The FOXA2 transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas.
BACKGROUND
Uterine carcinosarcomas (UCSs) are a rare but clinically aggressive form of cancer. They are biphasic tumors consisting of both epithelial and sarcomatous components. The majority of uterine carcinosarcomas are clonal, with the carcinomatous cells undergoing metaplasia to give rise to the sarcomatous component. The objective of the current study was to identify novel somatically mutated genes in UCSs.


METHODS
We whole exome sequenced paired tumor and nontumor DNAs from 14 UCSs and orthogonally validated 464 somatic variants using Sanger sequencing. Fifteen genes that were somatically mutated in at least 2 tumor exomes were Sanger sequenced in another 39 primary UCSs.


RESULTS
Overall, among 53 UCSs in the current study, the most frequently mutated of these 15 genes were tumor protein p53 (TP53) (75.5%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (34.0%), protein phosphatase 2, regulatory subunit A, alpha (PPP2R1A) (18.9%), F-box and WD repeat domain containing 7 (FBXW7) (18.9%), chromodomain helicase DNA binding protein 4 (CHD4) (17.0%), and forkhead box A2 (FOXA2) (15.1%). FOXA2 has not previously been implicated in UCSs and was predominated by frameshift and nonsense mutations. One UCS with a FOXA2 frameshift mutation expressed truncated FOXA2 protein by immunoblotting. Sequencing of FOXA2 in 160 primary endometrial carcinomas revealed somatic mutations in 5.7% of serous, 22.7% of clear cell, 9% of endometrioid, and 11.1% of mixed endometrial carcinomas, the majority of which were frameshift mutations.


CONCLUSIONS
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.
['Le Gallo|Matthieu|M|', 'Rudd|Meghan L|ML|', 'Urick|Mary Ellen|ME|', 'Hansen|Nancy F|NF|', '|||', 'Merino|Maria J|MJ|', 'Mutch|David G|DG|', 'Goodfellow|Paul J|PJ|0000-0002-0260-4583', 'Mullikin|James C|JC|', 'Bell|Daphne W|DW|0000-0001-7314-3932']
D018262:Adenocarcinoma, Clear Cell D001324:Autoantigens D002277:Carcinoma D018269:Carcinoma, Endometrioid D002296:Carcinosarcoma D045744:Cell Line, Tumor D058534:Class I Phosphatidylinositol 3-Kinases D016889:Endometrial Neoplasms D000073979:F-Box-WD Repeat-Containing Protein 7 D005260:Female D051542:Hepatocyte Nuclear Factor 3-beta D006801:Humans D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex D053842:Microsatellite Instability D009154:Mutation D018297:Neoplasms, Cystic, Mucinous, and Serous D016133:Polymerase Chain Reaction D054648:Protein Phosphatase 2 D017422:Sequence Analysis, DNA D016159:Tumor Suppressor Protein p53 D014594:Uterine Neoplasms
mutation carcinosarcoma exome endometrial carcinoma uterine cancer endometrial cancer