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Gastroenterology. 2015 Nov;149(6):1446-53. doi: 10.1053/j.gastro.2015.07.052. Epub 2015 Aug 3.

Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.

Author information

1
Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois.
2
Centre for Epidemiology and Biostatistics, the University of Melbourne, Parkville, Victoria, Australia.
3
Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona.
4
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
5
Department of Medicine, Division of Oncology, Stanford University, California.
6
University of Michigan, Ann Arbor, Michigan.
7
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
8
University of Illinois at Chicago, Chicago, Illinois.
9
Dana-Farber Cancer Institute, Boston, Massachusetts.
10
City of Hope, Duarte, California.
11
Cleveland Clinic, Cleveland, Ohio.
12
University of California, San Francisco, California.
13
MD Anderson Cancer Center, Houston, Texas.
14
Ohio State University, Columbus, Ohio.
15
Creighton University School of Medicine, Omaha, Nebraska.
16
Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois. Electronic address: skupfer@medicine.bsd.uchicago.edu.

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.

KEYWORDS:

African Descent; Colon Cancer; DNA Repair; Hereditary Non-Polyposis Colorectal Cancer

PMID:
26248088
PMCID:
PMC4648287
DOI:
10.1053/j.gastro.2015.07.052
[Indexed for MEDLINE]
Free PMC Article

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