Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol

Area of Science:

• Oncology
• Genetics
• Bioinformatics

Background:

• Next-generation sequencing (NGS) in cancer research can uncover clinically significant germline variants.
• Understanding patient preferences for returning incidental findings is crucial for ethical research practices.

Purpose of the Study:

• To determine patient preferences for the return of incidental germline results from cancer genomic sequencing.
• To assess the prevalence of pathogenic germline variants (PGVs) in advanced cancer patients undergoing targeted exome sequencing.

Main Methods:

• Targeted exome sequencing of 202 genes was performed on tumor and normal DNA from 1000 advanced cancer patients.
• Actionable variants were identified in 19 genes, including those recommended by ACMG and PALB2.
• Patient preferences for return of results were collected, and incidental findings were confirmed via CLIA testing with genetic counseling.

Main Results:

• Of 1000 patients, 43 (4.3%) had likely PGVs in cancer-related genes.
• Previously unrecognized pathogenic germline mutations were found in 2.3% of patients.
• 99% of patients consented for germline testing desired to receive incidental results, with all proceeding to genetic counseling and validation.

Conclusions:

• Genomic sequencing in cancer research frequently identifies actionable germline variants.
• A robust plan for returning germline results, including genetic counseling, is essential for responsible genomic research and clinical integration.