The Asp1822Val variant of the APC gene is a common polymorphism without clinical implications

Ruíz-Ponte, Clara; Vega, Ana; Conde, Roberto Cortés; Barros, Francisco; Carracedo, Angel

doi:10.1136/jmg.38.10.e33

Cited by 13 publications

(9 citation statements)

References 6 publications

(1 reference statement)

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“…The functional significance of the Asp1822Val substitution is unknown, although this amino acid change is located in the center of a h-catenin down-regulation domain (18). The clinical relevance of this polymorphism is also uncertain and previous work suggests that Asp1822Val may either be a low-penetrance allele that increases risk of developing colorectal cancer (16) or a common polymorphism without clinical implication (19). Slattery et al (17) found that individuals consuming a low-fat diet were at reduced risk if they were homozygous for the 1822Val allele, suggesting that the influence of dietary and lifestyle factors on risk of colorectal cancer might vary by Asp1822Val genotype.…”

Section: Introductionmentioning

confidence: 98%

APC Asp1822Val and Gly2502Ser Polymorphisms and Risk of Colorectal Cancer and Adenoma

Tranah

Giovannucci

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene is an important initiating factor in the early stages of the adenoma-carcinoma sequence. The aim of this study was to investigate the two most common APC variants (Asp1822Val and Gly2502Ser) and their association with colorectal cancer and adenoma and whether these relationships are influenced by dietary and lifestyle factors. We analyzed 556 adenoma cases and 557 matched controls and 197 cancer cases and 490 matched controls nested within the Nurses' Health Study cohort, 274 cancer cases and 456 matched controls nested within the Physicians' Health Study cohort, and 375 adenoma cases and 724 matched controls nested within the Health Professionals Follow-up Study cohort. APC Asp1822Val and Gly2502Ser polymorphisms were not associated with risk of colorectal cancer or adenoma. For colorectal cancer, a significant interaction was found between Asp1822Val genotype and postmenopausal hormone (PMH) use among postmenopausal women (P interaction = 0.03). Current PMH use was associated with reduced risk overall and a statistically significant lower risk of colorectal cancer among carriers of one or two copies of the APC 1822Val allele (relative risk, 0.46; 95% confidence interval, 0.24-0.88) relative to wild-type never or past PMH users. Our results suggest that cigarette smoking, alcohol intake, and family history of colorectal cancer were positively associated and regular aspirin intake was inversely associated with colorectal adenoma in men and women. No gene-environment interactions were observed with these risk factors or with other dietary risk factors previously hypothesized to interact with the APC

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Section: Introductionmentioning

confidence: 98%

APC Asp1822Val and Gly2502Ser Polymorphisms and Risk of Colorectal Cancer and Adenoma

Tranah

Giovannucci

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…The results from our study are intriguing because they support previous conclusions that these common and rare allele variants of APC likely influence colorectal carcinogenesis (7,8,22). A number of studies support the importance of variation in APC on colorectal adenoma with weak to no association with colorectal cancer (9,10,12,13,15,17,18,23). These data suggest that modest acting variants might act as predisposing variants for adenoma development but are insufficient alone as risk factors for cancer.…”

Section: Discussionmentioning

confidence: 91%

“…Subsequently, the 1822V variant was reclassified as a common APC polymorphism ( frequency %0.22) that lacked clinical significance (23), a conclusion that was challenged by Macdonald and Wallis who suggested that the 1822 minor variant might act as a lowpenetrance allele (23). Slattery et al (24) found no significant associations between colon cancer risk and carriage of the D1822V variant.…”

Section: Introductionmentioning

confidence: 99%

Presence of a TA Haplotype in the APC Gene Containing the Common 1822 Polymorphism and Colorectal Adenoma

Egan¹,

Jacobs²,

Martı́nez³

et al. 2008

Cancer Research

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Acquired or inherited mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are causally linked to colorectal cancer. Given the significance of APC in colorectal cancer, we investigated the association between common single-nucleotide polymorphisms (SNP) in the APC gene and the odds of developing metachronous colorectal adenomas as a surrogate measure of colorectal cancer risk. Coding SNPs at codons 486, 1678, 1822, 1960, and 2502 were analyzed in a total of 1,399 subjects who participated in two randomized clinical trials for the prevention of colorectal adenomas. No association was found for any single SNP and the odds of metachronous adenoma. In contrast, a TA haplotype (codons 486 and 1822) was associated with a statistically significant 27% and 26% reduction in the odds of any and nonadvanced metachronous adenoma after adjustment for baseline adenoma characteristics [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.59-0.91 and OR, 0.74; 95% CI, 0.57-0.94], respectively. No significant reduction in odds was observed for advanced metachronous lesions. Diplotype analysis revealed a strong gene dose effect with carriers of two alleles containing TT-AA (codons 486 and 1822, respectively) having an 89% lower odds for advanced metachronous adenomas (OR, 0.11; 95% CI, 0.01-0.80) when compared with the common CC-AA diplotype (codons 486 and 1822, respectively). Our findings support an important role for germ-line allele sequence in the APC gene and individual risk of metachronous adenomatous polyps. [Cancer Res 2008;68(14):6006-13]

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“…The A1822T APC polymorphism has previously been reported (in both heterozygous and homozygous states) in families with apparent clinical AFAP syndromes, as well as in families without AFAP or other neoplastic syndromes [3][4][5][6].…”

Section: Casementioning

confidence: 99%

Hereditary neoplasia syndromes and the role of the surgeon

Coviello

Wascher

2007

Familial Cancer

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The complex and often variable clinical presentations of patients with hereditary neoplasia syndromes mandates a multidisciplinary approach to management. The involvement of surgeons in the assessment and management of these patients is essential, in that the majority of patients affected with hereditary neoplasms will, at some point, require resection of the target organs affected by specific gene mutations, with prophylactic or therapeutic intent, or both. As the pathogenesis of the known hereditary neoplasia syndromes becomes better understood at the molecular level, innovative targeted therapies will, inevitably, supplant or replace surgery as the primary treatment modality for these diseases. Until that time, however, surgeons will continue to play a prominent role in the care of patients with hereditary neoplasia syndromes. As is already occurring within many other clinical specialties, the incorporation of at least a basic understanding of the genetic mechanisms of disease transmission and expression are essential within the surgical specialties, as the two cases presented herein demonstrate. In this paper, we present two cases that illustrate many of the challenges inherent in the surgical management of patients with hereditary neoplasia syndromes: a patient with attenuated familial adenomatous polyposis syndrome, and a patient with multiple endocrine neoplasia syndrome, type 2-B.

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The Asp1822Val variant of the APC gene is a common polymorphism without clinical implications

Cited by 13 publications

References 6 publications

APC Asp1822Val and Gly2502Ser Polymorphisms and Risk of Colorectal Cancer and Adenoma

APC Asp1822Val and Gly2502Ser Polymorphisms and Risk of Colorectal Cancer and Adenoma

Presence of a TA Haplotype in the APC Gene Containing the Common 1822 Polymorphism and Colorectal Adenoma

Hereditary neoplasia syndromes and the role of the surgeon

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