Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract.
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.
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Jelena
J
Mirkovic
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, MA, USA.
Lynette M
LM
Sholl
Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, MA, USA.
Elizabeth
E
Garcia
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, MA, USA.
Neal
N
Lindeman
Harvard Medical School, Boston, MA, USA.|Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, MA, USA.|Dana-Farber Cancer Institute, Boston, MA, USA.
Laura
L
MacConaill
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Michelle
M
Hirsch
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.|Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, MA, USA.
Paola
P
Dal Cin
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Melissa
M
Gorman
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Justine A
JA
Barletta
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Marisa R
MR
Nucci
Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
W Glenn
WG
McCluggage
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.|Harvard Medical School, Boston, MA, USA.
Brooke E
BE
Howitt
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008565:Membrane Proteins / Q000235:genetics; D008649:Mesonephroma / Q000235:genetics*; D008875:Middle Aged; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics*
C117307:KRAS protein, human; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)