<i>ARID1A</i>Mutations in Endometriosis-Associated Ovarian Carcinomas

Wiegand, Kimberly C.; Shah, Sohrab P.; Al‐Agha, Osama M.; Zhao, Yongjun; Tse, Kane; Zeng, Thomas; Senz, Janine; McConechy, Melissa K.; Anglesio, Michael S.; Kalloger, Steve E.; Yang, Winnie; Heravi-Moussavi, Alireza; Giuliany, Ryan; Chow, Christine; Fee, John; Zayed, Abdalnasser; Prentice, Leah M; Melnyk, Nataliya; Turashvili, Gulisa; Delaney, Allen; Madore, Jason; Yip, Stephen; McPherson, Andrew; Ha, Gavin; Bell, Lynda; Fereday, Sián; Tam, Angela; Galletta, Laura; Tonin, Patricia N.; Provencher, Diane; Miller, Dianne; Jones, Steven J.M.; Moore, Richard A.; Morin, Gregg B.; Oloumi, Arusha; Boyd, Niki; Aparicio, Samuel; Shih, Ie Ming; Mes-Masson, Anne-Marie; Bowtell, David D.L.; Hirst, Martin; Gilks, Blake; Marra, Marco A.; Huntsman, David G.

doi:10.1056/nejmoa1008433

Cited by 1,518 publications

(1,361 citation statements)

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“…We identified a nonsense mutation in PRUNE2 that was reported to be a potentially oncogenic30 but not therapeutically targetable mutated genes at that time. No somatic mutation of cancer‐associated genes frequently mutated in epithelial ovarian cancer—such as TP53, 31 KRAS, 32 PIK3CA ,33 and ARID1A 34—was detected.…”

Section: Discussionmentioning

confidence: 98%

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Tamura

Nakaoka

Yoshihara

et al. 2018

Genes Chromosomes & Cancer

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Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in‐frame fusion transcripts: MXD4–NUTM1 and ARL6–POT1. Most NUTM1 exons were retained in the MXD4–NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

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Section: Discussionmentioning

confidence: 98%

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Tamura

Nakaoka

Yoshihara

et al. 2018

Genes Chromosomes & Cancer

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“…Using immunohistochemistry it was demonstrated that ARID1A mutations result in the loss of the protein BRG-associated factor 250a (BAF250a), which is a large subunit of transcriptionregulating Human SWI/SNF complexes and has an important role in the control of cell proliferation and tumor suppression. 7,9,10 Recently, Guan et al 11 found somatic ARID1A mutations in 10/25 uterine endometrioid carcinomas, and could also confirm a strong correlation to loss of BAF250a expression by immunohistochemistry.…”

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confidence: 88%

“…Using whole-exome sequencing, recurrent mutations in ARID1A were recently reported in ovarian clear cell carcinomas and endometrioid ovarian carcinomas by two independent groups. 7,8 Wiegand et al 7 found mutations in ARID1A in 46% of 119 ovarian clear cell carcinomas and 30% of 33 endometrioid ovarian carcinomas but in none of 76 high-grade serous carcinomas. Likewise, Jones et al 8 observed ARID1A-mutations in 57% of 42 ovarian clear cell carcinomas.…”

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confidence: 99%

“…7 Loss of BAF250a expression could therefore represent a key mechanism and early step in the transformation of endometriosis into cancer. 7,8 The aim of this study is to examine if loss of BAF250a expression is present in benign endometriotic tissue. Therefore, we examined a large cohort of endometriotic lesions as well as a control cohort of ovarian cancer by immunohistochemistry.…”

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confidence: 99%

“…Therefore, we examined a large cohort of endometriotic lesions as well as a control cohort of ovarian cancer by immunohistochemistry. As loss of expression of this tumor-suppressor gene is regarded to be an early and crucial mechanism in endometriosis-associated ovarian carcinomas 7,11 it could be an important indicator of a risk for carcinogenic transformation.…”

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confidence: 99%

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Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation?

Samartzis

Noske

et al. 2012

Modern Pathology

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Mutations of the tumor-suppressor gene ARID1A result in the loss of protein expression of the BRG-associated factor 250a (BAF250a), a large subunit of transcription-regulating Human SWI/SNF complexes, which have an important role in the control of cell proliferation and tumor suppression. ARID1A mutations are particularly frequent in endometriosis-associated ovarian clear cell and endometrioid carcinomas, and were recently described as a possible key mechanism and early step in the transformation of endometriosis into cancer. Here, we examined the immunohistochemical expression pattern of BAF250a in a tissue microarray including 74 endometriosis and 30 endometrium samples. Ovarian cancer samples (n ¼ 136) served as a control. Epithelial BAF250a expression was assessable in 90/104 (87%) and stromal BAF250a expression in 95/104 (91%) of the endometriosis, and endometrium cases due to lack of adequate tissue in some spots. Complete lack of BAF250a expression was observed in three endometriomas (n ¼ 3/20, 15%) and one deep-infiltrating endometriosis sample (n ¼ 1/22, 5%), but in none of the peritoneal endometriosis (n ¼ 0/16) and eutopic endometrium samples (n ¼ 0/30). A comparison of the mean immunoreactivity scores revealed a significantly lower expression rate of BAF250a in endometriomas compared with normal endometrium (Po0.0005), as well as peritoneal (P ¼ 0.003) and deep-infiltrating endometriosis (P ¼ 0.02). Our data demonstrates that a complete loss of BAF250a expression is observable in some endometriotic lesions, especially in endometriomas. In addition, we report that a partial loss of BAF250a expression is occurring in the form of cell clusters indicating a clonal loss of BAF250a expression in these cells. The loss of expression of the tumor-suppressor protein BAF250a in some endometriomas possibly indicates a risk of malignant transformation in these cases, which could be of importance in the determination of individual treatment strategies. However, its role and value as a prognostic parameter in endometriosis needs to be further studied.

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Management of Ovarian Cancer

Konstantinopoulos

Awtrey²

2012

JAMA

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ARID1AMutations in Endometriosis-Associated Ovarian Carcinomas

Abstract: BACKGROUND-Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described.

Cited by 1,518 publications

References 32 publications

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation?

Management of Ovarian Cancer

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