Mutation Spectrum and Risk of Colorectal Cancer in African American Families With Lynch Syndrome

Rodrigo Santa Cruz Guindalini; Aung Ko Win; Cassandra Gulden; Noralane M. Lindor; Polly A. Newcomb; Robert W. Haile; Victoria Raymond; Elena Stoffel; Michael Hall; Xavier Llor; Chinedu I. Ukaegbu; Ilana Solomon; Jeffrey Weitzel; Matthew Kalady; Amie Blanco; Jonathan Terdiman; Gladis A. Shuttlesworth; Patrick M. Lynch; Heather Hampel; Henry T. Lynch; Mark A. Jenkins; Olufunmilayo I. Olopade; Sonia S. Kupfer


Gastroenterology. 2015;149(6):1446-1453. 

In This Article

Abstract and Introduction


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.


In the United States, colorectal cancer (CRC) is the second leading cause of cancer death. African Americans (AAs) have the highest CRC incidence and mortality of all populations.[1] The age at CRC diagnosis in AAs is younger overall,[2] and there is higher incidence of proximal and more advanced cancers in this population.[3–6] These epidemiological differences have prompted some to recommend earlier CRC screening for AAs, starting at age 45.[7,8] Causes of CRC disparities are not completely understood, and research has focused predominantly on socioeconomic factors. There is a growing body of evidence supporting an important role for biological factors,[9] including differences in genetic susceptibility[10,11] and tumor biology[6,12–14] between African and European American individuals with CRC. However, knowledge about the most common inherited CRC syndrome, Lynch syndrome, in the AA population is lacking.

Lynch syndrome, or hereditary nonpolyposis colorectal cancer, accounts for 3% to 5% of all cases of CRC[15] and is caused by mutations in 5 genes: MLH1, MSH2, MSH6, PMS2, and EPCAM. In addition to CRC, individuals with Lynch syndrome have an increased risk of uterine, ovarian, gastric, ureter, and renal pelvis cancers; and pancreas, small bowel, bile duct, brain, and sebaceous skin cancers.[16,17] Previous clinic-based studies performed in subjects of European descent estimate lifetime risk for CRC between 22.4% and 47%[18,19] when controlling for ascertainment bias. The overall proportions of MLH1, MSH2, MSH6, and PMS2 mutations in Lynch syndrome patients of European descent are 32%, 39%, 14%, and 15%, respectively.[20]

Although 3 novel MMR mutations (2 in MLH1 and 1 in MSH2) were described in AA families in 1999,[21] there have been no additional reports of Lynch syndrome in AAs, despite higher incidence of early onset and proximal colon cancers in this population. Moreover, it is not known whether the spectrum of mutations and cancer risks in AAs are the same as in individuals of European descent, given different population histories and genetic diversity. Given this gap in the field, we sought to determine the mutation spectrum, phenotype, and risk of cancers in AAs with mutations in mismatch repair (MMR) genes.