TGFBR1*6A is Somatically Acquired at High Frequency in Cancer and Switches TGF-β Responses

9511 Background: TGFBR1*6A is a common variant of the type I Transforming Growth Factor Beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a common tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. Methods: To determine if TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development, we genotyped tumor and non-tumor tissues from 531 patients with a diagnosis of head and neck, colorectal or breast cancer. We determined whether the three amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence. We stably transfected cancer cells with TGFBR1 and TGFBR1*6A to determine whether TGFBR1*6A acts as a dominant allele in cancer cells. Results: TGFBR1*6A is somatically acquired in 43% of colorectal cancer metastases and in 2% of colorectal and head and neck primary tumors. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A acts a dominant allele that switches TGF-beta growth inhibitory signals into growth stimulatory signals in cancer cells. Conclusions: TGFBR1*6A is somatically acquired at high frequency in cancer and bestows cancer cells with a dramatic growth advantage in the presence of TGF-β. The functional consequences of this conversion are mediated by TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-β signaling in cancer and suggest that TGFBR1*6A may become a therapeutic target in cancer. No significant financial relationships to disclose.