Colorectal Cancers in Patients With the (9A/6A) Polymorphism of TGFBR1 Exhibit Lesser Inter-(simple sequence repeat) PCR Genomic Instability and Present Clinically at Greater Age

摘要

TGFβ is involved in the response to DNA damage and signaling the cell cycle checkpoint response, in large part achieved by modulating the activity of the ATM kinase. We have investigated if the presence of a common polymorphism in the TGFβ receptor TGFBR1 might impact genomic instability in human colorectal cancer. In order to obtain statistically significant numbers of patients with the lesser polymorphism, one hundred seventy-seven colorectal cancer patients were genotyped for either the major form of the TGFBR1 receptor gene, homozygous for an internal segment of 9 alanines (9A/9A), or the lesser form, heterozygous for the polymorphism containing 6 alanines (9A/6A). Intrachromosomal genomic instability in the tumors was then quantified by the robust inter-(simple sequence repeat) PCR method. Tumors from all twenty-six patients heterozygous with the (9A/6A) polymorphism in TGFBR1 exhibited significantly lower genomic instability than from a randomly selected set [the first identified] of thirty-seven patients with the (9A/9A) polymorphism (p=0.0002, Mann-Whitney). The median age of onset for the (9A/6A) patients was 70 years, compared with a median age of onset of 63 years for the patients carrying the (9A/9A) form (p=0.031, Mann-Whitney). These results are consistent with the model wherein genomic instability facilitates tumor progression, with lesser instability associated with later disease presentation. Clinically, our findings may be developed into improved screening guidelines with respect to the age at which colonoscopy is initiated in carriers of the TGFBR1*6A allele.