Incidental MSH6 Germline Pathogenic Variant Identified through Tumor-Only Comprehensive Genomic Profiling in a...

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Small cell lung cancer (SCLC) is an aggressive malignancy.
• Germline mutations in mismatch repair (MMR) genes, like MSH6, are associated with Lynch syndrome, increasing cancer risk.
• Accurate germline variant identification is crucial for patient management and family screening.

Purpose of the Study:

• To investigate the utility of comprehensive genomic profiling (CGP) in identifying germline mutations in a small cell lung cancer (SCLC) patient.
• To confirm a diagnosis of Lynch syndrome based on genetic findings.
• To emphasize the importance of a tumor-to-germline testing approach and cascade testing in at-risk relatives.

Main Methods:

• A patient with limited-disease small cell lung cancer (LD-SCLC) underwent CGP during second-line therapy.
• Immunohistochemistry (IHC) was performed on tumor tissue to assess MMR protein expression.
• Germline genetic testing and cascade testing were conducted for family members.

Main Results:

• CGP revealed a germline MSH6 frameshift mutation in the SCLC patient.
• Lung tumor IHC showed retained MSH6 expression, but a prior colon cancer specimen demonstrated loss of MSH6 and deficient MMR.
• Germline testing confirmed Lynch syndrome, and cascade testing identified the mutation in the patient's daughter.

Conclusions:

• A tumor-to-germline workflow can uncover actionable germline mutations in cancer patients.
• MSH6 germline mutations can lead to Lynch syndrome, necessitating genetic counseling and cascade testing.
• Careful interpretation of genetic variants and MMR protein expression is vital, especially when discordant results arise between tumor and germline testing.