Frequency and pathogenicity of hereditary tumor-associated pathogenic variants in the Japanese general population using ToMMo 54KJPN data
Cancer Genetics and Therapeutics
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Primary Categories:
- Population Genetics
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Secondary Categories:
- Population Genetics
Introduction:
The frequency of pathogenic variants in hereditary tumors varies across populations and regions. The Tohoku Medical Megabank Organization (ToMMo) has been progressively releasing a whole-genome sequencing database of the general population in the Tohoku region of Japan, and in 2023, it released whole-genome sequencing data covering approximately 54,000 individuals (ToMMo 54KJPN). This study aims to identify unique characteristics of variant information specific to the Japanese population through secondary analysis of this data.
Methods:
To confirm the frequencies of pathogenic variants that may affect major hereditary tumor-related genes, we selected variants in BRCA1, BRCA2 and MMR related genes (MLH1, MSH2, PMS2 and MSH6) from ToMMo-54KJPN data (https://jmorp.megabank.tohoku.ac.jp/downloads/tommo-54kjpn-20230626-af_snvindelall). Next, we annotated these variants using ANNOVAR software with the ClinVar dataset (20230702, https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/). Through the analysis of 54KJPN, we comprehensively identified the prevalence of pathogenic variants registered in ClinVar for major hereditary tumor-related genes in the general Japanese population.
Results:
The carrier frequency of pathogenic variants in BRCA1/2 genes within the general population was 5.350 × 10^-3. Comparisons with the JOHBOC (Japanese Organization of Hereditary Breast and Ovarian Cancer) registry, variant registry of BRCA1/2 genes based on analysis of cancer patients and their families, revealed interesting findings. For example, the BRCA1:c.5096G>A variant, classified as an "Intermediate risk" variant, was widely present in the general population. Additionally, the frequency of variants within the BCCR (breast cancer cluster region) or OCCR (ovarian cancer cluster region) varied depending on the timing of data aggregation. Since BRCA1/2 genetic testing was covered by public insurance in Japan as a companion diagnostic test for ovarian cancer, the detection frequency of variants in the OCCR has noticeably increased. Furthermore, the total carrier frequency of pathogenic variants in MMR-related genes was unexpectedly high at 7.472 × 10^-3. A review of each variant frequency indicated that the MLH1:c.1039-1G>T splicing variant, evaluated as pathogenic in ClinVar, had a notably high frequency of 4.356 × 10^-3 in 54KJPN dataset. This variant might represent a genetic polymorphism specific to the Japanese population, suggesting a need for re-evaluation of its pathogenicity.
Conclusion:
The frequency of HBOC in the Japanese population is significantly higher than previously anticipated, and there is a risk of misdiagnosing of Lynch syndrome if one solely relies on ClinVar registrations. This study suggests that referencing variant frequency information specific to the Japanese population is essential when assessing the pathogenicity of variants and registered annotations in genetic databases.
The frequency of pathogenic variants in hereditary tumors varies across populations and regions. The Tohoku Medical Megabank Organization (ToMMo) has been progressively releasing a whole-genome sequencing database of the general population in the Tohoku region of Japan, and in 2023, it released whole-genome sequencing data covering approximately 54,000 individuals (ToMMo 54KJPN). This study aims to identify unique characteristics of variant information specific to the Japanese population through secondary analysis of this data.
Methods:
To confirm the frequencies of pathogenic variants that may affect major hereditary tumor-related genes, we selected variants in BRCA1, BRCA2 and MMR related genes (MLH1, MSH2, PMS2 and MSH6) from ToMMo-54KJPN data (https://jmorp.megabank.tohoku.ac.jp/downloads/tommo-54kjpn-20230626-af_snvindelall). Next, we annotated these variants using ANNOVAR software with the ClinVar dataset (20230702, https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/). Through the analysis of 54KJPN, we comprehensively identified the prevalence of pathogenic variants registered in ClinVar for major hereditary tumor-related genes in the general Japanese population.
Results:
The carrier frequency of pathogenic variants in BRCA1/2 genes within the general population was 5.350 × 10^-3. Comparisons with the JOHBOC (Japanese Organization of Hereditary Breast and Ovarian Cancer) registry, variant registry of BRCA1/2 genes based on analysis of cancer patients and their families, revealed interesting findings. For example, the BRCA1:c.5096G>A variant, classified as an "Intermediate risk" variant, was widely present in the general population. Additionally, the frequency of variants within the BCCR (breast cancer cluster region) or OCCR (ovarian cancer cluster region) varied depending on the timing of data aggregation. Since BRCA1/2 genetic testing was covered by public insurance in Japan as a companion diagnostic test for ovarian cancer, the detection frequency of variants in the OCCR has noticeably increased. Furthermore, the total carrier frequency of pathogenic variants in MMR-related genes was unexpectedly high at 7.472 × 10^-3. A review of each variant frequency indicated that the MLH1:c.1039-1G>T splicing variant, evaluated as pathogenic in ClinVar, had a notably high frequency of 4.356 × 10^-3 in 54KJPN dataset. This variant might represent a genetic polymorphism specific to the Japanese population, suggesting a need for re-evaluation of its pathogenicity.
Conclusion:
The frequency of HBOC in the Japanese population is significantly higher than previously anticipated, and there is a risk of misdiagnosing of Lynch syndrome if one solely relies on ClinVar registrations. This study suggests that referencing variant frequency information specific to the Japanese population is essential when assessing the pathogenicity of variants and registered annotations in genetic databases.