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

Rodrigo Santa Cruz Guindalini, Aung Ko Win, Cassandra Gulden, Noralane Morey 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. LynchMark A. Jenkins, Olufunmilayo I. Olopade, Sonia S. Kupfer

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background and 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.

Original languageEnglish (US)
Pages (from-to)1446-1453
Number of pages8
JournalGastroenterology
Volume149
Issue number6
DOIs
StatePublished - Nov 1 2015

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Hereditary Nonpolyposis Colorectal Neoplasms
African Americans
Colorectal Neoplasms
Mutation
DNA Mismatch Repair
Confidence Intervals
Genes
Neoplasms
Referral and Consultation
Retrospective Studies

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Guindalini, R. S. C., 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), 1446-1453. https://doi.org/10.1053/j.gastro.2015.07.052

Mutation Spectrum and Risk of Colorectal Cancer in African American Families with Lynch Syndrome. / Guindalini, Rodrigo Santa Cruz; Win, Aung Ko; Gulden, Cassandra; Lindor, Noralane Morey; Newcomb, Polly A.; Haile, Robert W.; Raymond, Victoria; Stoffel, Elena; Hall, Michael; Llor, Xavier; Ukaegbu, Chinedu I.; Solomon, Ilana; Weitzel, Jeffrey; Kalady, Matthew; Blanco, Amie; Terdiman, Jonathan; Shuttlesworth, Gladis A.; Lynch, Patrick M.; Hampel, Heather; Lynch, Henry T.; Jenkins, Mark A.; Olopade, Olufunmilayo I.; Kupfer, Sonia S.

In: Gastroenterology, Vol. 149, No. 6, 01.11.2015, p. 1446-1453.

Research output: Contribution to journalArticle

Guindalini, RSC, Win, AK, Gulden, C, Lindor, NM, Newcomb, PA, Haile, RW, Raymond, V, Stoffel, E, Hall, M, Llor, X, Ukaegbu, CI, Solomon, I, Weitzel, J, Kalady, M, Blanco, A, Terdiman, J, Shuttlesworth, GA, Lynch, PM, Hampel, H, Lynch, HT, Jenkins, MA, Olopade, OI & Kupfer, SS 2015, 'Mutation Spectrum and Risk of Colorectal Cancer in African American Families with Lynch Syndrome', Gastroenterology, vol. 149, no. 6, pp. 1446-1453. https://doi.org/10.1053/j.gastro.2015.07.052
Guindalini, Rodrigo Santa Cruz ; Win, Aung Ko ; Gulden, Cassandra ; Lindor, Noralane Morey ; Newcomb, Polly A. ; Haile, Robert W. ; Raymond, Victoria ; Stoffel, Elena ; Hall, Michael ; Llor, Xavier ; Ukaegbu, Chinedu I. ; Solomon, Ilana ; Weitzel, Jeffrey ; Kalady, Matthew ; Blanco, Amie ; Terdiman, Jonathan ; Shuttlesworth, Gladis A. ; Lynch, Patrick M. ; Hampel, Heather ; Lynch, Henry T. ; Jenkins, Mark A. ; Olopade, Olufunmilayo I. ; Kupfer, Sonia S. / Mutation Spectrum and Risk of Colorectal Cancer in African American Families with Lynch Syndrome. In: Gastroenterology. 2015 ; Vol. 149, No. 6. pp. 1446-1453.
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abstract = "Background and 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",
author = "Guindalini, {Rodrigo Santa Cruz} and Win, {Aung Ko} and Cassandra Gulden and Lindor, {Noralane Morey} and Newcomb, {Polly A.} and Haile, {Robert W.} and Victoria Raymond and Elena Stoffel and Michael Hall and Xavier Llor and Ukaegbu, {Chinedu I.} and Ilana Solomon and Jeffrey Weitzel and Matthew Kalady and Amie Blanco and Jonathan Terdiman and Shuttlesworth, {Gladis A.} and Lynch, {Patrick M.} and Heather Hampel and Lynch, {Henry T.} and Jenkins, {Mark A.} and Olopade, {Olufunmilayo I.} and Kupfer, {Sonia S.}",
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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 Morey

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.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Background and 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.

AB - Background and 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.

KW - African Descent

KW - Colon Cancer

KW - DNA Repair

KW - Hereditary Non-Polyposis Colorectal Cancer

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DO - 10.1053/j.gastro.2015.07.052

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