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Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.
Gastroenterology 2015; 149(6):1446-53G

Abstract

BACKGROUND & AIMS

African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome.

METHODS

We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk, studying members of the mutation-carrying families.

RESULTS

We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%-83.9%) for men and 29.7% (95% CI, 8.31%-76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44-56.5).

CONCLUSIONS

We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population.

Authors+Show Affiliations

Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois.Centre for Epidemiology and Biostatistics, the University of Melbourne, Parkville, Victoria, Australia.Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois.Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona.Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.Department of Medicine, Division of Oncology, Stanford University, California.University of Michigan, Ann Arbor, Michigan.University of Michigan, Ann Arbor, Michigan.Fox Chase Cancer Center, Philadelphia, Pennsylvania.University of Illinois at Chicago, Chicago, Illinois.Dana-Farber Cancer Institute, Boston, Massachusetts.City of Hope, Duarte, California.City of Hope, Duarte, California.Cleveland Clinic, Cleveland, Ohio.University of California, San Francisco, California.University of California, San Francisco, California.MD Anderson Cancer Center, Houston, Texas.MD Anderson Cancer Center, Houston, Texas.Ohio State University, Columbus, Ohio.Creighton University School of Medicine, Omaha, Nebraska.Centre for Epidemiology and Biostatistics, the University of Melbourne, Parkville, Victoria, Australia.Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois.Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois. Electronic address: skupfer@medicine.bsd.uchicago.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26248088

Citation

Guindalini, Rodrigo Santa Cruz, et al. "Mutation Spectrum and Risk of Colorectal Cancer in African American Families With Lynch Syndrome." Gastroenterology, vol. 149, no. 6, 2015, pp. 1446-53.
Guindalini RS, Win AK, Gulden C, et al. Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology. 2015;149(6):1446-53.
Guindalini, R. S., Win, A. K., Gulden, C., Lindor, N. M., Newcomb, P. A., Haile, R. W., ... Kupfer, S. S. (2015). Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology, 149(6), pp. 1446-53. doi:10.1053/j.gastro.2015.07.052.
Guindalini RS, et al. Mutation Spectrum and Risk of Colorectal Cancer in African American Families With Lynch Syndrome. Gastroenterology. 2015;149(6):1446-53. PubMed PMID: 26248088.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. AU - Guindalini,Rodrigo Santa Cruz, AU - Win,Aung Ko, AU - Gulden,Cassandra, AU - Lindor,Noralane M, AU - Newcomb,Polly A, AU - Haile,Robert W, AU - Raymond,Victoria, AU - Stoffel,Elena, AU - Hall,Michael, AU - Llor,Xavier, AU - Ukaegbu,Chinedu I, AU - Solomon,Ilana, AU - Weitzel,Jeffrey, AU - Kalady,Matthew, AU - Blanco,Amie, AU - Terdiman,Jonathan, AU - Shuttlesworth,Gladis A, AU - Lynch,Patrick M, AU - Hampel,Heather, AU - Lynch,Henry T, AU - Jenkins,Mark A, AU - Olopade,Olufunmilayo I, AU - Kupfer,Sonia S, Y1 - 2015/08/03/ PY - 2015/01/28/received PY - 2015/07/20/revised PY - 2015/07/22/accepted PY - 2015/8/7/entrez PY - 2015/8/8/pubmed PY - 2016/4/8/medline KW - African Descent KW - Colon Cancer KW - DNA Repair KW - Hereditary Non-Polyposis Colorectal Cancer SP - 1446 EP - 53 JF - Gastroenterology JO - Gastroenterology VL - 149 IS - 6 N2 - BACKGROUND & AIMS: African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome. METHODS: We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk, studying members of the mutation-carrying families. RESULTS: We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%-83.9%) for men and 29.7% (95% CI, 8.31%-76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44-56.5). CONCLUSIONS: We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/26248088/Mutation_spectrum_and_risk_of_colorectal_cancer_in_African_American_families_with_Lynch_syndrome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(15)01084-7 DB - PRIME DP - Unbound Medicine ER -