Identification of Germline Alterations in the Mad-homology 2 (MH2) Domain of SMAD3 and SMAD4 In Breast Cancer Susceptibility

• Main Author: Tram, Eric
• Other Authors: Ozcelik, Hilmi
• Language: en_ca
• Published: 2012
• Subjects: Breast cancer; germline mutations; SMAD3; SMAD4; Bioinformatics
• Online Access: http://hdl.handle.net/1807/33713

A feature of neoplastic cells is that mutations in the key intermediates of TGF-β signaling contribute to the loss of sensitivity to its anti-tumor effects. The role of SMAD3 and SMAD4 germline mutations in breast cancer predisposition is currently unclear. To address this, mutation analysis of the Mad-Homology 2 domains in 408 breast cancer cases and 710 controls recruited by the Breast Cancer Family Registry (BCFR) was performed using Denaturing High-Pressure Liquid Chromatography. This study identified 23 distinct intronic variants, and three coding variants c.1214T>C, c.1478G>A, and c.1701A>G in SMAD4. No aberrant splicing was observed, but qPCR analysis and tissue expression data showed significantly elevated SMAD3 expression relative to controls (p<0.05). For SMAD4, c.1478G>A from a familial breast cancer case showed a 5-fold expression change. Taken together, inactivating alterations are not driving tumorigenesis. Rather, aberrant germline expression provides novel insight into SMAD3 and SMAD4’s roles in breast cancer predisposition.