Genetic testing for hereditary nonpolyposis colorectal cancer

Area of Science:

• Oncology
• Genetics
• Gastroenterology

Background:

• Hereditary Nonpolyposis Colorectal Cancer (HNPCC) accounts for approximately 20% of colorectal cancers.
• HNPCC is an autosomal dominant syndrome linked to mismatch repair gene mutations.
• Screening for HNPCC involves assessing microsatellite instability (MSI), immunohistochemistry (IHC), and genetic sequencing.

Purpose of the Study:

• To evaluate the initial results of MSI, IHC, and genetic sequencing for mismatch repair gene mutations in patients suspected of HNPCC.
• To assess the utility of these tests in patients meeting Amsterdam Criteria (AC) or those with young age onset (YAO) colorectal cancer.

Main Methods:

• Patients were identified through a high-risk colorectal cancer clinic.
• Testing was performed on patients meeting AC or YAO (<40 years).
• MSI (5 NIH markers), IHC (MLH1, MSH2), and genetic sequencing (MLH1, MSH2) were utilized.

Main Results:

• Of 14 AC patients, 5 had MSH2 mutations and 2 had MLH1 variants; 3/4 with MSH2 mutations showed MSI-High (MSI-H) and MSH2 loss on IHC.
• Of 10 YAO patients, no mutations were identified, but 2/7 with available tissue showed MSI-H.
• Overall, genetic testing yielded mutations in only 5/14 AC patients, with variants of unknown significance in 2 others.

Conclusions:

• Genetic testing for HNPCC, even with strict criteria, has limited mutation detection rates.
• MSI and IHC are appropriate screening methods for HNPCC in young-onset colorectal cancer patients.
• Further investigation is needed to optimize HNPCC screening protocols.