Clin Gastroenterol Hepatol. 2011 Jun;9(6):497-502. doi: 10.1016/j.cgh.2010.10.021. Epub 2010 Nov 5.

Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer.

Limburg PJ, Harmsen WS, Chen HH, Gallinger S, Haile RW, Baron JA, Casey G, Woods MO, Thibodeau SN, Lindor NM.

Source

Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA. limburg.paul@mayo.edu

Abstract

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.

Comment in

Lynch syndrome in young-onset colorectal cancer: reassessing the role of the MSH6 gene. [Clin Gastroenterol Hepatol. 2011]
Lynch syndrome in young-onset colorectal cancer: reassessing the role of the MSH6 gene.Giráldez MD, Castells A, Castellví-Bel S. Clin Gastroenterol Hepatol. 2011 Sep; 9(9):806. Epub 2011 Apr 8.
How helpful is age at colorectal cancer onset in finding hereditary nonpolyposis colorectal cancer? [Clin Gastroenterol Hepatol. 2011]
How helpful is age at colorectal cancer onset in finding hereditary nonpolyposis colorectal cancer?Lynch PM. Clin Gastroenterol Hepatol. 2011 Jun; 9(6):458-60. Epub 2011 Apr 11.

PMID:: 21056691; [PubMed - indexed for MEDLINE]
PMCID:: PMC3058119

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Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer.
Clin Gastroenterol Hepatol. 2011 Jun ;9(6):497-502. doi: 10.1016/j.cgh.2010.10.021. Epub 2010 Nov 5 .

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