Role of MYH Polymorphisms in Sporadic Colorectal Cancer in China: A Case-control, Population-based Study

Purpose: Biallelic germline variants of the 8-hydroxyguanine (8-OG) repair gene MYH have been associatedwith colorectal neoplasms that display somatic G:CgT:A transversions. However, the effect of single germlinevariants has not been widely studied, prompting the present investigation of monoallelic MYH variants andsusceptibility to sporadic colorectal cancer (CRC) in a Chinese population. Patients and
Methods: BetweenJanuary 2006 and December 2012, 400 cases of sporadic CRC and 600 age- and sex-matched normal blood donorswere screened randomly for 7 potentially pathogenic germline MYH exons using genetic testing technology.Variants of heterozygosity at the MYH locus were assessed in both sporadic cancer patients and healthy controls.Univariate and multivariate analyses were performed to determine risk factors for cancer onset.
Results: Fivemonoallelic single nucleotide polymorphisms (SNPs) were identified in the 7 exon regions of MYH, which weredetected in 75 (18.75%) of 400 CRC patients as well as 42 (7%) of 600 normal controls. The region of exon 1proved to be a linked polymorphic region for the first time, a triple linked variant including exon 1-316 GgA,exon 1-292 GgA and intron 1+11 CgT, being identified in 13 CRC patients and 2 normal blood donors. Avariant of base replacement, intron 10-2 AgG, was identified in the exon 10 region in 21 cases and 7 controls,while a similar type of variant in the exon 13 region, intron 13+12 CgT, was identified in 8 cases and 6 controls.Not the only but a newly missense variant in the present study, p. V463E (Exon 14+74 TgA), was identified inexon 14 in 6 patients and 1 normal control. In exon 16, nt. 1678-80 del GTT with loss of heterozygosity (LOH)was identified in 27 CRC cases and 26 controls. There was no Y165C in exon 7 or G382D in exon 14, the hotspotvariants which have been reported most frequently in Caucasian studies. After univariate analysis andmultivariate analysis, the linked variant in exon 1 region (p=0.002), intron 10-2 AgG (p=0.004) and p. V463E(p=0.036) in the MYH gene were selected as 3 independent risk factors for CRC.
Conclusions: According to theseresults, the linked variant in Exon 1 region, Intron 10-2 AgG of base replacement and p. V463E of missensevariant, the 3 heterozygosity variants of MYH gene in a Chinese population, may relate to the susceptibility tosporadic CRC. Lack of the hot-spot variants of Caucasians in the present study may due to the ethnic differencein MYH gene.