R659X mutation in the MLH1 gene in hereditary non-polyposis colorectal cancer (HNPCC) in an Indian extended family.
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Date
2010-01
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Abstract
Background & objective: Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), is
a genetically heterogeneous disorder that is believed to account for 2–10 per cent of all the colorectal
cancer cases. The disease follows autosomal dominant inheritance pattern with high penetrance (85%)
and younger age of onset when compared to patients with sporadic tumours. HNPCC is associated
with germ-line mutations in the DNA mismatch repair (MMR) genes namely MLH1, MSH2, MSH6,
and PMS2. The present study was aimed at analyzing mismatch repair gene(s) in an extended Indian
family satisfying the Amsterdam criteria, and extending the analysis to general population to estimate
frequency of the mutations/polymorphisms observed.
Methods: A total 12 members of the HNPCC family were studied for genetic investigation. Ethnically
matched 250 normal individuals were also included as controls to study the observed mutations/
polymorphisms at population level.
Results: The analysis resulted in identification of a 1975C>T mutation in exon 17, resulting in substitution
of arginine residue with stop codon at codon 659. 655A>G substitution was also observed, resulting in
replacement of isoleucine with valine at codon 219. Similar analysis on 250 ethnically matched control
subjects revealed complete absence of R659X mutation, while I219V variant was found in 9.8 per cent
of the controls.
Interpretation & conclusion: R659X mutation correlates with disease phenotype, and 655A>G locus
is highly polymorphic. Our study suggested that R659X substitution was prime cause for the disease
phenotype in this family. I219V substitution is a polymorphism having no association with the disease
onset or segregation. The family members harbouring this mutation were advised to be under regular
medical surveillance.
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Keywords
colorectal cancer, gastric cancer, HNPCC, Lynch syndrome, MLH1 gene
Citation
Singh Rajender, Singh Pooja, Kumar M V Kranthi, Karwasra Rajendra, Singh Lalji, Thangaraj Kumarasamy. R659X mutation in the MLH1 gene in hereditary non-polyposis colorectal cancer (HNPCC) in an Indian extended family. Indian Journal of Medical Research. 2010 Jan; 131(1): 64-70.