No association between germline allele-specific expression of TGFBR1 and colorectal cancer risk in Caucasian and Ashkenazi populations

Colorectal cancer (CRC) is among the four most common cancers in industrialised countries, and is one of the leading causes of cancer-related deaths. Although familial clustering of CRC occurs in 20–30% of all cases, the known highly penetrant autosomal-dominant and -recessive forms of the disease account for less than 5% of all CRC cases (de la Chapelle, 2004; Lynch et al, 2009). Although additional low-penetrance alleles have been proposed in the last few years, the underlying genetic risk factors for CRC predisposition remain largely unknown (Hemminki et al, 2009). On the basis of previous evidence that pointed towards the importance of downstream signalling elements of the transforming growth factor β (TGF-β) pathway in CRC (Wood et al, 2007), and the known linkage peak for familial CRC in 9q22–31 where TGFBR1 is located (Wiesner et al, 2003; Kemp et al, 2006; Skoglund et al, 2006), we undertook the task of studying the role of TGFBR1 in CRC predisposition. Although risk-conferring germline genetic variants in this gene had not been identified, we reported that germline allele-specific expression (ASE) of TGFBR1, measured with the SNaPshot technique, occurred in ∼20% of informative CRC patients and ∼3% of informative controls, thus conferring a substantially increased risk of CRC (odds ratio 8.7, 95% confidence interval (CI): 2.6–29.1) (Valle et al, 2008). This differential allele-specific expression was suggested to be dominantly inherited and to alter the downstream SMAD-mediated TGF-β signalling (Valle et al, 2008). A subsequent report showed that APCMin/+;Tgfbr1+/− mice developed twice as many intestinal tumours and colonic carcinomas as APCMin/+;Tgfbr1+/+, supporting the role of TGFBR1 gene haploinsufficiency in CRC development (Zeng et al, 2009). Also, TGFBR1*6A, a common variant in exon 1 of the gene, has been weakly associated with CRC (Pasche et al, 2004; Skoglund et al, 2007). As allele-specific expression of TGFBR1 has the potential to be used in the clinical evaluation of CRC risk, the aim of this study was to further investigate the extent of ASE of TGFBR1 in CRC using the robust and specific pyrosequencing technique for ASE determination. In addition, we studied two different populations with different biological sources of non-tumour genetic material to evaluate ASE frequency in a variety of populations.