title: Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.
abstract: OBJECTIVE
  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.affiliation: Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois.
authors.forename: Rodrigo Santa Cruz
authors.initials: RS
authors.lastname: Guindalini
authors.affiliation: Centre for Epidemiology and Biostatistics, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.affiliation: Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Gulden
authors.affiliation: Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University, California.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.affiliation: University of Michigan, Ann Arbor, Michigan.
authors.forename: Victoria
authors.initials: V
authors.lastname: Raymond
authors.affiliation: University of Michigan, Ann Arbor, Michigan.
authors.forename: Elena
authors.initials: E
authors.lastname: Stoffel
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Hall
authors.affiliation: University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Chinedu I
authors.initials: CI
authors.lastname: Ukaegbu
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Ilana
authors.initials: I
authors.lastname: Solomon
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weitzel
authors.affiliation: Cleveland Clinic, Cleveland, Ohio.
authors.forename: Matthew
authors.initials: M
authors.lastname: Kalady
authors.affiliation: University of California, San Francisco, California.
authors.forename: Amie
authors.initials: A
authors.lastname: Blanco
authors.affiliation: University of California, San Francisco, California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Terdiman
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gladis A
authors.initials: GA
authors.lastname: Shuttlesworth
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lynch
authors.affiliation: Ohio State University, Columbus, Ohio.
authors.forename: Heather
authors.initials: H
authors.lastname: Hampel
authors.affiliation: Creighton University School of Medicine, Omaha, Nebraska.
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.affiliation: Centre for Epidemiology and Biostatistics, the University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.affiliation: Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois.
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.affiliation: Center for Clinical Cancer Genetics, the University of Chicago, Chicago, Illinois. Electronic address: skupfer@medicine.bsd.uchicago.edu.
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Kupfer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005190:Family; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
keywords: African Descent; Colon Cancer; DNA Repair; Hereditary Non-Polyposis Colorectal Cancer