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Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors.
Clin Cancer Res. 2007 Jan 01; 13(1):356-61.CC

Abstract

PURPOSE

There is a paucity of data quantifying the familial risk of colorectal cancer associated with mismatch repair (MMR)-deficient and MMR-stable tumors. To address this, we analyzed a population-based series of 1,042 colorectal cancer probands with verified family histories.

EXPERIMENTAL DESIGN

Constitutional DNA from probands was systematically screened for MYH variants and those with cancers displaying microsatellite instability (MSI) for germ-line MMR mutations; diagnoses of familial adenomatous polyposis and juvenile polyposis were established based on clinical phenotype and mutational analysis. Familial colorectal cancer risks were enumerated from age-, sex-, and calendar-specific population incidence rates. Segregation analysis was conducted to derive a model of the residual familial aggregation of colorectal cancer.

RESULTS

Germ-line predisposition to colorectal cancer was identified in 37 probands [3.4%; 95% confidence interval (95% CI), 2.4-4.6]: 29 with MLH1/MSH2 mutations, 2 with familial adenomatous polyposis, 1 with juvenile polyposis, and 5 with biallelic MYH variants. The risk of colorectal cancer in first-degree relatives of probands with MSI and MMR-stable cancers was increased 5.01-fold (95% CI, 3.73-6.59) and 1.31-fold (95% CI, 1.07-1.59), respectively. MSH2/MLH1 mutations were responsible for 50% of the overall excess familial risk and 80% of the risk associated with MSI cancers but 32% of the familial risk was unaccounted for by known loci. Genetic models based on major gene loci did not provide a better explanation of the residual familial aggregation than a simple polygenic model.

CONCLUSIONS

The information from our analyses should be useful in quantifying familial risks in clinical practice and in the design of studies to identify novel disease alleles.

Authors+Show Affiliations

Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17200375

Citation

Aaltonen, Lauri, et al. "Explaining the Familial Colorectal Cancer Risk Associated With Mismatch Repair (MMR)-deficient and MMR-stable Tumors." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 13, no. 1, 2007, pp. 356-61.
Aaltonen L, Johns L, Järvinen H, et al. Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clin Cancer Res. 2007;13(1):356-61.
Aaltonen, L., Johns, L., Järvinen, H., Mecklin, J. P., & Houlston, R. (2007). Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 13(1), 356-61.
Aaltonen L, et al. Explaining the Familial Colorectal Cancer Risk Associated With Mismatch Repair (MMR)-deficient and MMR-stable Tumors. Clin Cancer Res. 2007 Jan 1;13(1):356-61. PubMed PMID: 17200375.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. AU - Aaltonen,Lauri, AU - Johns,Louise, AU - Järvinen,Heikki, AU - Mecklin,Jukka-Pekka, AU - Houlston,Richard, PY - 2007/1/4/pubmed PY - 2007/4/14/medline PY - 2007/1/4/entrez SP - 356 EP - 61 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 13 IS - 1 N2 - PURPOSE: There is a paucity of data quantifying the familial risk of colorectal cancer associated with mismatch repair (MMR)-deficient and MMR-stable tumors. To address this, we analyzed a population-based series of 1,042 colorectal cancer probands with verified family histories. EXPERIMENTAL DESIGN: Constitutional DNA from probands was systematically screened for MYH variants and those with cancers displaying microsatellite instability (MSI) for germ-line MMR mutations; diagnoses of familial adenomatous polyposis and juvenile polyposis were established based on clinical phenotype and mutational analysis. Familial colorectal cancer risks were enumerated from age-, sex-, and calendar-specific population incidence rates. Segregation analysis was conducted to derive a model of the residual familial aggregation of colorectal cancer. RESULTS: Germ-line predisposition to colorectal cancer was identified in 37 probands [3.4%; 95% confidence interval (95% CI), 2.4-4.6]: 29 with MLH1/MSH2 mutations, 2 with familial adenomatous polyposis, 1 with juvenile polyposis, and 5 with biallelic MYH variants. The risk of colorectal cancer in first-degree relatives of probands with MSI and MMR-stable cancers was increased 5.01-fold (95% CI, 3.73-6.59) and 1.31-fold (95% CI, 1.07-1.59), respectively. MSH2/MLH1 mutations were responsible for 50% of the overall excess familial risk and 80% of the risk associated with MSI cancers but 32% of the familial risk was unaccounted for by known loci. Genetic models based on major gene loci did not provide a better explanation of the residual familial aggregation than a simple polygenic model. CONCLUSIONS: The information from our analyses should be useful in quantifying familial risks in clinical practice and in the design of studies to identify novel disease alleles. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/17200375/Explaining_the_familial_colorectal_cancer_risk_associated_with_mismatch_repair__MMR__deficient_and_MMR_stable_tumors_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17200375 DB - PRIME DP - Unbound Medicine ER -