Transforming growth factor beta receptor 1 variants as biomarkers for cervical neoplasia Free

2004

In the United States, 9,710 new cases and 3,700 deaths will occur from cervical cancer (CxCa) in 2006. This cancer goes through years of preinvasive changes before it becomes invasive. Approximately, 1.25 million women are diagnosed with low grade cervical intraepithelial neoplasia (CIN I) annually in the United States. More than 90% of histologically low grade (CIN I) preinvasive lesions and high grade (CIN II and III) preinvasive lesions are associated with human papilloma virus (HPV) but only 11% of low grade lesions progress to high grade lesions; thus factors in addition to HPV must be involved in progression of preinvasive lesions to CxCa. Here, we examined the possibility that two germline variants in the gene for transforming growth factor-β receptor 1 (TGFBR1), Int7G24A and TGFBR1*6A are associated with CxCa progression, clinical outcome, and altered markers of TGF-β signaling. The polymerase chain reaction (PCR) was employed along with restriction fragment length polymorphism (RFLP) on genomic DNA samples extracted from formalin fixed, paraffin embedded tissues of patients with cervical cancer. Markers of TGF-β signaling were detected immunohistochemically. We compared 104 patients with CxCa to 111 patients without cancer and found that CxCa patients were more likely to have the variants (p = 0.0172). Also, 65 patients with non-invasive cancer (carcinoma in situ, CIS) were compared to 39 patients with invasive or metastatic CxCa and the latter were more likely to be variant carriers (p = 0.0651). Of the 16 patients who died of CxCa, 75% (12/16) were carriers of one or both of the TGFBR1 variants. The presence of the variants was associated with significant differences in expression of markers of TGF-β signaling. When benign and malignant tissues were averaged, patients with either or both variants expressed significantly increased pSmad2 but significantly decreased TGFBR1 and TGF-β. In CxCa and CIS, pSmad2 expression was increased in patients with either or both variants compared to wild type patients. In normal and CIN I tissues TGFBR1 expression was decreased in variant carriers. We conclude that TGFBR1 variants are associated with CxCa, with death from CxCa, and with altered expression of markers of TGF-β signaling. Additional studies are needed to determine if germline variants in TGFBR1 contribute to neoplastic progression in the 1.25 million women diagnosed annually with CIN I.