Targeted Genomic Profiling Reveals Recurrent KRAS Mutations in Mesonephric-like Adenocarcinomas of the Female Genital Tract

Abstract

Mesonephric adenocarcinoma most commonly arises in the cervix and is presumed to be derived from normal or hyperplastic mesonephric remnants. It is characterized by recurrent KRAS mutations and lack of PIK3CA/PTEN alterations. Adenocarcinomas of the uterine corpus and ovary characterized by morphologic and immunophenotypic similarities to mesonephric adenocarcinoma have been reported. The pathogenesis of these tumors, which have been designated "mesonephric-like adenocarcinomas" is unknown, and it has been debated whether these represent mesonephric adenocarcinomas that arise in the endometrium/ovary or endometrioid adenocarcinomas that closely mimic mesonephric adenocarcinoma. The relationship at the molecular level between mesonephric adenocarcinomas and mesonephric-like adenocarcinomas is unknown. The aim of this study was to examine the molecular alterations in mesonephric-like adenocarcinomas to identify driver mutations and potential therapeutically targetable mutations, and to determine the relationship between mesonephric-like adenocarcinomas and mesonephric adenocarcinomas using targeted next-generation sequencing. Seven mesonephric-like adenocarcinomas (4 ovarian, 3 uterine corpus) underwent targeted next-generation sequencing to detect mutations, copy number variations and structural variants in exonic regions of 300 cancer genes, and 113 selected intronic regions across 35 genes. All 7 tumors (100%) harbored canonical activating KRAS mutations (4 G12D, 3 G12V). PIK3CA activating mutations were identified in 3 of 7 (43%) cases. There were no alterations in PTEN, ARID1A, or TP53 in any of the tumors. In copy number analysis, 5 of 7 (71%) tumors exhibited 1q gain, which was accompanied by 1p loss in 2 cases. In addition, 4 of 7 (57%) tumors had chromosome 10 gain, which was accompanied by gain of chromosome 12 in 3 cases. Mesonephric-like adenocarcinomas, similar to mesonephric adenocarcinomas, are characterized by recurrent KRAS mutations, gain of 1q, lack of PTEN mutations, and gains of chromosomes 10 and 12. PIK3CA mutations, which have not previously been identified in mesonephric adenocarcinoma, were found in 3 of 7 (43%) mesonephric-like adenocarcinomas in our study. Mesonephric-like adenocarcinomas exhibit strikingly similar molecular aberrations to mesonephric adenocarcinomas, but also frequently harbor PIK3CA mutations, demonstrating biological overlap with carcinomas of both mesonephric and Mullerian (endometrioid) differentiation. Given the previously documented association with endometriosis (ovarian neoplasms) and the prominent endometrial involvement (uterine corpus neoplasms), we believe these are best regarded as of Mullerian origin and representing adenocarcinomas which differentiate along mesonephric lines; as such, we propose the term mesonephric-like Mullerian adenocarcinoma.

Cytologic features of upper gynecologic tract adenocarcinomas exhibiting mesonephric‐like differentiation

“…These tumors frequently express cytokeratins (AE1/AE3, CAM 5.2, and CK7), epithelial membrane antigen, CD10, GATA3, PAX8, HMGA2, vimentin, calretinin, and CA 125, and are negative for hormone receptors and WT1 . Frequent mutations in KRAS , as well as mutations in NRAS , ARID1A , ARID1B , and SMARCA4 , have been reported in patients with mesonephric‐like adenocarcinomas …”

“…1,2 Examples in the upper gynecologic tract, such as in the uterine corpus and ovary, [3][4][5][6] are reported only rarely. Within this context, they have been referred to in the literature as "mesonephric-like adenocarcinoma" 3,6,7 because their association with mesonephric remnants has not been firmly established. However, similarities in their immunohistochemical and molecular signatures argue in favor of mesonephric differentiation.…”

“…However, similarities in their immunohistochemical and molecular signatures argue in favor of mesonephric differentiation. 7,8 Cancer Cytopathology August 2019 Histologically, mesonephric and mesonephric-like adenocarcinomas are characterized by variable architectural patterns including tubular, ductal/glandular, retiform/slit-like, sex cord-like, solid, or papillary, and may demonstrate a spindle cell component. [9][10][11][12] Eosinophilic material frequently is encountered within tubular lumens.…”

“…3,13 Frequent mutations in KRAS, as well as mutations in NRAS, ARID1A, ARID1B, and SMARCA4, have been reported in patients with mesonephric-like adenocarcinomas. 7,13 Here, we describe the cytomorphological features of a cohort of adenocarcinomas exhibiting mesonephric-like differentiation (AMDs) arising in the upper gynecologic tract.…”

Pulmonary metastasis of mesonephric‐like adenocarcinoma arising from the uterine body: a striking mimic of follicular thyroid carcinoma

“…However, the majority of the reported UB‐MNACs were predominantly located in the endometrium rather than in the deeper myometrium, and were not associated with mesonephric remnants . In addition to the frequent somatic KRAS mutations identifiable in the MNACs regardless of the tumour sites, UB‐MNACs show characteristic alterations such as frequent PIK3CA mutations and nearly universal immunopositivity for TTF‐1 . McFarland et al .…”