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Journal of Gynecologic Oncology logoLink to Journal of Gynecologic Oncology
. 2022 Oct 6;34(1):e6. doi: 10.3802/jgo.2023.34.e6

Elucidation of genomic origin of synchronous endometrial and ovarian cancer (SEO) by genomic and microsatellite analysis

Ikuko Sakamoto 1,2,✉, Yosuke Hirotsu 2, Kenji Amemiya 2,3, Takahiro Nozaki 1, Hitoshi Mochizuki 2, Masao Omata 2,4
PMCID: PMC9807354  PMID: 36245225

Abstract

Objective

Elucidation of clonal origin of synchronous endometrial and ovarian cancers (SEOs).

Methods

We reviewed 852 patients who diagnosed endometrial and/or ovarian cancer. Forty-five (5.3%) patients were diagnosed as SEOs. We evaluated blood and tissue samples from 17 patients. We analyzed the clonal origins of 41 samples from 17 patients by gene sequencing, mismatch microsatellite instability (MSI) polymerase chain reaction assay and immunohistochemical (IHC) staining of 4 repair genes.

Results

Sixteen of 17 patients had at least 2 or more trunk mutations shared between endometrial and ovarian cancer suggesting the identical clonal origins. The shared trunk mutation are frequently found in endometrial cancer of the uterus, suggesting the uterine primary. Four out of 17 (24%) SEOs had mismatch repair (MMR) protein deficiency and MSI-high (MSI-H) states. One case was an endometrial carcinoma with local loss of MSH6 protein expression by IHC staining, and the result of MSI analysis using the whole formalin-fixed, paraffin-embedded specimen was microsatellite stable. In contrast, ovarian tissue was deficient MMR and MSI-H in the whole specimen. This indicated that MMR protein deficiency could occur during the progression of disease.

Conclusion

Most SEOs are likely to be a single tumor with metastasis instead of double primaries, and their origin could be endometrium. In addition, SEOs have a high frequency of MMR gene abnormalities. These findings not only can support the notion of uterine primary, but also can help to expect the benefit for patients with SEOs by immuno-oncology treatment.

Keywords: Endometrial Carcinoma, Neoplasms, Epithelial Ovarian Cancer, Synchronous Multiple Primary, Molecular Genetics

Synopsis

Using gene sequencing, mismatch microsatellite instability polymerase chain reaction assay, and immunohistochemistry staining, we found that most synchronous endometrial and ovarian cancers have the same origin, which may be of uterine origin.

INTRODUCTION

Synchronous multiple cancers of the female genital tract, especially synchronous endometrial and ovarian cancers (SEOs), are reported as 1%–2% of all genital neoplasms [1,2,3]. Patients with disease of both the endometrium and the ovary can be classified into 3 groups: (1) synchronous and independent primary cancers of the endometrium and ovary, (2) endometrial cancer with metastasis to the adnexa, and (3) ovarian cancer with metastasis to the endometrium.

The distinction between independent primary tumors and metastasis from one site to the other (endometrium to the ovary or ovary to the endometrium) could be difficult on clinical and pathological features alone, but the distinction of the different groups on solid basis could be clinically significant in the management of SEOs.

In the past, the criteria for this distinction were based mostly on morphological features. Ulbright and Roth [4] proposed a set of histological criteria to distinguish the first 2 groups. Then Scully et al. [5] described a similar but more extensive list of clinical pathologic features. But more solid criteria for the distinction was needed for the benefit of patients’ care.

Recent studies by genetic analysis on the clonal origins of SEOs suggested that most SEOs were single primary tumors with metastasis [6,7,8]. In 3 studies combined, 52 out of 55 (96%) SEOs were genetically similar or identical tumors. However, in these studies, it was not elucidated which is the primary, e.g., uterus or ovary.

In this study, we examined 17 SEOs by molecular and immunohistochemical (IHC) analyses and tried to elucidate their genomic origins.

MATERIALS AND METHODS

1. Patients

Of 852 patients who underwent surgical treatment for endometrial and/or ovarian cancer between January 2008 and December 2019 in our hospital, 45 (5.3%) patients had tumors in both endometrium and ovary (SEOs). Under the approval of the Ethics Committee of our hospital (Yamanashi Central Hospital, Ethics Review Committee for Clinical and Genomic Research, approval No. 180), of these 45, we obtained informed consent and performed genetic analysis on 17 (29%) patients.

All resected specimens were reviewed according to the criteria proposed by Scully et al [5]. The features indicative of double primaries (DPs) included (1) clear histological distinction of tumors of the endometrium and ovary; (2) no or minimal myometrial invasion; (3) absence of lympho-vascular space invasion; (4) unilateral ovarian tumor; and/or (5) ovarian endometriosis present. In individual cases, we scored how many met these criteria as “DP features.” By these clinicopathological features, 10 out of 17 (59%) patients were considered as having DP and 7 (41%) as M (Table 1). We staged the cases according to the International Federation of Gynecology and Obstetrics guidelines [9].

Table 1. Clinicopathological judgement and genetic clonality of 17 synchronous endometrial and ovarian cancers.

Case Uterine tumor Ovarian tumor DP features Clinico-pathological judgement Genetic clonality
Histology Stage Size (mm) Lymphovascular invasion Myometrial invasion Histology Stage Site Size (mm) Endometriosis
1 EM IA 3 − - EM IIIC Lt 90 + 4 DP M
2 EM IA 35 − <1/2 EM IIC Lt 140 + 4 DP M
3 EM IA 5 − - S II Bilate 55/65 − 3 DP M
4 EM IIIC 20 + <1/2 EM IC Lt 75 + 3 DP M
5 EM IA 10 − <1/2 EM IA Rt 60 − 3 DP M
6 EM IA 30 + <1/2 S IV Rt 30 − 3 DP M
7 EM II 40 − <1/2 EM IA Rt 45 − 3 DP M
8 EM II 30 − <1/2 EM IIIC Lt 70 − 3 DP M
9 EM IA 40 − <1/2 EM IC Lt 170 − 3 DP M
10 EM IIIA 30 + <1/2 EM - Rt 30 − 2 M M
11 EM IIIA 40 − - EM - Bilate 90/Micro − 2 M M
12 EM IV 50 + <1/2 EM - Lt Micro − 2 M M
13 EM IIIA 80 + >1/2 EM - Lt 8 − 1 M M
14 S IIIA 60 + >1/2 S IC Lt 80 − 1 M DP
15 EM IA 50 + <1/2 EM IVB Bilate 80/60 − 1 DP M
16 EM IIIB Micro + >1/2 EM - Bilate Micro/Micro − 0 M M
17 EM IIIA 90 + >1/2 EM - Bilate 20/30 − 0 M M
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DP, double primary; EM, endometrioid; Lt, light; M, metastasis; Rt, right; S, serous; micro, under 1 mm.

2. Blood and tissue sample preparation and DNA extraction

After centrifuging peripheral blood samples, buffy coats were isolated and stored at −80°C until DNA extraction [10,11]. Buffy coat DNA was extracted using the QIAamp DNA Blood Mini QIAcube Kit (Qiagen, Hilden, Germany) with QIAcube (Qiagen). DNA concentration was determined using the NanoDrop 2000 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). We fixed tumor specimens with 10% buffered formalin to make formalin-fixed, paraffin-embedded (FFPE) tissues [12,13]. FFPE tissues were stained with hematoxylin and eosin and microdissected using the Arcturus LCM System (Thermo Fisher Scientific) to enrich tumor tissue [12]. Subsequently, the FFPE DNA was extracted using the QIAamp DNA FFPE Tissue Kit (Qiagen).

3. FFPE DNA quality analysis

To determine the FFPE DNA quality, we performed real-time polymerase chain reaction (PCR) assay as previously described [13]. In brief, we used 2 types of primer sets including TaqMan RNase P Detection Reagents Kit and the FFPE DNA QC Assay v2 (Thermo Fisher Scientific). We diluted the human control genomic DNA to create a 5-point serial dilution for a standard curve analysis and determined absolute DNA concentrations.

4. Selection and sequencing of 52 significantly mutated genes (SMGs) associated with gynecologic cancers

We searched the literature and selected genes on the basis of the following criteria: recurrently mutated genes relative to the background mutation rates analyzed by the MutSigCV, genes involved in signaling pathways and potential therapeutic targets [14,15]; and known drivers of gynecologic carcinogenesis reported by The Cancer Genome Atlas (TCGA) projects [16,17] and other projects [18,19,20,21]. Furthermore, we included the hotspot mutation site of each gene from the Catalogue of Somatic Mutations in Cancer (COSMIC) database [22]. Ion AmpliSeq designer software (Thermo Fisher Scientific) was used to generate in-house panel. Targeted sequencing was conducted as previously described [23]. Briefly, multiplex PCR of was performed using the Ion AmpliSeq™ Library Kit Plus (Thermo Fisher Scientific). Primer sequences were digested with a FuPa reagent and adaptor ligation was conducted with Ion Xpress™ Barcode Adapters (Thermo Fisher Scientific). Ligated library was purified with Agencourt AMPure XP reagents (Beckman Coulter, Brea, CA, USA). The library concentration was determined using an Ion Library Quantitation Kit (Thermo Fisher Scientific). Emulsion PCR and chip loading were performed on the Ion Chef System with the Ion PI Hi-Q Chef Kit (Thermo Fisher Scientific), and sequencing were conducted on the Ion Proton (Thermo Fisher Scientific).

Sequence data were processed using standard Ion Torrent Suite Software (version 5.0.4; Thermo Fisher Scientific) running on the Torrent Server. Data processing pipeline comprised signal processing, base calling, quality score assignment, read alignment to the human genome 19 reference (hg19), quality control of mapping and coverage analysis. Following the data analysis, we performed the annotation of single-nucleotide variants, insertions and deletions by using the Ion Reporter Server System (Thermo Fisher Scientific) and used the buffy coat DNA as a control to detect variants in tumors (Tumor–Normal pairs). We used the following filtering parameters for detecting somatic mutations: the minimum number of variant allele reads was 5, the minimum coverage depth was 10, UCSC Common SNPs was ‘not in’ and confident somatic variants was ‘in’ [24].

Actionable mutations were referred to the OncoKB database (update: September 17, 2020) from the Memorial Sloan Kettering Cancer Center [25]. In this study, we defined “oncogenic mutations” as mutations annotated as oncogenic or likely oncogenic by OncoKB database.

5. Microsatellite instability PCR (MSI-PCR) assay

MSI analysis was performed on FFPE tumor DNA using the MSI Analysis System v1.2 (Promega, Fitchburg, WI, USA) or MSI (FALCO) Kit (FALCO Biosystems, Kyoto, Japan). Both assays examined 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24, and MONO-27), as previously described [26]. Data were analyzed by GeneMapper Software 5 (Thermo Fisher Scientific). Tumors with more than 2 unstable microsatellite markers were defined as MSI-high (MSI-H). Tumors with less than one unstable marker were defined as microsatellite stable (MSS).

6. IHC

IHC of mismatch repair (MMR) proteins was performed as previously described [27]. Serial sections of FFPE tissue were deparaffinized and antigen activation was performed by heat treatment. We used the Dako EnVision FLEX kit, an automated staining instrument Autostainer Link 48 system (Dako, Copenhagen, Denmark), and primary monoclonal antibodies against anti-MLH1 (clone ES05; Dako), anti-MSH2 (clone FE11; Dako), anti-MSH6 (clone EP49; Dako), and anti-PMS2 (clone EP51; Dako). The tumors were classified into proficient MMR when all 4 MMR proteins were expressed in tumor nuclei and into deficient MMR (dMMR) when complete loss of the expression of at least one MMR protein.

7. Total number of samples analyzed

We analyzed the clonal origins of 41 samples (18 from uterus, 22 from ovaries and 1 from lymph node) from 17 patients by gene sequencing of 52 SMGs, mismatch MSI-PCR and IHC staining of 4 repair genes.

RESULTS

1. DP features

Among DP features scored according to Scully’s criteria, the highest score could be 5 and the lowest 0 (Table 1). We arbitrarily set DP as scores of 5 to 3, and M as scores of 2 to 0. By this scoring system, 10 (case 1 to 9, 15) were diagnosed as DP, and the rest as M (Table 1).

2. Genetic clonality

In order to see these clinical features are really reflecting genetic diagnosis, we analyzed the clonal origins of 41 samples (18 from uterus, 22 from ovaries and 1 from lymph node) from 17 patients by gene sequencing of 52 SMGs. Total of 235 mutations were detected from uterine and ovarian samples. Of the 235 mutations, 73 mutations (31%) were detected from uterine samples only and 121 (51%) from ovarian samples only. 41 mutations (17%) were shared between uterine and ovarian tissues.

Among oncogenic mutations defined by OncoKB, there were 65 mutations. Of 65, 19 (29%) were detected from uterine only, 20 (31%) from ovarian samples only, and 26 (40%) were shared. About half of the shared mutations between uterine and ovarian tumors were oncogenic mutations (Fig. 1).

Fig. 1. Venn diagram showing the overlap of gene mutations.

Fig. 1

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Sixteen of the 17 SEOs had at least 2 or more common mutations (median, 3.0 mutations) and a higher frequency of oncogenic mutations in common, suggesting a clonal origin between endometrial and ovarian tumors (Table 1, Fig. 2). Of 10, all cases with clinicopathological DP had the common mutations, suggesting the possibility of metastasis of either cancer (Fig. 2). Only one case (case 14) shared no mutations, indicating DP (Table 1, Fig. 2)

Fig. 2. Gene profiles of SEOs. Heatmap of gene mutations in patients with SEOs. These maps visualize the gene mutations in each cancer. Bold and italic gene mutations were oncogenic mutations defined by OncoKB.

Fig. 2

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AF, allele frequency; dMMR, deficient mismatch repair; LN, lymph node; Lt, left; Ov, ovarian tissue; pMMR, proficient mismatch repair; Rt, right; SEO, synchronous endometrial and ovarian cancer; Ut, uterine tissue.

The clinical classification showed 10 cases of DP and 7 cases of P, while the genetic classification showed 1 case of DP and 16 cases of M, with a concordance rate of 88%.

The most common oncogenic gene shared between endometrial and ovarian tumors was PTEN (6/17; 35.3%). This was followed by ARID1A, KRAS (5/17; 29.4%), PIK3CA (4/17; 23.5%), and TP53 (3/17; 17.6%) in order of frequency (Fig. 2, Fig. S1).

We examined what signaling pathways the oncogenic mutations contributed to Fig. S1. The most frequent pathway common to both tumors was PIK3 pathway (12/17 71%). This result was similar to that of endometrial cancer (84%) in the TCGA data [17].

3. MSI-PCR and IHC

We then examined MSI using 2 different methods (MSI-PCR and IHC). All results of IHC and MSI analysis were consistent in uterus and ovary, and 4 of 17 (24%) SEOs had MMR defects and MSI-H (Table 2). While the frequency of MSI is reported to be low in ovarian cancer, it is reported to be 20-30% in endometrial cancer, suggesting that the uterus is also the primary site of this finding.

Table 2. The result of MSI assay and IHC staining.

Case Clinico-pathologic judgement Genetic profile MSI/IHC
Uterine Ovary
1 DP M MSI-H/dMMR (MLH1&PMS2 loss) MSI-H/dMMR (MLH1&PMS2 loss)
2 DP M MSS/pMMR MSS/pMMR
3 DP M MSS/pMMR MSS/pMMR
4 DP M MSS/p&dMMR (MSH6 loss) MSI-H/pMMR (MSH6 loss)
5 DP M MSS/pMMR MSS/pMMR
6 DP M MSS/pMMR MSS/pMMR
7 DP M MSS/pMMR MSS/pMMR
8 DP M MSS/pMMR MSS/pMMR
9 DP M MSS/pMMR MSS/pMMR
10 M M MSI-H/dMMR (MLH2-MSH6 loss) MSI-H/dMMR (MLH2-MSH6 loss)
11 M M MSI-H/dMMR (MLH1-PMS2 loss) MSI-H/dMMR (MLH1-PMS2 loss)
12 M M MSS/pMMR MSS/pMMR
13 M M MSS/pMMR MSS/pMMR
14 M DP MSS/pMMR MSS/pMMR
15 DP M MSS/pMMR MSS/pMMR
16 M M MSS/pMMR MSS/pMMR
17 M M MSS/pMMR MSS/pMMR
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dMMR, deficient mismatch repair; DP, double primary; IHC, immunohistochemistry; M, metastasis; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSS, microsatellite instability stable; pMMR, proficient mismatch repair.

Among the 4 cases that showed MMR defects, case 4 was an endometrial carcinoma with local loss of MSH6 protein expression by IHC staining, and the result of MSI analysis using the whole FFPE specimen was MSS (Fig. 3). In contrast, ovarian tissue was dMMR and MSI-H in the whole specimen (Fig. 3). Therefore, we attempted to use laser capture microdissection to separate regions where protein expression was lost and regions where expression was maintained in uterine cancer. The results of the MSI test using microdissection were consistent with the IHC staining.

Fig. 3. MSH6 expression of case 4. EC with a discrete area with loss of MSH6. (A) ×40 OC all area with loss of MSH6. (B) ×100.

Fig. 3

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EC, endometrial cancer; OvC, ovarian cancer.

In addition, we identified germline mutations in these 4 cases of MMR defects. And found germline MSH6 mutations only in case 4.

DISCUSSION

The difference between a single tumor with metastasis and dual-primary tumors in SEOs has been one of the most challenging clinical questions among gynecologists. Van Altena et al. [28] reported that after correcting for age, stage, histology and tumor grade, the survival rates of patients with SEOs and single ovarian cancers are similar; they highlighted that conventional early gynecological cancer treatment for patients with SEOs could be inadequate.

Although several clinicopathological features were considered useful, tumors did not fulfil all the differential criteria in several cases [4,5]. Thus, IHC, MSI, loss of heterozygosity and the mutational analyses of single or small sets of genes have been used as markers to separate synchronous primary tumors from metastatic disease [29,30,31]. Almost all these studies could not identify shared molecular alternations in most SEOs.

In recent studies used massively parallel sequencing to define the clonal relationship between SEO, most SEOs represented a single tumor with metastasis. [7,8]. Our mutation data substantially supported a clonal lineage. Anglesio et al. [6] investigated 2 cases with different histological types between the uterus and the ovary (endometrioid and clear cell) and deduced metastases. In this study, we compared the clinical classification with the genetic classification. The concordance rate was 88%, suggesting the limitation of clinical classification, which is mainly based on morphological diagnosis. Only case 11 was diagnosed as DP based on genetic profile. From these results, we considered that most of the SEOs were single tumors with metastasis.

However, previous studies have not clarified whether the uterus or the ovaries are the origin of the tumor. The most frequently mutated gene in endometrial cancers in previous reports was PTEN (60.6%). This was followed by PIK3CA (49.8%), ARID1A (38%), TP53 (35.1%), and the majority of ovarian cancers were reported to be TP53 (83.1%) [32]. In this study, our results showed that the most frequent oncogenic gene in endometrial cancers was PTEN (9/17; 52.3%), followed by KRAS (6/17; 35.3%) and PIK3CA (5/17; 29.4%). Ovarian cancers showed PTEN (7/17; 41.2%), KRAS (5/17; 29.4%), and PIK3CA (5/17; 29.4%), which differed from the mutation frequency in normal ovarian cancer, and most of them were found in endometrial cancer.

Several prior reports suggest that PTEN mutations occur early in the neoplastic process of endometrial tumors and co-exist frequently with other mutations in the PI3K/AKT pathway [17,33]. Our results in this study also showed a high frequency of PI3K/AKT pathway abnormalities. There were striking similarities between the molecular profiles from the SEO subgroup and the TCGA 2013 endometrial carcinoma tumor set, implying the endometrium could be the primary origin for these cases rather than the ovary [17].

We added IHC and MSI-PCR. Several studies reported that the MMR deficiency was the most frequent in endometrial cancer (20%–30%). Whereas it was rare in ovarian cancer (0.5%–1%) [34,35,36]. In the current study, the frequency of MSI-H in SEO was 24%, which is comparable to the frequency of endometrial cancer. In other words, we thought that SEOs with MSI-H are likely to be ovarian metastasis of endometrial cancer, not DP cancer.

Furthermore, in case 4, the clinicopathological judgement was DP and the genetic classification was M. However, the MSI study showed areas of MSS and MSI-H in the endometrial tissue and only MSI-H in the ovarian tissue. Several studies on MSI have suggested that the loss of MSH6 protein expression may occur with tumor progression [37,38]. This indicated that MMR protein deficiency could occur during the progression of disease and it is highly probable that the cells in the MSI-H region of the endometrium metastasized to the ovary in the present case 4.

Regarding cases 3 and 6, which have different histopathologic diagnoses, we considered there were some limitations of morphological diagnosis. Anglesio et al. [6] concluded, as in the present case, that SEOs with some common mutations were not DP carcinoma but a single tumor with metastases, even though the histologic types are different.

In case 3, the histology of ovarian samples was diagnosed as “serous carcinoma,” but the genetic background was completely different from the characteristics of ovarian serous carcinoma (Table 1, Fig. 2). The uterine and ovarian samples shared a genetic mutation that is reported to be common in endometrial carcinomas [32]. Then we reexamined the histopathological sections. We found some areas that resembled serous carcinoma but were diagnostic of endometrial carcinoma. Several studies reported that cancers with the intratumor heterogeneity could change their morphology at the site of metastasis [39,40]. We considered that case 3 might fit that theory and that the ovarian lesions were most likely metastases of endometrial carcinoma. For case 6, among the gene mutations common to both uterine and ovarian samples, the TP53 gene, which is considered to be common in serous carcinoma, was found. However, the remaining gene mutations belonged to the PIK3 pathway (Figs. 1 and 2), and as in case 3, we suspected the ovarian lesions were metastases of endometrial cancer. There are several limitations to the current study. First, due to the rarity of SEOs, the number of patients included in this study was small. Secondly, only genetic variants were examined, and no epigenetic studies were performed. To validate the findings of this study, a larger cohort study should be conducted in the future.

In conclusion, most SEOs are likely to be a single tumor with metastasis and the origin might be endometrium especially they had endometrioid carcinoma. Furthermore, the frequency of MSI-H in SEOs could be higher than in endometrial cancers. The patients with SEOs may have more chances of immuno-oncology therapy than the patients with endometrial cancer alone.

Footnotes

Conflict of Interest: No potential conflict of interest relevant to this article was reported.

Author Contributions:
  • Conceptualization: S.I., O.M.
  • Data curation: S.I., M.H.
  • Formal analysis: S.I., H.Y.
  • Investigation: S.I., A.K., N.T.
  • Methodology: S.I., H.Y., M.H., O.M.
  • Project administration: S.I., O.M.
  • Validation: S.I., H.Y., A.K., N.T., M.H.
  • Visualization: S.I.
  • Writing - original draft: S.I.
  • Writing - review & editing: O.M.

SUPPLEMENTARY MATERIAL

Fig. S1

Relationship between oncogenic mutations and pathways in each case.

jgo-34-e6-s001.ppt (1.1MB, ppt)

References

  • 1.Ayhan A, Yalçin ÖT, Tuncer ZS, Gürgan T, Küçükali T. Synchronous primary malignancies of the female genital tract. Eur J Obstet Gynecol Reprod Biol. 1992;45:63–66. doi: 10.1016/0028-2243(92)90195-5. [DOI] [PubMed] [Google Scholar]
  • 2.Matlock DL, Salem FA, Charles EH, Savage EW. Synchronous multiple primary neoplasms of the upper female genital tract. Gynecol Oncol. 1982;13:271–277. doi: 10.1016/0090-8258(82)90040-3. [DOI] [PubMed] [Google Scholar]
  • 3.Tong SY, Lee YS, Park JS, Bae SN, Lee JM, Namkoong SE. Clinical analysis of synchronous primary neoplasms of the female reproductive tract. Eur J Obstet Gynecol Reprod Biol. 2008;136:78–82. doi: 10.1016/j.ejogrb.2006.09.010. [DOI] [PubMed] [Google Scholar]
  • 4.Ulbright TM, Roth LM. Metastatic and independent cancers of the endometrium and ovary: a clinicopathologic study of 34 cases. Hum Pathol. 1985;16:28–34. doi: 10.1016/s0046-8177(85)80210-0. [DOI] [PubMed] [Google Scholar]
  • 5.Scully RE, Young RH. In: Blaustein’s pathology of the female genital tract. Kurman RJ, Hedrick Ellenson L, Ronnett BM, editors. Cham: Springer International Publishing; 2002. Metastatic tumors of the ovary; pp. 987–990. [Google Scholar]
  • 6.Anglesio MS, Wang YK, Maassen M, Horlings HM, Bashashati A, Senz J, et al. Synchronous endometrial and ovarian carcinomas: evidence of clonality. J Natl Cancer Inst. 2016;108:djv428. doi: 10.1093/jnci/djv428. [DOI] [PubMed] [Google Scholar]
  • 7.Schultheis AM, Ng CK, De Filippo MR, Piscuoglio S, Macedo GS, Gatius S, et al. Massively parallel sequencing-based clonality analysis of synchronous endometrioid endometrial and ovarian carcinomas. J Natl Cancer Inst. 2016;108:djv427. doi: 10.1093/jnci/djv427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Chao A, Wu RC, Jung SM, Lee YS, Chen SJ, Lu YL, et al. Implication of genomic characterization in synchronous endometrial and ovarian cancers of endometrioid histology. Gynecol Oncol. 2016;143:60–67. doi: 10.1016/j.ygyno.2016.07.114. [DOI] [PubMed] [Google Scholar]
  • 9.FIGO Committee on Gynecologic Oncology. FIGO staging for carcinoma of the vulva, cervix, and corpus uteri. Int J Gynaecol Obstet. 2014;125:97–98. doi: 10.1016/j.ijgo.2014.02.003. [DOI] [PubMed] [Google Scholar]
  • 10.Sakamoto I, Hirotsu Y, Nakagomi H, Ouchi H, Ikegami A, Teramoto K, et al. BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer. Cancer. 2016;122:84–90. doi: 10.1002/cncr.29707. [DOI] [PubMed] [Google Scholar]
  • 11.Hirotsu Y, Nakagomi H, Sakamoto I, Amemiya K, Mochizuki H, Omata M. Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next-generation sequencing. Mol Genet Genomic Med. 2015;3:121–129. doi: 10.1002/mgg3.120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Amemiya K, Hirotsu Y, Oyama T, Omata M. Relationship between formalin reagent and success rate of targeted sequencing analysis using formalin fixed paraffin embedded tissues. Clin Chim Acta. 2019;488:129–134. doi: 10.1016/j.cca.2018.11.002. [DOI] [PubMed] [Google Scholar]
  • 13.Amemiya K, Hirotsu Y, Goto T, Nakagomi H, Mochizuki H, Oyama T, et al. Touch imprint cytology with massively parallel sequencing (TIC-seq): a simple and rapid method to snapshot genetic alterations in tumors. Cancer Med. 2016;5:3426–3436. doi: 10.1002/cam4.950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–339. doi: 10.1038/nature12634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015;521:489–494. doi: 10.1038/nature14410. [DOI] [PubMed] [Google Scholar]
  • 16.Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–615. doi: 10.1038/nature10166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Cancer Genome Atlas Research Network. Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73. doi: 10.1038/nature12113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Le Gallo M, O’Hara AJ, Rudd ML, Urick ME, Hansen NF, O’Neil NJ, et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet. 2012;44:1310–1315. doi: 10.1038/ng.2455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Liang H, Cheung LW, Li J, Ju Z, Yu S, Stemke-Hale K, et al. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer. Genome Res. 2012;22:2120–2129. doi: 10.1101/gr.137596.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Jones S, Wang TL, Kurman RJ, Nakayama K, Velculescu VE, Vogelstein B, et al. Low-grade serous carcinomas of the ovary contain very few point mutations. J Pathol. 2012;226:413–420. doi: 10.1002/path.3967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MD, Wendl MC, et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun. 2014;5:3156. doi: 10.1038/ncomms4156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Catalogue of Somatic Mutations in Cancer (COSMIC) COSMIC database [Internet] place unknown: COSMIC; 2022. Available from: https://cancer.sanger.ac.uk/cosmic . [Google Scholar]
  • 23.Goto T, Hirotsu Y, Mochizuki H, Nakagomi T, Shikata D, Yokoyama Y, et al. Mutational analysis of multiple lung cancers: discrimination between primary and metastatic lung cancers by genomic profile. Oncotarget. 2017;8:31133–31143. doi: 10.18632/oncotarget.16096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Hirotsu Y, Kojima Y, Okimoto K, Amemiya K, Mochizuki H, Omata M. Comparison between two amplicon-based sequencing panels of different scales in the detection of somatic mutations associated with gastric cancer. BMC Genomics. 2016;17:833. doi: 10.1186/s12864-016-3166-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol. 2017;2017:PO.17.00011. doi: 10.1200/PO.17.00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Takaoka S, Hirotsu Y, Ohyama H, Mochizuki H, Amemiya K, Oyama T, et al. Molecular subtype switching in early-stage gastric cancers with multiple occurrences. J Gastroenterol. 2019;54:674–686. doi: 10.1007/s00535-019-01547-z. [DOI] [PubMed] [Google Scholar]
  • 27.Hirotsu Y, Mochizuki H, Amemiya K, Ohyama H, Yoshimura D, Amano H, et al. Deficiency of mismatch repair genes is less frequently observed in signet ring cell compared with non-signet ring cell gastric cancer. Med Oncol. 2019;36:23. doi: 10.1007/s12032-019-1246-4. [DOI] [PubMed] [Google Scholar]
  • 28.van Altena AM, Geels YP, Bulten J, Kiemeney LA, de Hullu JA, Massuger LF. Why do women with double primary carcinoma of the endometrium and ovary have a favorable prognosis? Int J Gynecol Pathol. 2012;31:344–351. doi: 10.1097/PGP.0b013e31823ef951. [DOI] [PubMed] [Google Scholar]
  • 29.Ikeda Y, Oda K, Nakagawa S, Murayama-Hosokawa S, Yamamoto S, Ishikawa S, et al. Genome-wide single nucleotide polymorphism arrays as a diagnostic tool in patients with synchronous endometrial and ovarian cancer. Int J Gynecol Cancer. 2012;22:725–731. doi: 10.1097/IGC.0b013e31824c6ea6. [DOI] [PubMed] [Google Scholar]
  • 30.Ramus SJ, Elmasry K, Luo Z, Gammerman A, Lu K, Ayhan A, et al. Predicting clinical outcome in patients diagnosed with synchronous ovarian and endometrial cancer. Clin Cancer Res. 2008;14:5840–5848. doi: 10.1158/1078-0432.CCR-08-0373. [DOI] [PubMed] [Google Scholar]
  • 31.Moreno-Bueno G, Gamallo C, Pérez-Gallego L, de Mora JC, Suárez A, Palacios J. β-catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. Diagn Mol Pathol. 2001;10:116–122. doi: 10.1097/00019606-200106000-00008. [DOI] [PubMed] [Google Scholar]
  • 32.National Center for Biomedical Ontology. BioPortal web site [Internet] place unknown: National Center for Biomedical Ontology; 2022. Available from: https://bioportal.bioontology.org/ [Google Scholar]
  • 33.Cheung LW, Hennessy BT, Li J, Yu S, Myers AP, Djordjevic B, et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 2011;1:170–185. doi: 10.1158/2159-8290.CD-11-0039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–413. doi: 10.1126/science.aan6733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22:1342–1350. doi: 10.1038/nm.4191. [DOI] [PubMed] [Google Scholar]
  • 36.Bonneville R, Krook MA, Kautto EA, Miya J, Wing MR, Chen HZ, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;2017:1–15. doi: 10.1200/PO.17.00073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Stelloo E, Jansen AM, Osse EM, Nout RA, Creutzberg CL, Ruano D, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2017;28:96–102. doi: 10.1093/annonc/mdw542. [DOI] [PubMed] [Google Scholar]
  • 38.McAlpine J, Leon-Castillo A, Bosse T. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses. J Pathol. 2018;244:538–549. doi: 10.1002/path.5034. [DOI] [PubMed] [Google Scholar]
  • 39.Ramón Y Cajal S, Sesé M, Capdevila C, Aasen T, De Mattos-Arruda L, Diaz-Cano SJ, et al. Clinical implications of intratumor heterogeneity: challenges and opportunities. J Mol Med (Berl) 2020;98:161–177. doi: 10.1007/s00109-020-01874-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–892. doi: 10.1056/NEJMoa1113205. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Fig. S1

Relationship between oncogenic mutations and pathways in each case.

jgo-34-e6-s001.ppt (1.1MB, ppt)

Articles from Journal of Gynecologic Oncology are provided here courtesy of Asian Society of Gynecologic Oncology & Korean Society of Gynecologic Oncology and Colposcopy

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