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Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.
JAMA. 2011 Jun 08; 305(22):2304-10.JAMA

Abstract

CONTEXT

Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome.

OBJECTIVE

To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes.

DESIGN, SETTING, AND PARTICIPANTS

Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed.

MAIN OUTCOME MEASURE

Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias.

RESULTS

Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations.

CONCLUSIONS

MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years.

Authors+Show Affiliations

Université Lyon 1, Centre National de la Recherche Scientifique UMR5558, Villeurbanne, Centre Léon Bérard, Lyon, Cedex 08, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

21642682

Citation

Bonadona, Valérie, et al. "Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome." JAMA, vol. 305, no. 22, 2011, pp. 2304-10.
Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22):2304-10.
Bonadona, V., Bonaïti, B., Olschwang, S., Grandjouan, S., Huiart, L., Longy, M., Guimbaud, R., Buecher, B., Bignon, Y. J., Caron, O., Colas, C., Noguès, C., Lejeune-Dumoulin, S., Olivier-Faivre, L., Polycarpe-Osaer, F., Nguyen, T. D., Desseigne, F., Saurin, J. C., Berthet, P., ... Bonaïti-Pellié, C. (2011). Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA, 305(22), 2304-10. https://doi.org/10.1001/jama.2011.743
Bonadona V, et al. Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome. JAMA. 2011 Jun 8;305(22):2304-10. PubMed PMID: 21642682.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. AU - Bonadona,Valérie, AU - Bonaïti,Bernard, AU - Olschwang,Sylviane, AU - Grandjouan,Sophie, AU - Huiart,Laetitia, AU - Longy,Michel, AU - Guimbaud,Rosine, AU - Buecher,Bruno, AU - Bignon,Yves-Jean, AU - Caron,Olivier, AU - Colas,Chrystelle, AU - Noguès,Catherine, AU - Lejeune-Dumoulin,Sophie, AU - Olivier-Faivre,Laurence, AU - Polycarpe-Osaer,Florence, AU - Nguyen,Tan Dat, AU - Desseigne,Françoise, AU - Saurin,Jean-Christophe, AU - Berthet,Pascaline, AU - Leroux,Dominique, AU - Duffour,Jacqueline, AU - Manouvrier,Sylvie, AU - Frébourg,Thierry, AU - Sobol,Hagay, AU - Lasset,Christine, AU - Bonaïti-Pellié,Catherine, AU - ,, PY - 2011/6/7/entrez PY - 2011/6/7/pubmed PY - 2011/6/11/medline SP - 2304 EP - 10 JF - JAMA JO - JAMA VL - 305 IS - 22 N2 - CONTEXT: Providing accurate estimates of cancer risks is a major challenge in the clinical management of Lynch syndrome. OBJECTIVE: To estimate the age-specific cumulative risks of developing various tumors using a large series of families with mutations of the MLH1, MSH2, and MSH6 genes. DESIGN, SETTING, AND PARTICIPANTS: Families with Lynch syndrome enrolled between January 1, 2006, and December 31, 2009, from 40 French cancer genetics clinics participating in the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study; 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6) were analyzed. MAIN OUTCOME MEASURE: Age-specific cumulative cancer risks estimated using the genotype restricted likelihood (GRL) method accounting for ascertainment bias. RESULTS: Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%-70%) for MLH1 mutation carriers, 48% (95% CI, 30%-77%) for MSH2, and 12% (95% CI, 8%-22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%-80%), 21% (95% CI, 8%-77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%-65%), 24% (95% CI, 3%-52%), and 1% (95% CI, 0%-3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%-7%) for endometrial cancer nor 1% (95% CI, 0%-3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations. CONCLUSIONS: MSH6 mutations are associated with markedly lower cancer risks than MLH1 or MSH2 mutations. Lifetime ovarian and endometrial cancer risks associated with MLH1 or MSH2 mutations were high but do not increase appreciably until after the age of 40 years. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/21642682/Cancer_risks_associated_with_germline_mutations_in_MLH1_MSH2_and_MSH6_genes_in_Lynch_syndrome_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2011.743 DB - PRIME DP - Unbound Medicine ER -