CHEK2 Founder Variants and Thyroid Cancer Risk

Area of Science:

• Genetics and Genomics
• Oncology
• Cancer Predisposition Syndromes

Background:

• Germline pathogenic variants in the CHEK2 gene are linked to increased breast cancer risk.
• Previous studies suggested a possible association between CHEK2 variants and non-medullary thyroid cancer (NMTC) risk, primarily based on data from Polish populations.
• Common CHEK2 variants in non-Polish populations, such as c.1100del and c.470T>C/p.I157T, differ from those predominantly studied in Poland.

Purpose of the Study:

• To investigate the association of three common CHEK2 founder variants (c.444+1G>A, c.1100del, and c.470T>C/p.Ile157Thr) with NMTC susceptibility.
• To evaluate the impact of these specific CHEK2 variants on NMTC risk in diverse, unselected patient cohorts outside of Poland.

Main Methods:

• A case-control study design was employed, analyzing three distinct groups of unselected NMTC patients.
• Genetic data from Genome-Wide Association Study (GWAS) analyses (1544 NMTC cases, 1593 controls), ORIEN Avatar exome sequencing (789 NMTC cases), and The Cancer Genome Atlas (TCGA) germline sequencing (499 NMTC cases) were utilized.
• The frequency of the three selected CHEK2 variants was assessed, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

Main Results:

• The Polish-specific variant c.444+1G>A was found in only one NMTC case.
• The CHEK2 c.1100del variant showed ORs for NMTC ranging from 1.71 to 2.64 across the study groups.
• The CHEK2 c.470T>C/p.I157T variant demonstrated ORs for NMTC between 1.52 and 2.31 across the cohorts.

Conclusions:

• The CHEK2 variants c.1100del and c.470T>C/p.I157T appear to confer only a modest increase in the risk of developing non-medullary thyroid cancer.
• These findings are crucial for healthcare providers, indicating a relatively low magnitude of thyroid cancer risk associated with these specific common CHEK2 variants in non-Polish populations.
• The study highlights the importance of considering population-specific variant frequencies when assessing cancer predisposition.