Abstract 1334: Implication of the 3′UTR region of TGFβR1 with MSS HNPCC and sporadic colorectal cancer.
Authors: Munoz Xicola Rosa M. , Doyle Brian , Rawson Jamie , Garre Pilar , Abuli Anna , Lee Esther , Murugappan Sathyaraj , Bessa Xavier , Bujanda Luis , Balaguer Francesc , Castellvi-Bel Sergi , Clofent Juan , Alenda Cristina , Jover Rodrigo , Ruiz-Ponte Clara , Singal Sapna , Andreu Montserrat , Carracedo Angel , Castells Antoni , Ellis Nathan , Caldes Trinidad , LLor Xavier 
Published: August 2014

Background: Colorectal cancer (CRC) is among all common malignancies one with the highest percentage of familial clustering. Thus almost 20% of cases develop in families with at least another affected member. Individuals in these families have a higher risk of developing CRC. Known mutations responsible for several CRC syndromes only explain a small proportion of familial cases but the underlying basis of most still remains unknown. Over half of CRCs that are highly suspicious for an autosomal dominant hereditary pattern of malignancy, as expressed by the Amsterdam criteria, are not explained by known genetic mutations. These cases are known as microsatellite stable hereditary non-polyposis CRC (MSS-HNPCC) or colorectal cancer type X. Aims: To identify new genetic variants that can potentially modulate CRC risk and contribute to hereditability. Methods: We sequenced the coding sequence of MGMT, AXIN2, CTNNB1, TGFβRI and TGFβRII genes and we genotyped 10 common low risk variants, in 30 MSS-HNPCC patients. Potentially relevant variants were genotyped in 308 sporadic cases and 425 cancer-free controls. Logistic regression was used to estimate cancer risk (OR (95%CI)) associated with the genetic variants identified using SPSS (IBM v20.0). Results: A haplotype containing 3 variants (rs67687202, rs868 and rs334354) in high linkage disequilibrium (LD) was found to be associated in a very strong manner with MSS-HNPCC patients and to a lesser degree with sporadic CRC. Thus both MSS-HNPCC and sporadic CRC showed a significantly lower minor allele frequency (MAF) than controls (MAF 0.07, MAF 0.23 vs MAF 0.29) for rs67687202. The AA genotype of rs868 associates with a strong risk for CRC in MSS-HNPCC patients (OR=7.9 (2.7-23.1) P&lt;0.001) and also in sporadic CRC patients but much more modestly (OR=1.6 (1.2-2.2) P=0.001). According to prediction models, the AA genotype for rs868 results in a tighter complementary binding for the family of let-7 miRNAs, which inhibits TGFβR1 translation. On the other hand, the GG genotype increases the hybridization energy of binding for miR-98 and let-7c and completely eliminates the binding for let-7d. We did not identify any association of 10 low risk variants or an accumulation of these risk alleles in MSS-HNPCC patients, which suggests that clustering of common risk alleles is not contributing to cancer development in these families. Conclusions: We describe for the first time a haplotype presumably involved in controlling TGFβR1 expression that has an extremely high association with MSS-HNPCC suggesting a deep contribution of this genetic component to familial CRC. The effect could be due to the more efficient binding of miRNA let-7, which inhibits the TGFβR1 transcript. This further supports other findings that suggest the important role of TGFβR1 as a susceptibility factor in CRC. An accumulation of low susceptibility variants is an unlikely explanation for the high cancer risk in MSS-HNPCC.

Citation Format: Rosa M. Munoz Xicola, Brian Doyle, Jamie Rawson, Pilar Garre, Anna Abuli, Esther Lee, Sathyaraj Murugappan, Xavier Bessa, Luis Bujanda, Francesc Balaguer, Sergi Castellvi-Bel, Juan Clofent, Cristina Alenda, Rodrigo Jover, Clara Ruiz-Ponte, Sapna Singal, Montserrat Andreu, Angel Carracedo, Antoni Castells, Nathan Ellis, Trinidad Caldes, Xavier LLor. Implication of the 3′UTR region of TGFβR1 with MSS HNPCC and sporadic colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1334. doi:10.1158/1538-7445.AM2013-1334