Article

Germline Susceptibility to Colorectal Cancer Due to Base-Excision Repair Gene Defects

Colon Cancer Genetics Group, School of Clinical and Molecular Medicine, University of Edinburgh, United Kingdom.
The American Journal of Human Genetics (Impact Factor: 10.99). 07/2005; 77(1):112-9. DOI: 10.1086/431213
Source: PubMed

ABSTRACT DNA repair is a key process in the maintenance of genome integrity. Here, we present a large, systematically collected population-based association study (2,239 cases; 1,845 controls) that explores the contribution to colorectal cancer incidence of inherited defects in base-excision repair (BER) genes. We show that biallelic MUTYH defects impart a 93-fold (95% CI 42-213) excess risk of colorectal cancer, which accounts for 0.8% of cases aged <55 years and 0.54% of the entire cohort. Penetrance for homozygous carriers was almost complete by age 60 years. Significantly more biallelic carriers had coexisting adenomatous polyps. However, notably, 36% of biallelic carriers had no polyps. Three patients with heterozygous MUTYH defects carried monoallelic mutations in other BER genes (OGG1 and MTH1). Recessive inheritance accounted for the elevated risk for those aged <55 years. However, there was also a 1.68-fold (95% CI 1.07-2.95) excess risk for heterozygous carriers aged >55 years, with a population attributable risk in this age group of 0.93% (95% CI 0%-2.0%). These data provide the strongest evidence to date for a causative role of BER defects in colorectal cancer etiology and show, to our knowledge for the first time, that heterozygous MUTYH mutations predispose to colorectal cancer later in life. These findings have clinical relevance for BER gene testing for patients with colorectal cancer and for genetic counseling of their relatives.

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Available from: Susan Mary Farrington, Aug 26, 2015
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    • "A biallelic germline defect within a DNA glycosylase, mutY Homology (MUTYH), was initially found in families that had excess colorectal tumors with somatic mutations in the adenomatous polyposis coli gene [157]. A subsequent larger study revealed that biallelic germline MUTYH defects conferred 93 fold excess risk of colon cancer with penetrance by age 60 [158] [159] and may also confer increased risk for endometrial cancer [160]. Mutations in another glycosylase, 8 Oxoguanine (OGG1), have been associated with laryngeal cancers [161] while gastric cancers harbor inactivating mutations in glycosylase nei endonuclease VIII-like 1 (NEIL1) [162]. "
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    ABSTRACT: Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Seminars in Cancer Biology 04/2015; DOI:10.1016/j.semcancer.2015.03.005 · 9.33 Impact Factor
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    • "A biallelic germline defect within a DNA glycosylase, mutY Homology (MUTYH), was initially found in families that had excess colorectal tumors with somatic mutations in the adenomatous polyposis coli gene [157]. A subsequent larger study revealed that biallelic germline MUTYH defects conferred 93 fold excess risk of colon cancer with penetrance by age 60 [158] [159] and may also confer increased risk for endometrial cancer [160]. Mutations in another glycosylase, 8 Oxoguanine (OGG1), have been associated with laryngeal cancers [161] while gastric cancers harbor inactivating mutations in glycosylase nei endonuclease VIII-like 1 (NEIL1) [162]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.
    Seminars in Cancer Biology 03/2015; ePub ahead of print. · 9.33 Impact Factor
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    • "In accordance with this assumption, the largest population-based case-control study assessing CRC risk in MYH variation carriers, has proposed that monoallelic MYH variation carriers could be at increased risk in their advanced age (55 years). To sum up, larger sample sizes, population-based studies, specific-variation analysis and proper methodologic approaches are needed to conform the weak gene effect (Farrington et al., 2005; Peterlongo et al., 2005; Jenkins et al., 2006; Tenesa et al., 2006). "
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    ABSTRACT: Purpose: Biallelic germline variants of the 8-hydroxyguanine (8-OG) repair gene MYH have been associated with colorectal neoplasms that display somatic G:C?T:A transversions. However, the effect of single germline variants has not been widely studied, prompting the present investigation of monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC) in a Chinese population. Patients and Methods: Between January 2006 and December 2012, 400 cases of sporadic CRC and 600 age- and sex-matched normal blood donors were 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: Five monoallelic single nucleotide polymorphisms (SNPs) were identified in the 7 exon regions of MYH, which were detected in 75 (18.75%) of 400 CRC patients as well as 42 (7%) of 600 normal controls. The region of exon 1 proved to be a linked polymorphic region for the first time, a triple linked variant including exon 1-316 G?A, exon 1-292 G?A and intron 1+11 C?T, being identified in 13 CRC patients and 2 normal blood donors. A variant of base replacement, intron 10-2 A?G, 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 C?T, 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 T?A), was identified in exon 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 hot- spot variants which have been reported most frequently in Caucasian studies. After univariate analysis and multivariate analysis, the linked variant in exon 1 region (p=0.002), intron 10-2 A?G (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 these results, the linked variant in Exon 1 region, Intron 10-2 A?G of base replacement and p. V463E of missense variant, the 3 heterozygosity variants of MYH gene in a Chinese population, may relate to the susceptibility to sporadic CRC. Lack of the hot-spot variants of Caucasians in the present study may due to the ethnic difference in MYH gene.
    Asian Pacific journal of cancer prevention: APJCP 11/2013; 14(11):6403-9. DOI:10.7314/APJCP.2013.14.11.6403 · 2.51 Impact Factor
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