Chromosome 8q23.3 and 11q23.1 Variants Modify Colorectal Cancer Risk in Lynch Syndrome

doi:10.1053/j.gastro.2008.09.033

Gastroenterology

Volume 136, Issue 1, January 2009, Pages 131-137

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https://doi.org/10.1053/j.gastro.2008.09.033 Get rights and content

Background & Aims

Recent genome-wide association studies have identified common low-risk variants for colorectal cancer (CRC). To assess whether these influence CRC risk in the Lynch syndrome, we genotyped these variants in a large series of proven mutation carriers.

Methods

We studied 675 individuals from 127 different families from the Dutch Lynch syndrome Registry whose mutation carrier status was known. We genotyped 8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1 variants in carriers of a mismatch repair gene mutation. Univariate and multivariate analysis was used to analyse the association between the presence of a risk variant and CRC risk.

Results

A significant association was found between CRC risk and rs16892766 (8q23.3) and rs3802842 (11q23.1). For rs16892766, possession of the C-allele was associated with an elevated risk of CRC in a dose-dependent fashion, with homozygosity for CC being associated with a 2.16-fold increased risk. For rs3802842, the increased risk of CRC associated with the C-allele was only found among female carriers, while CRC risk was substantially higher among homozygous (hazard ratio [HR] 3.08) than among heterozygous carriers of the C-allele (HR 1.49). In an additive model of both variants, the risk was significantly associated with the number of risk alleles (HR 1.60 for carriers of 2 or more risk alleles). The effects were stronger in female carriers than in male carriers.

Conclusion

We have identified 2 loci that are significantly associated with CRC risk in Lynch syndrome families. These modifiers may be helpful in identifying high-risk individuals who require more intensive surveillance.

Section snippets

Methods

We studied 675 individuals from 127 different families from the Dutch HNPCC (LS) Registry whose mutation carrier status was known. This national registry was established in 1985 to promote and coordinate surveillance in these families, and collates the results of colonoscopic findings and surgery. All patients known at the registry gave informed consent for registration. Collection of blood samples from gene carriers was undertaken with informed consent and ethical review board approval in

Results

All 675 carriers and a series of 863 healthy individuals were genotyped for the SNPs rs6983267, rs12953717, rs4779584, rs10795668, rs16892766, and rs3802842. To ensure genotype quality, 5% of samples were typed in duplicate with a concordance of greater than 98%. None of the SNP genotype frequencies deviated significantly from that expected under HWE (Table 2). In the univariate Kaplan–Meier analysis, CRC penetrance differs significantly in male carriers for rs16892766, when stratified by

Discussion

LS is the most common inherited form of CRC caused by a defect in one of the MMR genes. It has been estimated that in the general population, 1 in 500–1000 individuals carries such a defect.¹⁵ Recent genome-wide association studies identified 6 loci on various chromosomes that were significantly associated with CRC in the general population.2, 3, 4, 5

In this study, we evaluated whether these variants also influence CRC risk in a large series of carriers of an MMR-gene mutation. Two variants

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It is characterised by an increased predisposition to most notably CRC and endometrial cancer, but also gastric cancer, ovarian cancer, hepatobiliary tract cancer, urinary tract cancer, brain cancer and skin cancers, and the cancers often occur at a younger age (See Fig. 1) (Aarnio et al., 1999; Abdel-Rahman et al., 2006; Grover et al., 2009; Hampel et al., 2005; Vasen et al., 2007; Vasen et al., 2001b). This risk varies depending both on the affected MMR gene and on the gene loci involved (Plaschke et al., 2004; ten Broeke et al., 2015; Vasen et al., 2001a; Wijnen et al., 2009). To facilitate genetic counselling and clinical practice, an interactive website providing the complete distributions of all cancer types, depending on gene defect, from any age is now available at is available at http://www.lscarisk.org (Moller et al., 2015).
Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumor screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumours have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC.
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We present here two cases of papillary thyroid carcinoma (PTC) in patients affected by Lynch syndrome (LS). The first case is a 47-year-old woman with typical hereditary non-polyposis colorectal cancer (HNPCC) syndrome, reported with endometrial and ovarian carcinoma at age 43, and colon cancer at age 45. The patient underwent total thyroidectomy and central node dissection in 2007, at 47 years old, with a histological diagnosis of PTC (T1aN1a). Molecular genetics showed a germ-line mutation of the MLH1 gene, 1858 G>T(E620X), with substitution of glycine with a stop codon at position 620. This mutation has pathogenetic significance and was considered responsible for the various tumours of the HNPCC spectrum. In particular, in the same kindred, spanning 5 generations, there were 5 members with colorectal cancer, 4 with endometrial cancer, 3 with gastric and 2 with breast cancer. The second case is a 34-year-old man with typical HNPCC syndrome with colonic resection for colon cancer at age 21. The patient underwent total thyroidectomy with central and lateral node dissection in 2010, at age 34, with a histological diagnosis of PTC with nodal metastases (pT4N1b). Molecular genetic analysis showed a germ-line mutation of the MSH2 gene (thymine insertion at position 907). This mutation had pathogenetic significance and was considered responsible for HNPCC development. Two similar cases have been reported: a 39-year-old woman, and a 44-year-old woman, affected by HNPCC syndrome, with anaplastic thyroid carcinoma and undifferentiated thyroid carcinoma, respectively. We reviewed the Lynch syndrome literature on the history, genetics and expanding tumour spectrum of this condition.
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: The authors disclose the following: The study was partly funded with a Dutch Cancer Society Grant UL2005-3247 to T.W., J.T.W., and H.M.

: Contributors: J.T.W., R.M.B., I.P.T., R.S.H., T.W., P.D., H.M., and H.F.V. conceived the idea for the relevant analyses and drafted the manuscript. R.E., S.J.C., A.M., and M.P. were responsible for the SNP analyses. R.M.B. and D.G. performed the statistical analyses. C.M.T., M.G.A., E.G.G., F.J.H., N.H., F.H.M., T.A.O., R.H.S., S.V., A.W., F.M.N., and J.H.K. provided clinical data and patient material. All authors critically reviewed the report and approved the final version.

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Clinical—Alimentary TractChromosome 8q23.3 and 11q23.1 Variants Modify Colorectal Cancer Risk in Lynch Syndrome

Background & Aims

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Hepatology

Hereditary colorectal cancer

N Engl J Med

German HNPCC ConsortiumThe additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1

Cancer Lett

DNMT3b polymorphism and hereditary nonpolyposis colorectal cancer age of onset

Cancer Epidemiol Biomarkers Prev

IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer

J Natl Cancer Inst

Cytochrome P450 17A1 and catechol O-methyltransferase polymorphisms and age at Lynch syndrome colon cancer onset in Newfoundland

Clin Cancer Res

A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21

Nat Genet

Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24

Nat Genet

Multiple regions within 8q24 independently affect risk for prostate cancer

Nat Genet

Clinical—Alimentary Tract
Chromosome 8q23.3 and 11q23.1 Variants Modify Colorectal Cancer Risk in Lynch Syndrome