Improved Molecular Diagnosis for Lynch Syndrome

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a hereditary predisposition to malignancy caused by germline mutations in DNA repair genes.

People with Lynch syndrome (LS) have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, and skin, and women with this disorder have a high risk of cancer of the ovaries and lining of the uterus.


Scientists at the Bellvitge Biomedical Research Institute (Barcelona, Spain) evaluated the role of the postmeiotic segregation increased 2 (PMS2) gene in LS by assessing the pathogenicity of variants of unknown significance (VUS) detected in the mutational analysis of PMS2 in a series of Spanish patients.

From a cohort of 202 LS suspected patients, 13 patients showing loss of PMS2 expression in tumors were screened for germline mutations in PMS2, using a long range polymerase chain reaction (PCR) based strategy and multiplex ligation dependent probe amplification (MLPA). Pathogenicity assessment of PMS2 VUS was performed evaluating clinicopathological data, frequency in control population and in silico and in vitro analyses at the ribonucleic acid (RNA) and protein level. PCR products were sequenced using a Big Dye Terminator Cycle Sequencing kit on the 3130XL Genetic Analyzer (Applied Biosystems; Foster City, CA, USA).

Mutational analysis of PMS2 is particularly complex since there are multiple pseudogenes with sequences similar to that of genes, but with no protein expression capacity. The investigators used a special methodology that avoids pseudogenes and identifies mutations in PMS2 in a more reliable way. Subsequently, the functional study of variants of unknown significance made by the scientists and those at the Johann Wolfgang Goethe-University (Frankfurt, Germany) has allowed classifying the variants identified in the PMS2 gene.

The authors detected pathogenic PMS2 mutations in 69% of patients harboring LS associated tumors with loss of PMS2 expression. In all, PMS2 mutations account for 6% of the LS cases identified. The comprehensive functional analysis was shown to have been useful in the classification of PMS2 VUS and contributes to refining the role of PMS2 in LS. The study was published on May 24, 2013, in the Journal of Medical Genetics.

Related Links:
Bellvitge Biomedical Research Institute
Applied Biosystems
Johann Wolfgang Goethe-University