Multimethod Testing Strategy May Benefit Patients with Lynch Syndrome

Image © A and N Photography/ Shutterstock.com

A new three-pronged approach may help better identify patients who have Lynch syndrome, an inherited cancer susceptibility syndrome that predisposes individuals to various cancers, according to researchers at Baylor College of Medicine.

Results are published in the September 2015 online edition of The Journal of Molecular Diagnostics.^{1, 2}

Researchers describe a multimethod strategy to overcome existing technological limitations by more accurately identifying PMS2 gene mutations. They report that this new approach may help improve diagnosis and support appropriate genetic counseling and medical management.

The majority of cases of Lynch syndrome are attributed to heterozygous germline mutations in the DNA mismatch repair genes MLH1 and MSH2. The current methods for DNA sequencing and deletion analysis can successfully detect these mutations. However, at least 16% or more cannot be analyzed with these methods because individuals have a mutation in another mismatch repair gene, PMS2.

About 3% of colorectal cancers are due to Lynch syndrome and close blood relatives of patients with Lynch syndrome have a 50% chance of inheritance. The role that PMS2 genetic mutations play in Lynch syndrome has been underestimated due to technological hurdles. “PMS2 mutations have been grossly underestimated due to technical difficulties in handling complex genomic structure. A comprehensive approach to unequivocally identify PMS2 mutations remained to be developed,” said lead investigator Lee-Jun C. Wong, PhD, who is with Baylor College of Medicine in Houston.

The investigators have come up with a three-part strategy. It included combining targeted capture next-generation sequencing (NGS), multiplex ligation-dependent probe amplification, and long-range PCR followed by NGS to simultaneously detect point mutations and copy number changes of the PMS2 gene. “The results from three methods serve as cross validation for enhanced accuracy and reduced turnaround time,” said co-investigator Victor Wei Zhang, MD, PhD, who is in the Department of Molecular and Human Genetics at Baylor.

The researchers believe that this combined strategy provides a new tool for reliable molecular analysis of any genes containing multiple copies of highly homologous sequences. 

In January 2009, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group issued recommendations regarding genetic testing strategies in patients with newly diagnosed colorectal cancer. Although only 2% to 4% of colorectal cancers are due to Lynch syndrome, identification of these individuals is seen as a critical way to improve their own health as well as the health of their blood relatives.

Individuals with Lynch syndrome have a 16% risk of developing a second primary colorectal cancer within 10 years, and first-degree and second-degree family members with Lynch syndrome face a 35% to 45% risk of a new cancer by age 70.

References:

• Li J, Dai H, Feng Y, et al. (2015). A Comprehensive Strategy for Accurate Mutation Detection of the Highly Homologous PMS2. The Journal of Molecular Diagnostics, 17(5): 545–553.
• The Journal of Molecular Diagnostics Press Release. (2015). New Strategy Improves Detection of Genetic Mutations in Hereditary Colorectal Cancer.