Abstract
PurposeConstitutively decreased TGFBR1 allelic expression is emerging as a potent modifier of colorectal cancer risk in mice and humans. This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors.Patients and MethodsWe assessed the frequency of constitutively decreased TGFBR1 allelic expression and association with SNPs covering the TGFBR1 locus using RNA and DNA extracted from the peripheral blood lymphocytes of 118 consecutive patients with biopsy-proven adenocarcinoma of the colon or the rectum.ResultsWe found that 11(9.3%) of 118 patients exhibited decreased TGFBR1 allelic expression (TGFBR1 ASE). TGFBR1 ASE was strongly associated with three SNPs in linkage disequilibrium with each other: rs7034462 (p = 7.2 × 10-4), TGFBR1*6A (p = 1.6 × 10-4) and rs11568785 (p = 1.4 × 10-4).ConclusionThese results confirm the high prevalence of constitutively decreased TGFBR1 allelic expression among patients with colorectal cancer. The association of this phenotype with TGFBR1*6A, rs7034462 and rs1156875 suggests an association between TGFBR1 SNPs and colorectal cancer, which warrants additional studies.
Highlights
Clues regarding important genetic targets in colorectal cancer have come from the study of two hereditary neoplastic syndromes: Familial Adenomatous Polyposis (FAP) and Lynch syndrome, formerly named hereditary non-polyposis colorectal cancer (HNPCC)
Several recent genome-wide association studies have identified ten additional low penetrance susceptibility alleles including BMP2[3], BMP4[3] and SMAD7[3,4], which all belong to the Transforming Growth Factor Beta (TGF-β) superfamily of growth factors
Frequency of the TGFBR1 ASE phenotype In this cross sectional study of 118 consecutivelyrecruited patients with colorectal cancer 74 (62.7%) individuals were heterozygous for informative TGFBR1 SNPs
Summary
Clues regarding important genetic targets in colorectal cancer have come from the study of two hereditary neoplastic syndromes: Familial Adenomatous Polyposis (FAP) and Lynch syndrome, formerly named hereditary non-polyposis colorectal cancer (HNPCC). The genetic mechanisms underlying FAP and Lynch syndrome are well-understood, they only account for approximately 0.2% and 2% of all colorectal cancers, respectively. Several recent genome-wide association studies have identified ten additional low penetrance susceptibility alleles including BMP2[3], BMP4[3] and SMAD7[3,4], which all belong to the Transforming Growth Factor Beta (TGF-β) superfamily of growth factors. These findings provide strong support for the notion that the TGF-β signaling pathway is implicated in colorectal cancer susceptibility[5]
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