The <i>FOXA2</i> transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas

Gallo, Matthieu Le; Rudd, Meghan L.; Urick, Mary Ellen; Hansen, Nancy F.; Merino, María J.; Mutch, David G.; Goodfellow, Paul J.; Mullikin, James C.; Bell, Daphne W.

doi:10.1002/cncr.30971

Cited by 28 publications

(30 citation statements)

References 43 publications

(97 reference statements)

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“…15 In addition, TP53 (75.5%) and PIK3CA (34.0%) mutations are most frequently observed in uterine carcinosarcoma. 16 Consistent with these reports, we identified TP53 mutations in the two patients with carcinosarcomas and in a patient with endometrioid carcinoma at stage IIIc2. Additionally, PIK3CA and KRAS mutations were identified in one of the two cases with cervical adenocarcinoma.…”

Section: Discussionsupporting

confidence: 90%

“…It is of note that frequent mutations of TP53 have been found in aggressive endometrial carcinomas including high‐grade serous types and carcinosarcomas . In addition, TP53 (75.5%) and PIK3CA (34.0%) mutations are most frequently observed in uterine carcinosarcoma . Consistent with these reports, we identified TP53 mutations in the two patients with carcinosarcomas and in a patient with endometrioid carcinoma at stage IIIc2.…”

Section: Discussionsupporting

confidence: 89%

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Efficacy of liquid‐based genetic diagnosis of endometrial cancer

et al. 2018

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Although liquid‐based cytology (LBC) has increased the sensitivity of cytological diagnosis of endometrial cancer (EC) compared with conventional smear cytology, the sensitivity of LBC for the detection of EC is between 70% and 96% and remains unsatisfactory. In the present study, we compared the efficacy of LBC with liquid‐based genetic diagnosis (LBGDx) by amplicon sequencing of five genes including PTEN,PIK3CA,CTNNB1,KRAS, and TP53 in 48 LBC subjects who underwent endometrial screening. Consequently, LBC classified 15 samples as “positive or suspicious for malignancy” and the 15 were later confirmed as EC. However, LBC failed to identify five cases who were diagnosed as EC by additional transvaginal ultrasound and endometrial curettage, indicating that the sensitivity of cytology alone was 75% (15/20). LBGDx identified 11 pathogenic PTEN variants in 10 subjects, six PIK3CA variants in nine, three CTNNB1 variants in five, two KRAS variants in four, and three TP53 variants in three. Collectively, at least one pathogenic variant was identified in 19 subjects, which included 17 EC (15 endometrioid carcinoma and 2 endometrial carcinosarcomas), and one cervical adenocarcinoma. However, LBGDx did not identify any pathogenic mutations in three of the 20 EC, indicating that the sensitivity of LBGDx alone was 85% (17/20). Although five EC were negative for malignancy by LBC and three were negative for pathogenic mutations by LBGDx, the combination of LBC and LBGDx would successfully diagnose all 20 EC. These data suggested that LBGDx is a useful strategy to improve the sensitivity of screening of EC by LBC.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

Efficacy of liquid‐based genetic diagnosis of endometrial cancer

et al. 2018

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“…The majority of FOXA2 mutations are loss-of-function defects (frameshift and nonsense alleles), consistent with FOXA2 ’s role as a tumor suppressor. 26, 27 Primary tumor specimens rarely have a second mutation or other identifiable abnormality. Haploinsufficiency for FOXA2 could be sufficient to drive endometrial tumorigenesis, as has been proposed for a number of tumor suppressors.…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

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Rush

Smith

et al. 2018

Intl Journal of Cancer

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FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

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“…Furthermore, FOXA1 and FOXA2 act in concert with other nuclear receptors, including ESR1 and glucocorticoid receptor (41,42). Of note, FOXA2 is a tumor suppressor gene that is frequently mutated during the development of adenocarcinoma (22,23) and down-regulated in endometriosis (43). Future studies should explore how FOXA2 regulates chromatin accessibility and impacts gene regulation in concert with steroid hormone receptors and other transcription factors in the GE of normal and diseased human endometrium.…”

Section: Foxa2 Regulated Ligands and Stromal Cell Decidualizationmentioning

confidence: 99%

“…Of note, leukemia inhibitory factor is a critical GE-derived factor essential for uterine receptivity and blastocyst implantation (1,20). In humans, FOXA2 is also expressed in GE of the uterus and is mutated or down-regulated in several of the most prevalent uterine diseases, including complex atypical endometrial hyperplasia (21), uterine carcinosarcomas and carcinomas (22,23), and endometriosis (24). However, little is known about the biology of FOXA2 in the human uterus.…”

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Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

et al. 2019

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The pioneer forkhead box (FOX)A2 transcription factor is specifically expressed in the glands of the uterus, which are central to endometrial function and fertility. In mice, FOXA2 is a critical regulator of uterine gland development in the neonate and gland function in the adult. An integrative approach was used here to define the FOXA2 cistrome in the human endometrium. Genome‐wide mapping of FOXA2 binding intervals by chromatin immunoprecipitation sequencing was performed using proliferative (P)‐ and midsecretory (MS)‐phase endometrium and integrated with the transcriptome determined by RNA sequencing. Distinctive FOXA2 binding intervals, enriched for different transcription factor binding site motifs, were detected in the P and MS endometrium. Pathway analysis revealed different biologic processes regulated by genes with FOXA2 binding intervals in the P and MS endometrium. Thus, FOXA2 is postulated to regulate gene expression in concert with other transcription factors and impact uterine gland development and function in a cycle phase–dependent manner. Analyses also identified potential FOXA2‐regulated genes that influence uterine receptivity, blastocyst implantation, and stromal cell decidualization, which are key events in pregnancy establishment.—Kelleher, A. M., Behura, S. K., Burns, G. W., Young, S. L., DeMayo, F. J., Spencer, T. E. Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium. FASEB J. 33, 8543–8554 (2019). http://www.fasebj.org

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The FOXA2 transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas

Abstract: Collectively, the findings of the current study provide compelling genetic evidence that FOXA2 is a pathogenic driver gene in the etiology of primary uterine cancers, including UCSs. Cancer 2018;124:65-73. © 2017 American Cancer Society.

Cited by 28 publications

References 43 publications

Efficacy of liquid‐based genetic diagnosis of endometrial cancer

Efficacy of liquid‐based genetic diagnosis of endometrial cancer

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

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