TY - JOUR
T1 - Prevalence of Alterations in DNA Mismatch Repair Genes in Patients With Young-Onset Colorectal Cancer
AU - Limburg, Paul J.
AU - Harmsen, William S.
AU - Chen, Helen H.
AU - Gallinger, Steven
AU - Haile, Robert W.
AU - Baron, John A.
AU - Casey, Graham
AU - Woods, Michael O.
AU - Thibodeau, Stephen N.
AU - Lindor, Noralane M.
N1 - Funding Information:
Funding Funding for and conduct of the gene mutation analyses were provided by Myriad Genetic Laboratories, Salt Lake City, UT. The Colon Cancer Family Registry is supported by NIH National Cancer Institute grants CA074783 ( Ontario Registry for Studies of Familial Colorectal Cancer ), U01 CA074800 ( Mayo Clinic Cooperative Family Registry for Colon Cancer Studies ), and U01 CA074799 ( USC Familial Colorectal Neoplasia Collaborative Group ), as well as U01 CA097735 ( Australian Colorectal Cancer Family Registry ), UO1 CA074794 ( Seattle Colorectal Cancer Family Registry ), and U01 CA074806 ( University of Hawaii Colorectal Cancer Family Registry ).
PY - 2011/6
Y1 - 2011/6
N2 - Background & Aims: Direct germline analysis could be used to screen high-risk patients for mutations in DNA mismatch repair genes associated with Lynch Syndrome. We examined the prevalence of mutations in MLH1, MSH2, and MSH6 in a population-based sample of patients with young-onset (age <50 years) colorectal cancer (CRC). Methods: Young-onset CRC cases were randomly selected from 3 Colon Cancer Family Registry sites. DNA was extracted from peripheral blood leukocytes; MLH1, MSH2, and MSH6 were sequenced, and duplication and deletion analyses was performed for MLH1 and MSH2. Results were reported as deleterious or suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry results in secondary analyses. Results: Among 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% confidence interval [CI], 2.8%-9.9%), 12 had likely neutral alterations (6.2%; 95% CI, 3.2%-10.5%), 14 had variants of uncertain significance (7.2%; 95% CI, 4.0%-11.8%), 2 had a likely neutral alteration and a variant of uncertain significance (1.0%; 95% CI, 0.1%-3.7%), and 156 had no alteration detected (80.0%; 95% CI, 73.7%-85.4%). Sensitivity, specificity, and positive and negative predictive values for detecting deleterious/suspected deleterious mutations, based on ACII, were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185), respectively; based on immunohistochemistry these values were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18), and 99.3% (136/137), respectively. Conclusions: In a population-based sample of young-onset CRC cases, germline mutations in MLH1, MSH, and/or MSH6 were more prevalent than reported for CRC patients overall. Because only about 5% of young-onset CRC cases had confirmed deleterious or suspected deleterious mutations, further comparative effectiveness research is needed to determine the most appropriate screening strategy for Lynch Syndrome in this high-risk group.
AB - Background & Aims: Direct germline analysis could be used to screen high-risk patients for mutations in DNA mismatch repair genes associated with Lynch Syndrome. We examined the prevalence of mutations in MLH1, MSH2, and MSH6 in a population-based sample of patients with young-onset (age <50 years) colorectal cancer (CRC). Methods: Young-onset CRC cases were randomly selected from 3 Colon Cancer Family Registry sites. DNA was extracted from peripheral blood leukocytes; MLH1, MSH2, and MSH6 were sequenced, and duplication and deletion analyses was performed for MLH1 and MSH2. Results were reported as deleterious or suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry results in secondary analyses. Results: Among 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% confidence interval [CI], 2.8%-9.9%), 12 had likely neutral alterations (6.2%; 95% CI, 3.2%-10.5%), 14 had variants of uncertain significance (7.2%; 95% CI, 4.0%-11.8%), 2 had a likely neutral alteration and a variant of uncertain significance (1.0%; 95% CI, 0.1%-3.7%), and 156 had no alteration detected (80.0%; 95% CI, 73.7%-85.4%). Sensitivity, specificity, and positive and negative predictive values for detecting deleterious/suspected deleterious mutations, based on ACII, were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185), respectively; based on immunohistochemistry these values were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18), and 99.3% (136/137), respectively. Conclusions: In a population-based sample of young-onset CRC cases, germline mutations in MLH1, MSH, and/or MSH6 were more prevalent than reported for CRC patients overall. Because only about 5% of young-onset CRC cases had confirmed deleterious or suspected deleterious mutations, further comparative effectiveness research is needed to determine the most appropriate screening strategy for Lynch Syndrome in this high-risk group.
KW - Cancer Genetics
KW - Colon Cancer
KW - Genetics
KW - Mutation Analysis
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U2 - 10.1016/j.cgh.2010.10.021
DO - 10.1016/j.cgh.2010.10.021
M3 - Article
C2 - 21056691
AN - SCOPUS:79957469844
SN - 1542-3565
VL - 9
SP - 497
EP - 502
JO - Clinical Gastroenterology and Hepatology
JF - Clinical Gastroenterology and Hepatology
IS - 6
ER -