Evidence of linkage to chromosomes 10p15.3-p15.1, 14q24.3-q31.1 and 9q33.3-q34.3 in non-syndromic colorectal cancer families

Abstract

Up to 25% of colorectal cancer (CRC) may be caused by inherited genetic variants that have yet to be identified. Previous genome-wide linkage studies (GWLSs) have identified a new loci postulated to contain novel CRC risk genes amongst affected families carrying no identifiable mutations in any of the known susceptibility genes for familial CRC syndromes. To undertake a new GWLS, we recruited members from 54 non-syndromic families from Australia and Spain where at least two first-degree relatives were affected by CRC. We used single-nucleotide polymorphism arrays to genotype 98 concordant affected relative pairs that were informative for linkage analyses. We tested for genome-wide significance (GWS) for linkage to CRC using a quantile statistic method, and we found that GWS was achieved at the 5% level. Independently, using the PSEUDO gene-dropping algorithm, we also found that GWS for linkage to CRC was achieved (P=0.02). Merlin non-parametric linkage analysis revealed significant linkage to CRC for chromosomal region 10p15.3-p15.1 and suggestive linkage to CRC for regions on 14q and 9q. The 10p15.3-p15.1 has not been reported to be linked to hereditary CRC in previous linkage studies, but this region does harbour the Kruppel-like factor 6 (KLF6) gene that is known to be altered in common CRC. Further studies aimed at localising the responsible genes, and characterising their function will give insight into the factors responsible for susceptibility in such families, and perhaps shed further light on the mechanisms of CRC development.

Figure 1

Merlin linkage analysis using data from all families containing two or more affected members: plots of the likelihood of SNPs on chromosomes being linked to CRC. Locations for genes known to be causative for known syndromes are shown as vertical lines. The dotted vertical lines indicate the locations of genes known or suspected to be causative for established familial CRC syndromes or from other GWLS or GWAS: (1) EPHB2, (2) MUTYH, (3) MSH2, (4) MSH6, (5) MLH1, (6) APC, (7) PMS2, (8) rs7014346/TCF4-binding site,^, (9) TGFBR1,^, (10) BMPR1A, (11) PTEN, (12) CRAC1, (13) HIC1, (14) TP53,^{, ,} (15) SMAD7, (16) SMAD4 and (17) STK11.