Table 8.
Whole-exome sequencing studies on hepatobiliary and pancreatic cancers.
| Cancer Type | N | Findings | Clinical Implications | Reference |
|---|---|---|---|---|
| HB | 6 | 21 mutated genes, including mutations in the WNT pathway | Larger studies are required to explore the mutational background of HB | [141] |
| HCC (HBV positive) | 10 (110 samples, including PVTTs and intrahepatic metastases) |
ARID1A was mutated in 14 of 110 samples (13%) ARID1A loss-of-function mutations may be crucial for HCC invasion and metastasis |
ARID1A is a potential novel biomarker for treatment and prognosis | [142] † |
| NAFLD-related HCC | 10 (11 samples, WES, TS, CNV studies) | 12 genes were frequently mutated including novel genes (FGA, SYNE1) | Larger studies are required to confirm the validity of novel genes | [143] |
| PDA (acinar differentiation) | 23 | Potentially targetable mutations in well-known genes (BRCA2, PALB2, ATM, BAP1, BRAF and JAK1) were identified in 1/3 of patients | This study supports the conduction of umbrella studies | [144] |
| HCC | 24 WES (NGS); 125 CNA in total with CGH array analysis |
New recurrent mutations in ARID1A, RPS6KA3, NFE2L2 and IRF2
Inactivation of chromatin remodelers was frequent and was associated with alcohol Wnt/b-catenin pathway promotes tumorigenesis through both oxidative stress metabolism and MAPK pathways |
Association of environmental risk factors with specific gene mutations could improve screening and early diagnosis | [145] |
| PDA from VLTSs (≥10 years) | 35 (8 WES, 27 TS) | Frequently mutated genes were identified (KRAS, TP53, RNF43, CDKN2A, and SMAD4) Combined WES and TS data showed no significant difference between VLTSs and patients unselected for survival |
Validity of these data must be investigated by larger studies | [146] |
| FLC | 78 (48 WES + TES, 58 whole-transcriptome, 41 SNP arrays) | Identification of 3 molecular classes: proliferation with altered mTOR pathway, inflammation with altered cytokine production genes and unannotated | Larger studies are required to confirm the validity of the developed prognostic 8-gene expression signature (PEAR1, KRTAP, KLRD1, OSBPL8, RPL32, SLC26A11, RGS11 and RAPGEF1) | [147] |
| HCC | 87 | Substantial genetic heterogeneity NFE2L2-KEAP1 and MLL pathways were recurrently mutated |
Further larger WES studies are needed for completing the cancer driver genes catalog and developing individualized therapy | [148] |
| PDA | 99 with early stage (I and II; WES and CNA) | Substantial genetic heterogeneity 8 novel mutated genes: EPC1 and ARID2 (chromatin modification), ATM (DNA damage repair), ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6 |
The novel mutated genes identified could potentially be used as therapeutic targets but validation is required by larger studies | [149] |
| PDA | 101 (24 WES and 77 TS) | Mutated chromatin regulating genes MLL, MLL2, MLL3, ARID1A were associated with improved survival Detection of ctDNA was associated with predictable recurrence 6.5 months before occurrence |
These genes may have prognostic significance and ctDNA could potentially be used as a biomarker to predict recurrence | [150] |
| PDA | 109 | Identification of multiple novel mutated genes in PDA, with select genes harboring prognostic significance KRAS mutations were observed in >90% of cases ARID1A was a marker of poorer outcome RBM10 mutation was associated with longer survival BRAF and PIK3CA mutations expand the spectrum of oncogenic drivers |
PDA is a complex cancer and WES can provide insight on pathogenesis, diagnosis and therapeutic management of these tumors | [151] |
| ICC | 135 (7 fresh frozen samples, 107 FFPE, 21 FFPE mixed HCC-ICC; WES in 8, WGS in 1) | Chromosomal translocation t(10;12)(q26;q12) leads to FGFR2–PPHLN1 fusion; it is successfully inhibited by a selective FGFR2 inhibitor in vitro | Novel fusion event (FGFR2–PPHLN1) could provide therapeutic benefit Most CCA patients harbor potentially targetable molecular alterations |
[152] |
| HCC | 231 (WES and CNA) | Mutated RB1 was a predictor of recurrence and poor survival after HCC resection | RB1 mutations could be used as a prognostic molecular biomarker for resectable HCC | [153] |
| HCC | 243 | 28% of the tumors featured genetic alterations targeted by FDA-approved drugs and 3 groups of genes were associated with risk factors: CTNNB1 (alcohol), TP53 (HBV) and AXINI | Association of environmental risk factors with specific genes provides new potential for HCC prevention and early-stage diagnosis | [154] |
| HCC | 503 (452 WES) * | TERT alterations were identified in 68% of the patients AXIN1 was more frequently mutated in HBV-positive and ARID1A in non-virus cases Druggable kinase alterations were rarely found (<2%) |
Mutations in genes coding for metabolic enzymes, chromatin remodelers and mTOR pathway could provide diagnostic and therapeutic potential | [155] ‡ |
Comparative genomic hybridization (CGH); copy-number alteration (CNA); fibrolamellar hepatocellular carcinoma (FLC); formalin-fixed paraffin-embedded (FFPE); hepatoblastoma (HB); hepatocellular carcinoma (HCC); intrahepatic cholangiocarcinoma (ICC); pancreatic ductal adenocarcinoma (PDA); single nucleotide polymorphism (SNP); targeted sequencing (TS); very long-term survivor (VLTS); whole-exome sequencing (WES); * 22 cases of WGS are included in Table 9; † WES analysis was performed on the Illumina Genome Analyzer II platform, which is no longer available for order on the official Illumina website; ‡ WES analysis was performed on the SureSelect Human All Exon V3 or V4 platform from Agilent Technologies.