Use of mutation profiles to refine the classification of endometrial carcinomas

McConechy, Melissa K.; Ding, Jiarui; Cheang, Maggie C.U.; Wiegand, Kimberly C.; Senz, Janine; Tone, Alicia A.; Yang, Winnie; Prentice, Leah M; Tse, Kane; Zeng, Thomas; McDonald, Helen; Schmidt, Amy P.; Mutch, David G.; McAlpine, Jessica N.; Hirst, Martin; Shah, Sohrab P.; Lee, Cheng‐Han; Goodfellow, Paul J.; Gilks, C. Blake; Huntsman, David G.

doi:10.1002/path.4056

Cited by 279 publications

(283 citation statements)

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“…Our study found that mesonephric carcinoma is characterized by a limited number of molecular aberrations that may be diagnostically useful and therapeutically important. The common mutations in mesonephric carcinoma are significantly different from those reported in other cervical and endometrial adenocarcinomas 19,20,28,29 and in the TCGA datasets by accessing the cBioPortal for Cancer Genomics, 30,31 (www.cbioportal.org). For example, KRAS/NRAS mutations are the most common molecular aberration detected in mesonephric carcinoma (81%); in contrast, these mutations are less common in other cervical and endometrial adenocarcinomas (less than 30%), [32][33][34] particularly in the microsatellite stable endometrioid adenocarcinomas and the serous endometrial carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract

et al. 2015

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Mesonephric carcinoma is a rare form of gynecologic cancer derived from mesonephric remnants usually located in the lateral wall of the uterine cervix. An analogous tumor occurs in the adnexa, female adnexal tumor of probable Wolffian origin. The pathogenesis and molecular events in mesonephric carcinoma are not known. The aim of this study was to examine the molecular alterations in mesonephric carcinoma to identify driver mutations and therapeutically targetable mutations. This study consisted of 19 tumors from 17 patients: 18 mesonephric carcinomas (15 primary tumors and three metastatic tumors) and 1 female adnexal tumor of probable Wolffian origin. In two patients, both primary and metastatic tumors were available. Genomic DNA was isolated and targeted next-generation sequencing was performed to detect mutations, copy number variations, and structural variants by surveying full exonic regions of 300 cancer genes and 113 selected intronic regions across 35 genes. Fluorescence in situ hybridization (FISH) for 1p and 1q was performed in two cases. Eighty-one percent (13/16) of mesonephric carcinomas had either a KRAS (n = 12) or NRAS (n = 1) mutation. Mutations in chromatin remodeling genes (ARID1A, ARID1B, or SMARCA4) were present in 62% of mesonephric carcinomas. All mesonephric carcinomas lacked mutations in PIK3CA and PTEN. The most common copy number alteration was 1q gain, found in 12 (75%) mesonephric carcinomas; this was confirmed by FISH in two cases. Mesonephric carcinoma is characterized by molecular alterations that differ from those of more common variants of cervical and endometrial adenocarcinoma, which harbor KRAS/NRAS mutations in 7% and 25% of cases, respectively. KRAS/NRAS mutations are common in mesonephric carcinoma and are often accompanied by gain of 1q and mutations in chromatin remodeling genes. Targeting inhibitors of the RAS/MAPK pathway may be useful in the treatment of mesonephric carcinoma.

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Section: Discussionmentioning

confidence: 99%

Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract

et al. 2015

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“…Interestingly, a similar approach to the subclassification of high-grade endometrial carcinomas using mutational profiles did not generate a reliable multivariate logistic regression model. 13 This is possibly due to the lower discrimination of mutational data between types: that is, PI3K mutations are seen in endometrioid carcinoma FIGO grade 3 and serous carcinoma. It has also been shown that certain immunohistochemical markers such as PTEN 'outperform gene sequencing'.…”

Section: Modern Pathology (2013) 26 1594-1604mentioning

confidence: 99%

“…[10][11][12][13][14][15] The aim of this study was to assess specifically the interobserver agreement, recorded by gynecological pathologists from five academic centers across Canada, of histological type in high-grade endometrial carcinomas. A second aim was to correlate morphological diagnosis with a set of six routine immunohistochemical markers (TP53, CDKN2A (p16), ER, PGR, Ki67, and VIM) as well as a set of six experimental immunohistochemical markers (PTEN, ARID1A, CTNNB1, IGF2BP3, HNF1B, and TFF3).…”

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confidence: 99%

Reproducibility of histological cell type in high-grade endometrial carcinoma

et al. 2013

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Subclassification of endometrial carcinoma according to histological type shows variable interobserver agreement. The aim of this study was to assess specifically the interobserver agreement of histological type in high-grade endometrial carcinomas, recorded by gynecological pathologists from five academic centers across Canada. In a secondary aim, the agreement of consensus diagnosis with immunohistochemical marker combinations was assessed including six routine (TP53, CDKN2A (p16), ER, PGR, Ki67, and VIM) and six experimental immunohistochemical markers (PTEN, ARID1A, CTNNB1, IGF2BP3, HNF1B, and TFF3). The paired interobserver agreement ranged from j 0.50 to 0.63 (median 0.58) and the intraobserver agreement from j 0.49 to 0.67 (median 0.61). Consensus about histological type based on morphological assessment was reached in 72% of high-grade endometrial carcinomas. A seven-marker immunohistochemical panel differentiated FIGO grade 3 endometrioid from serous carcinoma with a 100% concordance rate compared with the consensus diagnosis. More practically, a three-marker panel including TP53, ER, and CDKN2A (p16) can aid in the differential diagnosis of FIGO grade 3 endometrioid from endometrial serous carcinoma. Our study demonstrates that the inter-and intraobserver reproducibility of histological type based on morphology alone are mostly moderate. Ancillary techniques such as immunohistochemical marker panels are likely needed to improve diagnostic reproducibility of histological types within high-grade endometrial carcinomas.

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“…In addition, no PPP2R1B mutations were detected in our samples. The combined results of previous studies demonstrated that PPP2R1A mutations frequently occurred in breast, lung and endometrial carcinoma, as well as in OCCC and ovarian endometrioid carcinoma (5)(6)(7)(8)(9)(10)(11). Furthermore, the mutation frequencies of PPP2R1A in OCCC and ovarian endometrioid carcinoma patients were 4.1-9.1% (mean, 7.4%) and 10.0-12.2% (mean, 11.1%), respectively (5)(6)(7)(8).…”

Section: Discussionmentioning

confidence: 76%

“…Subsequent studies confirmed this finding and also revealed frequent PPP2R1A mutations in patients with ovarian endometrioid carcinoma (6)(7)(8). Additionally, a high frequency of PPP2R1A mutations was also identified in several subtypes of endometrial carcinoma, with the highest frequency demonstrated in the serous subtype (6)(7)(8)(9). Furthermore, previous studies revealed that PPP2R1A mutations were present in patients with breast and lung malignancies, but absent in patients with (10,11), suggesting a general effect of PPP2R1A mutations on human cancer.…”

Section: Introductionmentioning

confidence: 63%

Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer

Wang

Zou

Liu

et al. 2013

Molecular Medicine Reports

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Abstract. Protein phosphatase 2, regulatory subunit A, α (PPP2R1A) and β (PPP2R1B) are paralogous subunits of the heterotrimeric protein phosphatase 2 (PP2A) holoenzyme that catalyzes the dephosphorylation of target substrate proteins. Subtype-specific PPP2R1A mutations have been frequently observed in ovarian and endometrial cancer. Mutations in the paralogous genes were frequently observed in human malignancies. Thus, the present study aimed to analyze the mutation frequencies of the paralogous PPP2R1A and PPP2R1B genes in patients with primary and secondary ovarian cancer. A total of 251 patients with primary (n=234) and secondary (n=17) ovarian cancer were analyzed for the presence of PPP2R1A and PPP2R1B mutations by direct sequencing. For PPP2R1A, a heterozygous, somatic mutation (c.771G>T, p.W257C) was identified in 1 out of 37 patients (2.7%) with primary ovarian endometrioid carcinoma. The mutant sample was that of a 46-year-old female, who was also diagnosed with ectopic endometriosis in the benign ovary. No PPP2R1A mutations were detected in the remaining 250 patients with ovarian cancer. For PPP2R1B, no mutations were detected in our samples. The results of this study suggested that PPP2R1A mutations are less common in Chinese patients with ovarian cancer when compared with European and American patients. Furthermore, our study also supported previous observations that PPP2R1B mutations were absent in ovarian cancer, suggesting that PPP2R1B mutations are not actively involved in the pathogenesis of ovarian cancer. IntroductionProtein phosphatase 2, regulatory subunit A, α (PPP2R1A) and β (PPP2R1B) are paralogous subunits of the heterotrimeric protein phosphatase 2 (PP2A) holoenzyme, which catalyzes the dephosphorylation of target substrate proteins (www.ensembl.org) (1). PPP2R1A and PPP2R1B belong to the Huntington-elongation-A subunit-TOR (HEAT) repeat protein family, and are required as scaffolds for the formation of the heterotrimeric PP2A complex (2). PPP2R1A and PPP2R1B each contain 15 tandemly repeated HEAT motifs. It has been previously demonstrated that the HEAT repeats 2-8 and 11-15 were involved in binding to the regulatory and catalytic subunits of PP2A, respectively (3). In addition, mutations located in the HEAT 2 and 11 motifs promoted tumorigenesis; the mutant PPP2R1A proteins were defective in binding to the regulatory and catalytic subunits of PP2A, resulting in a decrease in PP2A activity and thus facilitating tumor progression (4).A previous whole-exome sequencing attempt identified recurrent PPP2R1A mutations in 3 out of 42 patients (7.1%) with ovarian clear cell carcinoma (OCCC) (5). Subsequent studies confirmed this finding and also revealed frequent PPP2R1A mutations in patients with ovarian endometrioid carcinoma (6-8). Additionally, a high frequency of PPP2R1A mutations was also identified in several subtypes of endometrial carcinoma, with the highest frequency demonstrated in the serous subtype (6-9). Furthermore, previous studies revealed that PPP2R1A mutations were present ...

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Use of mutation profiles to refine the classification of endometrial carcinomas

Abstract: The classification of endometrial carcinomas is based on pathological assessment of tumour cell type; the different cell types (endometrioid, serous, carcinosarcoma, mixed, and clear cell) are 11 Corresponding

Cited by 279 publications

References 52 publications

Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract

Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract

Reproducibility of histological cell type in high-grade endometrial carcinoma

Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer

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