Mutational landscape implicates epithelial-mesenchymal transition gene TGF-β2 mutations for uterine carcinosarcoma after adjuvant tamoxifen therapy for breast carcinoma

Ling Shen; Liangli Hong; Songxia Zhou; Guohong Zhang; Ruiqin Mai

Mutational landscape implicates epithelial-mesenchymal transition gene TGF-β2 mutations for uterine carcinosarcoma after adjuvant tamoxifen therapy for breast carcinoma

Int J Clin Exp Pathol. 2019 Mar 1;12(3):996-1002. eCollection 2019.

Authors

Ling Shen¹, Liangli Hong², Songxia Zhou³, Guohong Zhang³, Ruiqin Mai⁴

Affiliations

¹ Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shantou University Medical College Shantou, Guangdong, China.
² Department of Pathology, The First Affiliated Hospital of Shantou University Medical College Shantou, Guangdong, China.
³ Department of Pathology, Shantou University Medical College Shantou 515031, Guangdong, China.
⁴ Department of Laboratory Medicine, Shantou University Medical College Shantou 515031, Guangdong, China.

PMID: 31933910
PMCID: PMC6945146

Abstract

Uterine carcinosarcoma (UCS) is a rare aggressive malignancy. Several reports previously described UCS occurring after tamoxifen therapy for breast carcinoma. However, the genetic landscape of tamoxifen-related UCS remains unclear. We performed whole-exome sequencing of two UCSs after tamoxifen therapy for breast carcinoma to determine mutational profile of UCSs and those corresponding breast carcinomas. Our results demonstrated that 374 somatic variants in 141 genes were shared across the two UCSs, whereas no shared somatic variations across the breast carcinomas were found. Pathway analysis indicated the MAPK pathway, including the epithelial-mesenchymal transition (EMT) inducer gene TGF-β2 mutations (c. 1039G > A and c. 1040C > T, both p.A347T), recurrently occurred in UCS, while ER-related gene EP300 (p.P16L) and ESR1 (p.V355I) mutations were identified independently in breast carcinomas. These findings highlight the EMT-related gene TGF-β2 variants in the tumorigenesis of tamoxifen-related UCS, support the possibility that tamoxifen mediates its effect on UCS by enhancing mutations of driver genes, and also provides the rationale for clinical investigation in ER-related gene mutation in breast carcinoma to predict the risk for UCS after tamoxifen treatment.

Keywords: Mutations; TGF; uterine carcinosarcoma.