missense_D1085N
19 exm1427412 [A/G] LDLR 0.036119711 Missense_D168N, Silent, Missense_D127N, Silent, Missense_D47N, Missense_D168N
19 exm1401343 [G/C] MBD3 0.032967033 Missense_E275D
19 exm1426542 [G/C] SLC44A2 0.024509804 Missense_E550Q, Missense_E552Q
19 exm1430165 [C/G] ZNF20, ZNF625-ZNF20 0.036119711 Missense_F292L, Silent, Missense_F289L
19 exm1427443 [A/G] LDLR 0.033333333 Missense_G324S, Missense_G156S, Missense_G283S, Missense_G197S, Missense_G203S, Missense_G324S
19 exm1422969 [T/A] ZNF559-ZNF177, ZNF177 0.029411765 Missense_I295F, Silent, Missense_I295F, Missense_I455F
19 exm1415176 [A/G] EMR1 0.044117647 Missense_I487V, Missense_I398V, Missense_I539V, Missense_I539V, Missense_I362V
19 exm1422878 [A/T] ZNF559, ZNF559-ZNF177 0.027568922 Missense_N364I,Silent, Missense_N258I, Silent, Silent, Missense_N300I, Silent, Silent, Silent, Silent
19 exm1428643 [T/G] RGL3 0.049113876 Missense_P162H, Missense_P162H
19 exm1397678 [T/C] ELANE 0.033333333 Missense_P257L
19 exm1403544 [A/G] JSRP1 0.047619048 Missense_P267S
19 exm1414494 [T/G] C3 0.018181818 Missense_P836T
19 exm1409449 [A/C] PLIN4 0.032967033 Missense_R1208M
19 exm1408191 [A/G] CREB3L3 0.04747162 Missense_R392Q
19 exm1409319 [T/C] HDGFRP2 0.032967033 Missense_T50I, Missense_T50I
19 exm1423686 [T/C] COL5A3 0.015151515 Missense_V1691I
19 exm1415181 [A/G] EMR1 0.014705882 Missense_V537I, Missense_V448I, Missense_V589I, Missense_V589I, Missense_V412I
19 exm1415213 [G/C] EMR1 0.021708683 Missense_V672L, Missense_V583L, Missense_V659L, Missense_V724L, Missense_V547L
1 exm101053 [T/C] LCE5A 0.034965035 Nonsense_R79X
12 exm1022625 [G/C] GLIPR1L2 0.027472527 Nonsense_Y144X
13 exm1082947 [T/G] UPF3A 0.038461538 Nonsense_E258X, Nonsense_E291X
15 exm1177922 [A/G] MAN2C1 0.045454545 Nonsense_R878X, Nonsense_R878X, Nonsense_R895X, Nonsense_R779X
17 exm1312366 [A/G] SLFN13 0.049773756 Nonsense_R647X
17 exm1352015 [A/C] C17orf77 0.044117647 Nonsense_C207X
1 exm-rs984222 [C/G] TBX15 0.020979021 Silent
1 exm-rs1342038 [A/G] LOC100506023 0.024509804 Silent
1 exm-rs1023252 [T/G] CLCN6 0.025641026 Silent
2 exm-rs1351164 [T/C] DIRC3 0.025641026 Silent
2 exm-rs6732434 [A/G] PPP1R1C 0.035714286 Silent
2 exm-rs17027258 [A/G] SLC9A4 0.043601651 Silent
2 exm-rs41464348 [A/G] LTBP1 0.013986014 Silent, Silent, Silent, Silent, Silent
3 exm-rs6439334 [A/G] CPNE4 0.045454545 Silent
3 exm-rs4370013 [A/T] CNTN4 0.019766611 Silent, Silent
3 exm-rs10935120 [A/G] CEP63 0.010989011 Silent, Silent, Silent, Silent
4 exm-rs2273 [T/C] SDAD1 0.033333333 Silent
4 exm-rs1391099 [A/G] INPP4B 0.049773756 Silent, Silent
5 exm-rs26232 [T/C] C5orf30 0.043956044 Silent
5 exm-rs31489 [A/C] CLPTM1L 0.044547644 Silent
6 exm-rs9276431 [T/C] HLA-DQA2 0.004545455 Silent
6 exm-rs2071556 [T/G] HLA-DMB 0.014705882 Silent
6 exm-rs887466 [A/G] PSORS1C3 0.015151515 Silent
6 exm-rs2213568 [A/C] HLA-DQA2 0.027777778 Silent
6 exm-rs2074470 [A/G] OR11A1 0.028571429 Silent
6 exm-rs2242668 [T/C] LSM2 0.028571429 Silent
6 exm-rs6908425 [T/C] CDKAL1 0.038461538 Silent
6 exm-rs444921 [T/C] SKIV2L 0.047385621 Silent
6 exm-rs2844775 [A/G] TRIM26 0.006993007 Silent, Silent
6 exm-rs3130383 [A/C] TRIM26 0.008333333 Silent, Silent
6 exm-rs8321 [A/C] ZNRD1 0.020979021 Silent, Silent
6 exm-rs9262113 [A/G] PRR3 0.027472527 Silent, Silent
6 exm-rs9487094 [A/G] PPIL6 0.027472527 Silent, Silent
6 exm-rs3132672 [A/C] TRIM26 0.027777778 Silent, Silent
6 exm-rs4148871 [A/G] TAP2 0.040090344 Silent, Silent
6 exm-rs6916921 [T/C] NFKBIL1 0.026923077 Silent, Silent, Silent, Silent
6 exm-rs707939 [A/C] MSH5, MSH5-SAPCD1 0.004662005 Silent, Silent, Silent, Silent, Silent
6 exm-rs620202 [T/G] BRD2 0.027472527 Silent, Silent, Silent, Silent, Silent
6 exm-rs485502 [T/C] BRD2 0.035714286 Silent, Silent, Silent, Silent, Silent
7 exm-rs730497 [A/G] GCK 0.012820513 Silent
7 exm-rs864745 [T/C] JAZF1 0.049773756 Silent
7 exm-rs10256972 [A/C] C7orf50 0.043956044 Silent, Silent, Silent
8 exm-rs7009183 [A/G] LOC100616530 0.042986425 Silent, Silent,S ilent, Silent, Silent, Silent, Silent, Silent, Silent
9 exm-rs10491539 [T/G] SH3GL2 0.011363636 Silent
9 exm-rs17584499 [T/C] PTPRD 0.047619048 Silent
10 exm-rs7085433 [A/G] TIMM23 0.031991744 Silent
10 exm-rs1913517 [A/G] WDFY4, LRRC18 0.04747162 Silent, Silent
11 exm-rs7926971 [A/G] TEAD1 0.028101929 Silent
12 exm-rs2970818 [A/T] C12orf4 0.018059856 Silent
12 exm-rs10846934 [T/C] TMEM132B 0.018942963 Silent
12 exm-rs1491942 [G/C] LRRK2 0.027472527 Silent
12 exm-rs12579350 [A/G] ANO2 0.035947712 Silent
12 exm-rs7134594 [T/C] MMAB 0.040559441 Silent, Silent
12 exm1036101 [T/G] TCHP 0.045454545 Silent, Silent
14 exm-rs7140150 [T/C] FRMD6 0.019230769 Silent
14 exm-rs7159841 [T/C] MDGA2 0.033841159 Silent
15 exm-rs4775785 [T/C] SHC4 0.047619048 Silent
15 exm-rs6494537 [T/C] DENND4A 0.034965035 Silent, Silent
15 exm-rs12440440 [A/G] RYR3 0.042744021 Silent, Silent
15 exm-rs1378942 [A/C] CSK 0.044117647 Silent, Silent
15 exm-rs886144 [T/C] SV2B 0.044117647 Silent, Silent
15 exm-rs12915189 [A/G] CRTC3 0.047619048 Silent, Silent
15 exm-rs8043440 [T/C] GABRB3 0.047619048 Silent, Silent
16 exm-rs6564869 [A/C] GAN 0.035714286 Silent
17 exm-rs2589133 [A/G] RPTOR 0.027472527 Silent, Silent
19 exm1421853 [T/C] MUC16 0.032967033 Silent
19 exm1431071 [C/G] MAN2B1 0.035714286 Silent, Silent
19 exm-rs2279008 [T/C] MYO9B 0.044117647 Silent, Silent
20 exm-rs487656 [A/G] LOC284757 0.043601651 Silent
21 exm-rs2826891 [T/C] NCAM2 0.001998002 Silent
21 exm-rs7275212 [A/T] ERG 0.045454545 Silent, Silent, Silent, Silent, Silent, Silent, Silent
22 exm-rs139553 [T/C] MEI1 0.045796309 Silent
Y exm-rs9341313 [T/G] EIF1AY 0.018181818 Silent
1 exm131743 [T/C] HMCN1, MIR548F1 0.031991744 Synonymous_A4302A, Silent
1 exm-rs1142287 [T/C] SCAMP3 0.032868733 Synonymous_G126G, Synonymous_G100G
11 exm-rs4453265 [T/C] C2CD3 0.047385621 Synonymous_V1641V
12 exm1041028 [T/C] RNFT2 0.017857143 Synonymous_L183L, Synonymous_L183L
12 exm1043795 [T/C] ACADS 0.043956044 Synonymous_N120N
12 exm1051188 [T/C] PIWIL1 0.034965035 Synonymous_A26A, Synonymous_A26A
13 exm1068030 [A/G] ESD 0.015151515 Synonymous_I157I
16 exm1215196 [A/G] PPL 0.038461538 Synonymous_A826A
16 exm1244602 [T/C] KATNB1 0.033333333 Synonymous_D410D
16 exm1210664 [T/C] MEFV 0.032967033 Synonymous_L590L, Missense_D438N
17 exm1279218 [A/G] ATP2A3 0.031857032 Synonymous_A632A, Synonymous_A632A, Synonymous_A632A, Synonymous_A632A, Synonymous_A632A, Synonymous_A632A, Synonymous_A632A
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**

PRCC vs. normalrenal tissue; Fisher’s exact test.

Abbreviations: PRCC, Papillaryrenal cell carcinoma; Chr, chromosome; SNP, single nucleotidepolymorphism.

Table 4.

Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the 287 missense mutated genes of Papillary renal cell carcinoma (p < 0.05) detected by Human Exome BeadChip technology

Category Cluster Term Gene Count % P Value Genes
GOTERM_BP_FAT Cell adhesion GO:0007155~cell adhesion 65 6.220095694 1.78E-05 MTSS1, AEBP1, NRP1, CLSTN2, CLSTN1, PCDHA1, PCDHGA1, CLEC4A, COL12A1, SPON1, RET, PCDHB5, CNTNAP5, CDHR1, COL22A1, MYH9, SSPO, GPR98, SIGLEC1, SIGLEC6, HAS1, CPXM1, RELN, CNTN4, COL24A1, DST, ADAMTS13, ITGA11, CRNN, CDH3, DCHS1, ITGAM, LAMB3, COL7A1, SORBS1, AGGF1, ITGAX, FAT4, FAT1, COL27A1, ACAN, COL6A1, LPP, PPFIBP1, HSPG2, COL15A1, PCDH15, NID1, COL5A3, COL4A6, VWF, CASS4, COL19A1, LAMA3, DSG2, EMR1, ERBB2IP, CDH17, FREM2, TMEM8A, LAMA5, FREM1, MUC5B, CDH11, MUC16
GOTERM_BP_FAT GO:0022610~biological adhesion 65 6.220095694 1.90E-05 MTSS1, AEBP1, NRP1, CLSTN2, CLSTN1, PCDHA1, PCDHGA1, CLEC4A, COL12A1, SPON1, RET, PCDHB5, CNTNAP5, CDHR1, COL22A1, MYH9, SSPO, GPR98, SIGLEC1, SIGLEC6, HAS1, CPXM1, RELN, CNTN4, COL24A1, DST, ADAMTS13, ITGA11, CRNN, CDH3, DCHS1, ITGAM, LAMB3, COL7A1, SORBS1, AGGF1, ITGAX, FAT4, FAT1, COL27A1, ACAN, COL6A1, LPP, PPFIBP1, HSPG2, COL15A1, PCDH15, NID1, COL5A3, COL4A6, VWF, CASS4, COL19A1, LAMA3, DSG2, EMR1, ERBB2IP, CDH17, FREM2, TMEM8A, LAMA5, FREM1, MUC5B, CDH11, MUC16
GOTERM_BP_FAT GO:0007156~homophilic cell adhesion 16 1.531100478 0.004375914 RET, PCDHB5, CLSTN2, CDHR1, CLSTN1, PCDH15, PCDHA1, CDH3, DCHS1, PCDHGA1, DSG2, FAT4, FREM2, CDH17, FAT1, CDH11
GOTERM_BP_FAT GO:0016337~cell-cell adhesion 24 2.296650718 0.024451853 RET, CLSTN2, PCDHB5, CDHR1, CLSTN1, PCDH15, CRNN, PCDHA1, MYH9, CDH3, ITGAM, DCHS1, GPR98, PCDHGA1, SIGLEC1, COL19A1, DSG2, FAT4, CDH17, FREM2, FAT1, ACAN, CNTN4, CDH11
GOTERM_BP_FAT Microtubule-based movement GO:0007018~microtubule-based movement 14 1.339712919 0.007391122 DNAH11, DNAH9, OPA1, DNAH12, KIF11, DNAH17, BICD2, DNAH5, KIF2C, MACF1, TUBAL3, DYNC2H1, TUBB1, DST
GOTERM_BP_FAT GO:0030705~cytoskeleton-dependent intracellular transport 8 0.765550239 0.020201062 OPA1, MACF1, MYH2, MYH4, MYH14, MYH6, MYH9, DST
GOTERM_BP_FAT GO:0000226~microtubule cytoskeleton organization 15 1.435406699 0.026238636 RET, CEP120, KIF11, CETN3, TBCE, BRCA2, PLK1S1, MYH9, KIF2C, SASS6, MACF1, BUB1B, MAP7, TUBB1, DST
GOTERM_BP_FAT GO:0007010~cytoskeleton organization 35 3.349282297 0.018418181 MTSS1, BMP10, CEP120, CETN3, TTN, KIF2C, MACF1, SORBS1, OBSL1, TUBB1, RET, KIF11, SPTBN5, TBCE, BRCA2, CECR2, ARHGEF17, MYH6, PLK1S1, RICTOR, MYH9, PALLD, PLCE1, SASS6, KRT19, ERBB2IP, XIRP2, LAMA5, LIMCH1, PRR5-ARHGAP8, BUB1B, MAP7, ARAP3, DST, CDC42BPB
GOTERM_BP_FAT GO:0007017~microtubule-based process 25 2.392344498 0.004789572 DNAH11, DNAH9, DNAH12, CEP120, DNAH17, CETN3, DNAH5, KIF2C, MACF1, DYNC2H1, TUBB1, RET, KIF11, OPA1, TBCE, BRCA2, PLK1S1, MYH9, BICD2, SASS6, TUBAL3, BUB1B, MAP7, DST, MAP3K11
GOTERM_BP_FAT Signaling pathway GO:0007229~integrin-mediated signaling pathway 11 1.052631579 0.003945816 ADAMTS7, VAV3, ITGAX, ERBB2IP, ADAMTS13, LAMA5, ITGA11, MYH9, DST, ITGAM, ADAMDEC1
GOTERM_BP_FAT GO:0035023~regulation of Rho protein signal transduction 15 1.435406699 7.82E-04 OBSCN, VAV3, RALBP1, PREX2, ARHGEF17, RICTOR, TTN, FARP1, MCF2L2, PLEKHG2, SYDE2, RASGRF2, TIAM1, ARAP3, KALRN
GOTERM_BP_FAT GO:0051056~regulation of small GTPase mediated signal transduction 25 2.392344498 0.004617191 ERBB2, PREX2, RGL3, TTN, MCF2L2, PLEKHG2, TIAM1, KNDC1, OBSCN, VAV3, RALBP1, SIPA1L2, ARHGEF17, RICTOR, FARP1, PLCE1, SYDE2, RASGRF2, TBC1D28, GRTP1, C6ORF170, RELN, ARAP3, TBC1D8B, KALRN
GOTERM_BP_FAT GO:0046578~regulation of Ras protein signal transduction 21 2.009569378 0.009082897 OBSCN, VAV3, RALBP1, ERBB2, PREX2, ARHGEF17, RICTOR, TTN, FARP1, MCF2L2, PLCE1, PLEKHG2, SYDE2, RASGRF2, TBC1D28, TIAM1, GRTP1, C6ORF170, ARAP3, TBC1D8B, KALRN
GOTERM_BP_FAT GO:0007167~enzyme linked receptor protein signaling pathway 27 2.583732057 0.046239768 MTSS1, BMP10, FGFR4, NRP1, LTBP2, ERBB2, BDKRB2, TGFB1, SORBS1, TIAM1, GDF9, AGRN, EGF, ROS1, RET, PTPRG, SMAD4, GUCY2C, EPHA1, EPHA3, GUCY2D, EPHA5, PLCE1, ERBB2IP, NTRK2, FSHB, AKAP4
GOTERM_BP_FAT GO:0019722~calcium-mediated signaling 6 0.574162679 0.045969671 PLCE1, MCTP2, IL8, ALMS1, NFKBIL1, MCTP1
GOTERM_BP_FAT GO:0006468~protein amino acid phosphorylation 49 4.688995215 0.023096414 BMP10, PASK, RPS6KB2, PINK1, TTN, TGFB1, PSKH2, MAP3K5, AAK1, ROS1, IRAK2, RET, MYO3A, PHKG2, MYLK4, SRPK1, CDKL4, MAST4, HUNK, PLCE1, PROK1, RELN, LRRK2, LRRK1, EIF2AK4, KALRN, MAP3K11, FGFR4, ERBB2, STK10, C5, TRIB3, SGK223, TTBK2, EGF, AATK, OBSCN, FSCB, ATR, OXSR1, GUCY2C, EPHA1, EPHA3, GUCY2D, EPHA5, MAPK12, NTRK2, GRK6, CDC42BPB
GOTERM_BP_FAT Cell cycle process GO:0022402~cell cycle process 49 4.688995215 0.001052892 MLH3, TTN, TGFB1, KIF2C, DDX11, INCENP, PIWIL3, C11ORF82, TUBB1, ASPM, KIF11, CGRRF1, SGOL2, CCNF, POLE, PLK1S1, MYH9, NCAPD2, REC8, SASS6, PPM1D, FANCD2, BUB1B, HORMAD2, NUP43, DST, MAP3K11, CEP120, TIPIN, CETN3, KIAA1009, PLAGL1, PRUNE2, PSMF1, MACF1, MNS1, GFI1, ZWILCH, NFATC1, IL8, CENPF, BRCA2, TP73, RGS14, PSMB9, CCNB3, TEX15, MAPK12, APBB1
GOTERM_BP_FAT GO:0030203~glycosaminoglycan metabolic process 10 0.956937799 0.002400935 HYAL2, GCNT2, SPOCK3, XYLT1, HAS1, GALNT5, HEXB, ITIH5, DSE, GLCE
GOTERM_BP_FAT GO:0007049~cell cycle 60 5.741626794 0.003955172 STEAP3, MLH3, TTN, TGFB1, KIF2C, DDX11, INCENP, PIWIL3, C11ORF82, TUBB1, ASPM, KIF11, CGRRF1, SGOL2, POLE, CCNF, MCM2, PLK1S1, MYH9, AHR, NCAPD2, PPM1D, REC8, SASS6, EP300, RIF1, FANCD2, PRR5-ARHGAP8, BUB1B, TMPRSS11A, HORMAD2, NUP43, DST, MAP3K11, CEP120, CETN3, TIPIN, KIAA1009, PLAGL1, PSMF1, PRUNE2, MACF1, HJURP, MNS1, GFI1, ZWILCH, NFATC1, CKAP2, IL8, CENPF, BRCA2, ATR, RGS14, TP73, PSMB9, CCNB3, TEX15, ERBB2IP, MAPK12, APBB1
GOTERM_BP_FAT GO:0070192~chromosome organization involved in meiosis 4 0.38277512 0.029295159 REC8, TEX15, FANCD2, MLH3
GOTERM_BP_FAT GO:0000279~M phase 29 2.775119617 0.010713242 CEP120, TIPIN, CETN3, MLH3, TTN, KIAA1009, KIF2C, DDX11, INCENP, MNS1, PIWIL3, ZWILCH, TUBB1, ASPM, KIF11, SGOL2, CCNF, BRCA2, CENPF, MYH9, RGS14, NCAPD2, REC8, CCNB3, TEX15, FANCD2, BUB1B, HORMAD2, NUP43
GOTERM_BP_FAT GO:0007059~chromosome segregation 10 0.956937799 0.028905796 REC8, DDX11, HJURP, SGOL2, INCENP, CENPF, TTN, NUP43, SRPK1, NCAPD2
GOTERM_BP_FAT GO:0045005~maintenance of fidelity during DNA-dependent DNA replication 3 0.28708134 0.025738663 TIPIN, BRCA2, WRN
GOTERM_BP_FAT GO:0022403~cell cycle phase 35 3.349282297 0.008864905 CEP120, CETN3, TIPIN, MLH3, TTN, KIAA1009, PRUNE2, KIF2C, DDX11, INCENP, MNS1, PIWIL3, GFI1, ZWILCH, TUBB1, ASPM, NFATC1, KIF11, SGOL2, CCNF, POLE, CENPF, BRCA2, MYH9, RGS14, NCAPD2, CCNB3, REC8, PPM1D, TEX15, FANCD2, BUB1B, HORMAD2, NUP43, MAP3K11
GOTERM_BP_FAT Polysaccharide biosynthetic process GO:0006024~glycosaminoglycan biosynthetic process 6 0.574162679 0.004327438 GCNT2, XYLT1, HAS1, GALNT5, DSE, GLCE
GOTERM_BP_FAT GO:0005976~polysaccharide metabolic process 14 1.339712919 0.006372263 HYAL2, GCNT2, SPOCK3, PHKG2, GALNT5, HEXB, DSE, GLCE, XYLT1, HAS1, MGAM, GAA, ITIH5, AGL
GOTERM_BP_FAT GO:0000271~polysaccharide biosynthetic process 8 0.765550239 0.009446334 GCNT2, XYLT1, HAS1, GALNT5, PHKG2, DSE, AGL, GLCE
GOTERM_BP_FAT GO:0006023~aminoglycan biosynthetic process 6 0.574162679 0.006548599 GCNT2, XYLT1, HAS1, GALNT5, DSE, GLCE
GOTERM_BP_FAT GO:0006022~aminoglycan metabolic process 10 0.956937799 0.007510441 HYAL2, GCNT2, SPOCK3, XYLT1, HAS1, GALNT5, HEXB, ITIH5, DSE, GLCE
GOTERM_BP_FAT Tissue morphogenesis GO:0043062~extracellular structure organization 18 1.722488038 0.006517427 RXFP1, PCDHB5, ERBB2, UTRN, HSPG2, NRD1, NID1, COL5A3, COL5A2, SPINK5, COL4A6, TNFRSF11B, COL19A1, CRISPLD2, ACAN, COL12A1, AGRN, APBB1
GOTERM_BP_FAT GO:0030198~extracellular matrix organization 13 1.244019139 0.009627305 RXFP1, HSPG2, NID1, COL5A3, COL5A2, SPINK5, COL4A6, TNFRSF11B, COL19A1, CRISPLD2, ACAN, COL12A1, APBB1
GOTERM_BP_FAT GO:0032989~cellular component morphogenesis 32 3.062200957 0.023088526 BMP10, PLXNA3, SHROOM2, NRP1, COX10, ERBB2, TTN, TGFB1, MACF1, DYNC2H1, OBSL1, GDF9, ROBO3, NFATC1, OPA1, C2CD3, TBCE, ALMS1, MYH6, MYH9, SLIT2, KRT19, ERBB2IP, LAMA5, PRICKLE2, RELN, CNTN4, MAP7, APBB1, DST, CDC42BPB, KALRN
GOTERM_BP_FAT GO:0048729~tissue morphogenesis 17 1.626794258 0.032413281 DVL2, BMP10, RET, C2CD3, SMAD4, MYH6, NR4A3, TTN, GLI3, TCF7L1, SLIT2, FZD6, MACF1, FREM2, LAMA5, GAA, KLK14
GOTERM_BP_FAT GO:0043954~cellular component maintenance 8 0.765550239 2.54E-04 IQCB1, SHROOM2, CDHR1, PCDH15, CNGB1, ACAD11, USH2A, GPR98
GOTERM_BP_FAT GO:0048496~maintenance of organ identity 4 0.38277512 5.89E-04 IQCB1, ACAD11, USH2A, GPR98
GOTERM_BP_FAT Maintenance of organ identity GO:0050953~sensory perception of light stimulus 20 1.913875598 0.023223977 IQCB1, OPA1, MYO3A, BBS9, CDHR1, RP2, RP1L1, ALMS1, PCDH15, CNGB1, CDH3, CDS1, GPR98, GUCY2D, EYA4, EYS, HMCN1, IMPG1, ACAD11, USH2A
GOTERM_BP_FAT GO:0007601~visual perception 20 1.913875598 0.023223977 IQCB1, OPA1, MYO3A, BBS9, CDHR1, RP2, RP1L1, ALMS1, PCDH15, CNGB1, CDH3, CDS1, GPR98, GUCY2D, EYA4, EYS, HMCN1, IMPG1, ACAD11, USH2A
GOTERM_BP_FAT GO:0045494~photoreceptor cell maintenance 7 0.669856459 6.29E-04 IQCB1, CDHR1, PCDH15, CNGB1, ACAD11, USH2A, GPR98
GOTERM_BP_FAT GO:0050954~sensory perception of mechanical stimulus 11 1.052631579 0.0491677 KCNQ4, MYO3A, CHRNA9, MCOLN3, HEXB, TRPA1, GJB3, ALMS1, PCDH15, USH2A, GPR98
GOTERM_BP_FAT Muscle cell development, differentiation GO:0045214~sarcomere organization 4 0.38277512 0.023449715 BMP10, KRT19, MYH6, TTN
GOTERM_BP_FAT GO:0030239~myofibril assembly 5 0.4784689 0.023617794 BMP10, KRT19, OBSL1, MYH6, TTN
GOTERM_BP_FAT GO:0014706~striated muscle tissue development 13 1.244019139 0.025697664 BMP10, ERBB2, UTRN, HSPG2, NRD1, MYH6, TTN, COL19A1, EP300, GAA, OBSL1, ZFPM2, AGRN
GOTERM_BP_FAT GO:0031032~actomyosin structure organization 6 0.574162679 0.015342389 BMP10, KRT19, LIMCH1, OBSL1, MYH6, TTN
GOTERM_BP_FAT GO:0051146~striated muscle cell differentiation 11 1.052631579 0.019053324 BMP10, KRT19, ERBB2, UTRN, CACNA1H, NRD1, OBSL1, AGRN, MYH6, MYH9, TTN
GOTERM_BP_FAT GO:0055001~muscle cell development 9 0.861244019 0.009510235 BMP10, KRT19, ERBB2, UTRN, NRD1, OBSL1, AGRN, MYH6, TTN
GOTERM_BP_FAT GO:0042692~muscle cell differentiation 13 1.244019139 0.028805 BMP10, ERBB2, UTRN, NRD1, MYH6, TTN, MYH9, SYNE1, KRT19, MAPK12, OBSL1, CACNA1H, AGRN
GOTERM_BP_FAT GO:0060537~muscle tissue development 13 1.244019139 0.03581975 BMP10, ERBB2, UTRN, HSPG2, NRD1, MYH6, TTN, COL19A1, EP300, GAA, OBSL1, ZFPM2, AGRN
GOTERM_BP_FAT GO:0030048~actin filament-based movement 5 0.4784689 0.032123528 MYH2, MYH4, MYH14, MYH6, MYH9
GOTERM_BP_FAT GO:0055002~striated muscle cell development 9 0.861244019 0.006074436 BMP10, KRT19, ERBB2, UTRN, NRD1, OBSL1, AGRN, MYH6, TTN
GOTERM_BP_FAT GO:0007517~muscle organ development 22 2.105263158 0.00464554 BMP10, AEBP1, ERBB2, UTRN, HSPG2, ITGA11, CENPF, NRD1, MYH6, TTN, EP300, COL19A1, MAPK12, NEB, LAMA5, GAA, CACNA1H, OBSL1, ZFPM2, AGRN, UNC45B, UNC45A
GOTERM_BP_FAT GO:0048747~muscle fiber development 6 0.574162679 0.037333701 ERBB2, UTRN, NRD1, AGRN, MYH6, TTN
GOTERM_BP_FAT GO:0007507~heart development 19 1.818181818 0.040567691 DVL2, BMP10, NRP1, C2CD3, ERBB2, HSPG2, OXTR, MYH6, TTN, GLI3, PLCE1, EP300, SALL4, GAA, OBSL1, ZFPM2, ADAM19, NFATC3, NFATC1
GOTERM_BP_FAT Negative regulation GO:0050860~negative regulation of T cell receptor signaling pathway 3 0.28708134 0.025738663 ELF1, CBLB, UBASH3A
GOTERM_BP_FAT GO:0050858~negative regulation of antigen receptor-mediated signaling pathway 3 0.28708134 0.025738663 ELF1, CBLB, UBASH3A
GOTERM_BP_FAT GO:0010596~negative regulation of endothelial cell migration 4 0.38277512 0.035834358 BMP10, AGTR2, DLL4, TGFB1
GOTERM_BP_FAT GO:0045792~negative regulation of cell size 11 1.052631579 0.039161459 RTN4, BMP10, PLXNA3, AGTR2, NRP1, CGRRF1, SMAD4, GDF9, APBB1, TP73, TGFB1
GOTERM_BP_FAT GO:0030308~negative regulation of cell growth 11 1.052631579 0.025196073 RTN4, BMP10, PLXNA3, AGTR2, NRP1, CGRRF1, SMAD4, GDF9, APBB1, TP73, TGFB1
GOTERM_BP_FAT Cell death GO:0008219~cell death 51 4.880382775 0.036510953 STEAP3, RTN4, TSPO, FASTKD1, TGFB1, MAGED1, TNFRSF11B, MAP3K5, TIAM1, CLUL1, C11ORF82, CASP1, API5, MAGI3, OPA1, GZMA, PTPRH, SCN2A, CECR2, ARHGEF17, AHR, EP300, RASGRF2, ZFYVE27, ZFYVE26, SH3KBP1, BUB1B, KALRN, MAP3K11, C5, TRIB3, PRUNE2, PLEKHG2, ATN1, TTBK2, TRAF5, HIP1, AATK, CKAP2, OBSCN, CARD8, VAV3, ALMS1, CIDEA, FIG4, TP73, NFKBIL1, ATXN3, SYNE1, PARP4, APBB1
GOTERM_BP_FAT GO:0016265~death 51 4.880382775 0.039214579 STEAP3, RTN4, TSPO, FASTKD1, TGFB1, MAGED1, TNFRSF11B, MAP3K5, TIAM1, CLUL1, C11ORF82, CASP1, API5, MAGI3, OPA1, GZMA, PTPRH, SCN2A, CECR2, ARHGEF17, AHR, EP300, RASGRF2, ZFYVE27, ZFYVE26, SH3KBP1, BUB1B, KALRN, MAP3K11, C5, TRIB3, PRUNE2, PLEKHG2, ATN1, TTBK2, TRAF5, HIP1, AATK, CKAP2, OBSCN, CARD8, VAV3, ALMS1, CIDEA, FIG4, TP73, NFKBIL1, ATXN3, SYNE1, PARP4, APBB1
GOTERM_BP_FAT Other GO:0009566~fertilization 10 0.956937799 0.025036283 ACR, PLCZ1, APOB, TEX15, ZP2, CD46, HEXB, UBXN8, KLK14, AKAP4
GOTERM_BP_FAT GO:0007129~synapsis 4 0.38277512 0.029295159 REC8, TEX15, FANCD2, MLH3
KEGG_PATHWAY KEGG pathway hsa02010:ABC transporters 10 0.956937799 4.87E-04 ABCA10, ABCG5, TAP1, ABCC4, ABCC10, ABCC1, ABCB5, ABCA6, ABCA13, ABCB4
KEGG_PATHWAY hsa04512:ECM-receptor interaction 14 1.339712919 5.35E-04 COL4A1, HSPG2, ITGA11, COL5A3, COL5A2, COL4A6, HMMR, VWF, LAMB3, LAMA3, LAMA5, COL6A1, RELN, AGRN
KEGG_PATHWAY hsa04142:Lysosome 13 1.244019139 0.024611161 ARSB, AP1B1, HEXB, ASAH1, SLC11A1, NPC1, NAGPA, LAPTM5, IGF2R, GAA, CTSB, ATP6V0D2, GGA3
KEGG_PATHWAY hsa04610:Complement and coagulation cascades 9 0.861244019 0.032655465 F11, VWF, CR2, MASP1, FGA, C3, CD46, C5, BDKRB2
KEGG_PATHWAY hsa00630:Glyoxylate and dicarboxylate metabolism 4 0.38277512 0.044700865 MTHFD1, ACO1, HAO2, GRHPR
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Abbreviations: ECM, extracellular matrix.

Figure 2.

Figure 2

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Functional enrichment analysis of the 211 missense-mutated genes detected by exome sequencing in PRCC. A. The related biological process categories of the 211 missense-mutated genes in CRCC. B. The extracellular matrix (ECM)-receptor interaction pathway. red genes, mutated genes in PRCC. Pathway information was generated using the Kyoto Encyclopedia of Genes and Genomes database.

The missense mutation status of 19 genes was significantly different (P < 0.05) between the type 1 PRCC C and type 2 PRCC groups (Table 5). Alterations in EEF1D, RFNG, GPR142, and RAB37 genes were located in different chromosomal regions in the type 1 PRCC C and type 2 PRCC groups.

Table 5.

The 19 differentially missense mutated genes in type 1PRCC C vs. type 2 PRCC (P < 0.05)**

SNP_name Chr Alleles Mutation (s) Gene
exm330459 3p12.3 [C/G] Missense_H75D CNTN3
exm318874 3p21.2 [A/G] Missense_R425C, Missense_R426C VPRBP
exm506256 5q35.2 [A/G] Missense_A328T, Missense_A328T, Missense_A328T FGFR4
exm611166 7p15.2 [C/G] Missense_R132S HOXA11
exm693941 8p12 [A/G] Missense_T2181I TEX15
exm727114 8q24.3 [A/C] Missense_L361R, Missense_L361R EEF1D
exm919007 11q12.3 [G/C] Missense_A866P INTS5
exm940191 11q13.4 [A/G] Missense_R142Q DNAJB13
exm976848 12p13.3 [T/C] Missense_R606Q VWF
exm1185487 15q24-q25 [A/G] Missense_D1086N, Missense_D1086N AKAP13
exm1368709 17q25 [A/C] Missense_H288Q RFNG
exm1277466 17p13.3 [T/C] Missense_P285S OR1A1
exm1351674 17q25.1 [T/C] Missense_T407M GPR142
exm1352075 17q25.1 [T/G] Missense_T282K RAB37
exm1379777 18q11.2 [A/G] Missense_A152T TAF4B
exm1395964 19p13.3 [T/C] Missense_A314V, Missense_A227V MADCAM1
exm1529410 20p11.21 [T/C] Missense_P297S GZF1
exm1663015 Xq28 [T/C] Missense_V377A PNMA3
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**

Type 1 PRCC C vs. type 2 PRCC; Fisher’s exact test.

Abbreviations: PRCC, Papillary renal cell carcinoma; Chr., chromosome; SNP, single nucleotide polymorphism.

Discussion

PRCC is the second most prevalent renal tumor after renal clear cell carcinoma [1]. PRCC can be divided into two types based on the histomorphological features. The onset age and sex of PRCC patients are similar to ccRCC patients, with a peak incidence in 50-70-year-old men [1,11]. Herein, the average age of the patients was 53.9 years (range, 26-74 years). Compared with type 1, the mean age of type 2 PRCC patients was approximately 14 years lower (57.4 vs. 61.5 years), which is consistent with the results of previous studies [12,13].

Pathologically, type 2 tumors showed a higher Fuhrman grade (P = 0.049) and lymphovascular invasion (P = 0.049) than type 1, which have both been identified as prognostic factors [14,15], suggesting poorer outcomes in type 2 PRCC patients. While some studies have reported no clear correlation between PRCC type and prognosis [16,17], most have shown that type 1 PRCC has a better prognosis compared to type 2 [11-13,18]. Moreover, compared with the overall survival rates of patients with type 1 PRCC, those of type 2 PRCC were lower in this study, suggesting that tumor classification is indeed helpful for evaluating the prognosis of PRCC patients.

Immunohistochemically, all 13 tumors showed strong positivity for AMACR, while CK7 and Top IIα were overexpressed in types 1 and 2 PRCC, respectively. This is consistent with previous reports [1,19-21], suggesting that AMACR, CK7, and Top IIα are useful for the classification, diagnosis, and differential diagnosis of PRCC. Importantly, increased Top IIα expression correlates to poorer prognosis of various tumors, such as breast and colon cancer [22,23], and some researchers found that Top IIα expression is increased in type 2 PRCC with higher Fuhrman nuclear grade, and that the level of Top IIα positively correlates with tumor invasion [24]. Herein, type 1 PRCC did not express Top IIα, whereas 57.1% of type 2 PRCC cases did (4/7), indicating that Top IIα not only contributes to the differential diagnosis, classification, and prognosis of PRCC, but may also play a role in its development.

In order to further detect gene mutations, we analyzed the exon of 13 PRCC and 18 normal kidney tissues by whole-genome exon sequencing. In the cluster analysis, we identified 10 enriched clusters (Table 4), with the frequency of gene mutations related to the cell division cycle being the highest (Figure 2A). Cell division is an important process, and problems during the processing can result in abnormal cell division, proliferation, differentiation, and senescence. Numerous growth factors, cytokines, hormones, and cancer gene products regulate metabolism by influencing the cell division cycle. Meanwhile, the expression of many genes is restricted by the cell division cycle. Thus, our results suggest that these genes may play important roles in the occurrence and development of PRCC.

In the cell division cycle cluster, many interesting genes, such as MAP3K11 and KIF11, were identified. The protein encoded by MAP3K11 may activate MAPK8/JNK kinase, which regulates the JNK signal pathway and activates NF-kappa B signaling pathway, mediated by GTPases and CDC42, which in turn regulates cell proliferation and apoptosis [25,26]. Recently, MAP3K11 has been shown to play a role in the development of prostate, breast, and gastric cancers through interfering with cell proliferation and apoptosis [27-29]. KIF11 encodes a kinesin spindle protein, a member of the kinesin superfamily of microtubule-based motors, and plays a critical role in mitosis through mediation of centrosome separation and bipolar spindle assembly and maintenance. Reduced KIF11 expression leads to cell cycle arrest at mitosis and formation of monoastral microtubule arrays, and, ultimately, to tumor cell death [30-32]. Sun et al. [33] reported that KIF11 overexpression correlated with nuclear grade (P = 0.019), stage (P = 0.007), and tumor size (P = 0.033) in RCC, and as type 2 PRCC shows higher nuclear grade and stage and worse prognosis than type 1, it can be speculated that it is associated with MAP3K11 and KIF11 mutations; however, further studies are needed to confirm this hypothesis.

The pathway enrichment analysis revealed 5 related pathways (Table 4), with the “ABC transporter” pathway being the most significant pathway in PRCC. The ABC transporters form one of the largest known protein families, and couple ATP hydrolysis to active transport of a wide variety of substrates such as lipids, sterols, proteins, and drugs. Numerous studies have shown that this pathway plays an important role in the development of multi-drug resistant tumors [34-36]. These proteins can actively transport drugs from the intracellular to extracellular compartments, thereby reducing the intracellular concentration of drugs. Zhao et al. [36] showed that ABCC4 was highly expressed in lung cancer, and that reduced ABCC4 expression could inhibit tumor growth and proliferation. Walsh et al. [37] showed that ABCB1 and ABCC1 up regulation resulted in the development of multi-drug resistant RCC, and Hour et al. [38] reported that ABCD1 down regulation may be involved in renal tumorigenesis. Therefore, we inferred that mutations in the ABC pathways may reduce the effectiveness of chemotherapy drugs and promote the growth and proliferation of PRCC cells, and that inhibition of the ABC transporters may increase the efficacy of chemotherapy and slow down the development of PRCC.

Additionally, in the 5 related pathways, “ECM-receptor interaction” mutations commonly occurred (Figure 2B), with the mutation frequency of the collagen family genes being the highest. COL4A1 encodes the major type IV alpha collagen chain of basement membranes, which plays an essential role in tumorigenesis, growth, and metastasis. Delektorskaya et al. [39] suggested that type IV collagen shows different degrees of loss in colorectal cancer, which significantly correlated with the risk of metastasis. Others have found that type IV collagen promotes tumor cell migration and invasion in pancreatic cancer, and that the level of serum type IV collagen in these patients positively correlated with the risk of recurrence [40,41]. Moreover, RCC cells can also produce type IV collagen as a means to promote tumor invasion [42-44], indicating that the frequent mutations of the collagen genes may be one of factors responsible for the development of PRCC, and that evaluating the collagen levels of PRCC patient may be useful for assessing the tumor biological behavior and prognosis.

There have reports that type 1 and 2 PRCC show more copy number changes at 17q and 9p [45-48]. Furthermore, copy number changes at 17q were more common in TNM stage 1-2 PRCC and correlated with lower stage, less lymphatic metastases, and increased survival, whereas changes at 9p conversely correlated with higher stage (TNM stage 3-4) and nuclear grade, more lymphatic metastasis, and decreased survival [45-47]. Meanwhile, amplification of chromosome 17 is another characteristic of PRCC [45,49,50], and changes at 17q and 9p can aid the differential diagnosis, as well as predict the prognosis in different subtypes, suggesting that genes on these chromosomes may be related to the development of type 1 or 2 PRCC. The results from exon chip analyses are consistent with previous reports in the field, with some gene exon mutations being found in specific altered chromosomal regions. For example, ERBB2 locate on 17q12-20. ERBB2 encodes a member of the tyrosine kinase family. It is over expressed or amplified in several tumors, including breast, ovarian, and digestive tract tumors, and closely correlates with tumor occurrence, development, and prognosis [51]. Conversely, the over expression and amplification of ERBB2 is reportedly uncommon in RCC [52,53]. However, Duzcan et al. [54] found that the levels of Top IIα and ERBB2 were correlated, and that they were co-amplified. Herein, Top IIα was found to be over expressed in type 2 PRCC, and located on the common aberration chromosome 3p24; ERBB2 is located at 17q12-20, which showed amplification, and exon chip detection moreover revealed ERBB2 mutations. This suggests that Top IIα and ERBB2 may jointly participate in the occurrence and development of PRCC, and that exon chip analyses may facilitate the discovery of mutated genes in PRCC.

Using exome sequencing, we here found that the EEF1D, RFNG, GPR142, and RAB37 genes were located in different chromosomal regions in type 1 and 2 PRCC. RAB37, which is located at chromosome 17q25.1, more often showed gains in type 1 PRCC. Dobashi et al. [55] found that RAB37 was upregulated in RCC cells, and knockdown of RAB37 expression by specific siRNA caused significant reductions in cancer cell growth. Furthermore, Wu [56] also found that promoter/exon 1 methylation lead to down-regulation of hRAB37 in metastatic lung cancer, and that it may serve as a predictive biomarker of lung cancer progression. EEF1D, which is located at chromosome 8q24.3 and was more commonly mutated in type 2 PRCC, is also overexpressed in medulloblastoma [57] and right-sided colon cancer [58], and correlates with the invasive status of adriamycin-resistant variants of DLKP, a squamous lung cancer cell line [59]. Accordingly, we speculate that the mutations of RAB37 and EEF1D may play different roles in the development of type 1 and 2 PRCC.

In conclusion, our study shows that multiple gene mutations are present in PRCC. These gene mutations may provide clues regarding PRCC tumorigenesis and serve as a basis for future developments of targeted therapies against type 1 and 2 PRCC.

Acknowledgements

Supported by grants from the National Natural Science Foundation of China (NSFC, No. 81060383). We would like to thank Editage http://www.editage.cn/ for English language editing.

Disclosure of conflict of interest

None.

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