2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-A GENOME-FIRST APPROACH TO GERMLINE <em>CHEK2</em> CANCER RISK IN THE GEISINGER AND UK BIOBANK COHORTS

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A study using a "genome-first" approach examined the association between CHEK2 gene variants and cancer risk. The study analyzed two large cohorts, Geisinger and UK Biobank, which included individuals with and without CHEK2 variants. The variants were classified using variant annotation tools and cancer diagnoses were obtained from electronic health records, cancer registries, and death registries. Statistical analyses were conducted to assess the differences in cancer risks and survival rates.<br /><br />The study confirmed that pathogenic truncating variants (PTV) in CHEK2 are associated with an increased risk of cancer. Specifically, PTV variants were significantly associated with hematologic malignancies and solid organ cancers such as breast, prostate, kidney, bladder, and thyroid cancers. In the UK Biobank cohort, pathogenic missense variants (PMV) were found to be associated with lymphoid leukemia and chronic lymphocytic leukemia, while myeloid leukemia was more likely associated with PTV carriers.<br /><br />Age-dependent cancer penetrance was higher in CHEK2 carriers compared to non-carriers in both cohorts. Survival rates did not differ between all CHEK2 carriers and non-carriers in the Geisinger cohort, but CHEK2 carriers had lower overall survival rates in the UK Biobank cohort. However, there was no difference in survival rates between carriers and non-carriers who were already diagnosed with cancer in both cohorts.<br /><br />Furthermore, cancer cause mortality was higher in CHEK2 carriers compared to non-carriers in both cohorts. These findings can assist in genetic counseling for CHEK2 carriers, especially those without any cancer. The study highlights the importance of considering different variant types and their specific associations with cancer risks when evaluating CHEK2-related cancers.

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Presenting Author - Sun Young Kim, MD.PhD; Co-Author - Mark Ramos, PhD; Co-Author - Jung Kim, PhD; Co-Author - Jeremy S. Haley, MS; Co-Author - Shanker H. Rao, Ph.D; Co-Author - Uyenlinh Mirshahi, PhD; Co-Author - Barry Graubard, Ph.D; Co-Author - Hormuzd Katki, PhD; Co-Author - David Carey, PhD; Co-Author - Douglas R. Stewart, MD;

Meta Tag

Cancer Syndromes

Genotype-Phenotype Correlations

Phenotype

Population Genetics

Co-Author Mark Ramos, PhD

Co-Author Jung Kim, PhD

Co-Author Jeremy S. Haley, MS

Co-Author Shanker H. Rao, Ph.D

Co-Author Uyenlinh Mirshahi, PhD

Co-Author Barry Graubard, Ph.D

Co-Author Hormuzd Katki, PhD

Co-Author David Carey, PhD

Co-Author Douglas R. Stewart, MD

Presenting Author Sun Young Kim, MD.PhD

Keywords

genome-first approach

CHEK2 gene variants

cancer risk

large cohorts

pathogenic truncating variants (PTV)

solid organ cancers

lymphoid leukemia

myeloid leukemia

age-dependent cancer penetrance

genetic counseling