Identification of Molecular Pathway Aberrations in Uterine Serous Carcinoma by Genome-wide Analyses

Kuhn, Elisabetta; Wu, Ren Chin; Guan, Bin; Wu, Gang; Zhang, Jinghui; Wang, Yue; Song, Lei; Yuan, Xiguo; Wei, Lei; Roden, Richard B.S.; Kuo, Kuan-Ting; Nakayama, Kentaro; Clarke, Blaise A.; Shaw, Patricia; Olvera, Narciso; Kurman, Robert J.; Levine, Douglas A.; Wang, Tian Li; Shih, Ie Ming

doi:10.1093/jnci/djs345

Cited by 230 publications

(199 citation statements)

References 41 publications

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“…We report exome sequencing of a USC cohort five times larger than those recently reported (26,27). The results define the genetic hallmarks of uterine serous cancer.…”

Section: Discussionmentioning

confidence: 71%

Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

Zhao

Choi

Overton

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

291

274

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Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/ Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRDchromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.endometrial carcinoma | uterine serous papillary cancer | cancer genomics E ndometrial cancer is the most prevalent gynecologic tumor in women, with an annual incidence of 47,130 new cases and 8,010 deaths in 2012 in the United States (1). On the basis of clinical and histopathological features, endometrial cancer is classified into type I and type II disease groups (2). Type I tumors, which constitute the majority of cases, are generally diagnosed at an early stage, are low grade and endometrioid in histology, are associated with a history of hyperestrogenism, and typically have a good prognosis. In contrast, type II cancers are poorly differentiated, often with serous papillary [uterine serous carcinoma (USC)] or clear cell histology. Although these tumors account for a minority of endometrial cancers, the majority of relapses and deaths occur in this group of patients (2).Among type II cancers, USC represents the most biologically aggressive subtype (3, 4). Classically, the neoplastic epithelium is characterized by serous differentiation with psammoma bodies and a predominantly papillary architecture (3). Pleomorphic cytology with nuclear atypia, prominent nucleoli, a vescicular chromatin pattern, and high mitotic activity are seen. Clinically, USC has a propensity for early intra-abdominal and lymphatic spread (3) and is more commonly diagnosed in women of African ancestry (3-5). The overall 5-y survival of USC is only 30 ± 9% for all stages, and the recurre...

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“…We report exome sequencing of a USC cohort five times larger than those recently reported (26,27). The results define the genetic hallmarks of uterine serous cancer.…”

Section: Discussionmentioning

confidence: 71%

Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

Zhao

Choi

Overton

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

291

274

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“…[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).…”

mentioning

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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“…Since uterine carcinosarcomas are essentially metaplastic high‐grade carcinomas, it may be reasonable to speculate that CNAs may be more prevalent than point mutations, based on extrapolation of the genomic profiling data from high‐grade serous carcinoma 4, 5. With the aim of extending our earlier findings, the present study employed genomic copy number profiling.…”

Section: Discussionmentioning

confidence: 91%

Genomic profiling identifies GPC5 amplification in association with sarcomatous transformation in a subset of uterine carcinosarcomas

Chui

Have

Hoang

et al. 2018

The Journal of Pathology CR

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Uterine carcinosarcoma, also known as Malignant Mixed Müllerian Tumour, is a high‐grade biphasic neoplasm composed of sarcomatous elements thought to originate via transdifferentiation from high‐grade endometrial carcinoma. To identify molecular factors contributing to the histogenesis of this tumour, we analyzed DNA extracted from matched carcinoma and sarcoma components from 12 cases of carcinosarcoma by a molecular inversion probe microarray to assess genomic copy number alterations (CNAs) and allelic imbalances. Widespread CNAs were identified in tumours with serous histology in the carcinoma component (9/12), while the remaining three cases with endometrioid carcinoma were near‐diploid. Quantification of the extent of genomic aberrations revealed a significant increase in sarcoma relative to carcinoma in tumours with well‐delineated histologic components. Focal amplification of 13q31.3 was identified in 6/12 profiled tumours, of which four harboured the aberration exclusively in the sarcoma component. This result was verified by fluorescence in situ hybridization against GPC5, the only gene situated within the minimal region of amplification. In a validation cohort composed of 97 carcinosarcomas and other uterine sarcomas, amplification of GPC5 (GPC5/CEP13 ratio ≥ 2.2) was identified in 11/97 (11.3%) cases (9/64 carcinosarcoma, 1/3 rhabdomyosarcoma, 1/21 leiomyosarcoma, 0/8 adenosarcoma, 0/1 undifferentiated endometrial sarcoma) and an additional 4 (2.8%) cases had low level gains (GPC5/CEP13 ratio ≥1.5 but <2.2). The functional relevance of Glypican‐5, the gene product of GPC5, in regulating differentiation and lineage commitment was demonstrated in an endometrial carcinoma cell line in vitro. In conclusion, we identified GPC5 amplification as a molecular event mediating epithelial‐mesenchymal transdifferentiation in a subset of uterine carcinosarcomas.

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Identification of Molecular Pathway Aberrations in Uterine Serous Carcinoma by Genome-wide Analyses

Abstract: Molecular genetic aberrations involving the p53, cyclin E-FBXW7, and PI3K pathways represent major mechanisms in the development of uterine serous carcinoma.

Cited by 230 publications

References 41 publications

Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma

Reproducibility of histological cell type in high-grade endometrial carcinoma

Genomic profiling identifies GPC5 amplification in association with sarcomatous transformation in a subset of uterine carcinosarcomas

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