Original protocol for presumed germline pathogenic variants in cancer genome profiling tests
Cancer Genetics and Therapeutics
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Primary Categories:
- Genomic Medicine
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Secondary Categories:
- Genomic Medicine
Introduction:
Cancer genome profiling (CGP) tests often reveal presumed germline pathogenic variants (PGPVs) that go beyond cancer predisposition syndromes. While Japanese institutions have widely adopted the "Guidelines for the Communication Process in Genomic Medicine: Focusing on Comprehensive Tumor Genomic Profiling," we have independently developed our own protocol since 2019. In anticipation of the implementation of whole genome sequencing (WGS) in Japanese cancer genomic medicine, our protocol uniquely includes not only cancer predisposition syndromes but also other genetic diseases.
Methods:
At Okayama University Hospital in Japan, we developed a comprehensive protocol for PGPVs in CGP. The development process was based on both Japanese guidelines and international recommendations, including American College of Medical Genetics and Genomics Secondary Findings list version 3.2, American Society of Clinical Oncology guidelines, European Society for Medical Oncology Precision Medicine Working Group, and National Comprehensive Cancer Network guidelines. The protocol includes a custom gene list of 148 genes, which extends beyond hereditary cancer syndromes to include various genetic disease, anticipating WGS implementation. The list intentionally included genes with lower levels of evidence to provide broader screening capabilities. Our framework emphasized initial phenotype assessment to determine appropriate testing approaches. For tumor-only testing, special attention was given to variants in mismatch repair genes and BRCA1/2 regardless of variant allele frequency. In addition, specific genes (APC, NF1, PTEN, RB1, STK11, TP53) required careful evaluation of phenotype and family history.
Results:
The following are two cases where the PGPVs have been recommended to consult with the department of genetic medicine and confirmatory testing using our original protocol. Case 1: The proband was a patient in their 50s with pancreatic cancer. Tumor-only CGP revealed a PGPV in the ATM. This variant was reported as pathogenic in public databases, and based on the patient's phenotype and family history of breast cancer, confirmatory genetic testing was recommended. The genetic test result was positive, providing valuable information for the patient's relatives. Case 2: The proband was a patient in their 40s with breast cancer. Tumor-only CGP identified a missense variant in TP53 with a high variant allele frequency (67.7%). Given the patient's son's history of acute myeloid leukemia, Li-Fraumeni syndrome (LFS) was suspected and confirmatory testing was recommended. The test result was negative, which helped exclude the diagnosis of LFS.
Conclusion:
Our protocol represents a comprehensive approach to management of PGPVs that uniquely addresses both cancer predisposition syndromes and other genetic disease. The protocol's structured framework, particularly its emphasis on initial phenotype assessment and confirmatory testing criteria, helps to ensure appropriate variant evaluation and disclosure. While this strategy may identify more variants with lower levels of evidence, it allows for the detection of rare genetic diseases that may be missed in cancer-focused protocol. Though developed at a single institution, this systematic approach could be applicable to other institutions implementing CGP. Regular updates will be necessary as testing technologies evolve and new evidence emerges regarding the clinical significance of germline variants.
Cancer genome profiling (CGP) tests often reveal presumed germline pathogenic variants (PGPVs) that go beyond cancer predisposition syndromes. While Japanese institutions have widely adopted the "Guidelines for the Communication Process in Genomic Medicine: Focusing on Comprehensive Tumor Genomic Profiling," we have independently developed our own protocol since 2019. In anticipation of the implementation of whole genome sequencing (WGS) in Japanese cancer genomic medicine, our protocol uniquely includes not only cancer predisposition syndromes but also other genetic diseases.
Methods:
At Okayama University Hospital in Japan, we developed a comprehensive protocol for PGPVs in CGP. The development process was based on both Japanese guidelines and international recommendations, including American College of Medical Genetics and Genomics Secondary Findings list version 3.2, American Society of Clinical Oncology guidelines, European Society for Medical Oncology Precision Medicine Working Group, and National Comprehensive Cancer Network guidelines. The protocol includes a custom gene list of 148 genes, which extends beyond hereditary cancer syndromes to include various genetic disease, anticipating WGS implementation. The list intentionally included genes with lower levels of evidence to provide broader screening capabilities. Our framework emphasized initial phenotype assessment to determine appropriate testing approaches. For tumor-only testing, special attention was given to variants in mismatch repair genes and BRCA1/2 regardless of variant allele frequency. In addition, specific genes (APC, NF1, PTEN, RB1, STK11, TP53) required careful evaluation of phenotype and family history.
Results:
The following are two cases where the PGPVs have been recommended to consult with the department of genetic medicine and confirmatory testing using our original protocol. Case 1: The proband was a patient in their 50s with pancreatic cancer. Tumor-only CGP revealed a PGPV in the ATM. This variant was reported as pathogenic in public databases, and based on the patient's phenotype and family history of breast cancer, confirmatory genetic testing was recommended. The genetic test result was positive, providing valuable information for the patient's relatives. Case 2: The proband was a patient in their 40s with breast cancer. Tumor-only CGP identified a missense variant in TP53 with a high variant allele frequency (67.7%). Given the patient's son's history of acute myeloid leukemia, Li-Fraumeni syndrome (LFS) was suspected and confirmatory testing was recommended. The test result was negative, which helped exclude the diagnosis of LFS.
Conclusion:
Our protocol represents a comprehensive approach to management of PGPVs that uniquely addresses both cancer predisposition syndromes and other genetic disease. The protocol's structured framework, particularly its emphasis on initial phenotype assessment and confirmatory testing criteria, helps to ensure appropriate variant evaluation and disclosure. While this strategy may identify more variants with lower levels of evidence, it allows for the detection of rare genetic diseases that may be missed in cancer-focused protocol. Though developed at a single institution, this systematic approach could be applicable to other institutions implementing CGP. Regular updates will be necessary as testing technologies evolve and new evidence emerges regarding the clinical significance of germline variants.