Journal article
CHEK2 founder variants and thyroid cancer risk
Thyroid (New York, N.Y.), Vol.34(4), pp.477-483
04/2024
DOI: 10.1089/thy.2023.0529
PMCID: PMC10998703
PMID: 38279823
Abstract
Germline pathogenic variants in CHEK2 are associated with a moderate increase in the lifetime risk for breast cancer. Increased risk for other cancers, including non-medullary thyroid cancer (NMTC), has also been suggested. To date, data implicating CHEK2 variants in NMTC predisposition primarily derive from studies within Poland, driven by a splice site variant (c.444+1G>A) that is uncommon in other populations. In contrast, the predominant CHEK2 variants in non-Polish populations are c.1100del and c.470T>C/p.I157T, representing 61.1% and 63.8%, respectively, of all CHEK2 pathogenic variants in two large US-based commercial laboratory datasets. To further delineate the impact of common CHEK2 variants on thyroid cancer, we aimed to investigate the association of three CHEK2 founder variants (c.444+1G>A, c.1100del, and c.470T>C/p.Ile157Thr) on NMTC susceptibility in three groups of unselected NMTC patients.
The presence of three CHEK2 founder variants were assessed within three groups: (1) 1544 NMTC patients (and 1593 controls) from previously published GWAS analyses, (2) 789 NMTC patients with germline exome sequencing (ORIEN Avatar), and (3) 499 NMTC patients with germline sequence data available in The Cancer Genome Atlas (TCGA). A case-control study design was utilized with odds ratios calculated by comparison of all three groups with the OSU GWAS control group.
The predominant Polish variant (c.444+1G>A) was present in only one case. The proportion of patients with c.1100del was 0.92% in the GWAS group, 1.65% in the ORIEN Avatar group, and 0.80% in the TCGA group. The odds ratios (with 95% confidence intervals) for NMTC associated with c.1100del were 1.71 (0.73-4.29), 2.64 (0.95-7.63), and 2.5 (0.63-8.46), respectively. The proportion of patients with c.470T>C/p.I157T was 0.91% in the GWAS group, 0.76% in the ORIEN Avatar group, and 0.80% in the TCGA group, respectively. The odds ratios (with 95% confidence intervals) for NMTC associated with c.470T>C/p.I157T were 1.75 (0.74-4.39), 1.52 (0.42-4.96), and 2.31 (0.58-7.90), respectively.
Our analyses of unselected patients with NMTC suggest that CHEK2 variants c.1100del and c.470T>C/p.I157T have only a modest impact on thyroid cancer risk. These results provide important information for providers regarding the relatively low magnitude of thyroid cancer risk associated with these CHEK2 variants.
Details
- Title: Subtitle
- CHEK2 founder variants and thyroid cancer risk
- Creators
- Pamela Brock - The Ohio State UniversitySandya Liyanarachchi - The Ohio State UniversityTaina Tuulikki Nieminen - University of HelsinkiCarlos Chan - University of IowaWendy Kohlmann - Huntsman Cancer InstituteLeigh Anne Stout - Indiana UniversitySong Yao - Roswell Park Cancer InstituteAmanda La Greca - University of Colorado DenverKirk E Jensen - Uniformed Services University of the Health SciencesJill Kolesar - University of KentuckyBodour Salhia - University of Southern CaliforniaPat Gulhati - Rutgers, The State University of New JerseyJ Kevin Hicks - Moffitt Cancer CenterMatthew D Ringel - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- Thyroid (New York, N.Y.), Vol.34(4), pp.477-483
- DOI
- 10.1089/thy.2023.0529
- PMID
- 38279823
- PMCID
- PMC10998703
- NLM abbreviation
- Thyroid
- ISSN
- 1050-7256
- eISSN
- 1557-9077
- Language
- English
- Electronic publication date
- 01/27/2024
- Date published
- 04/2024
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Surgery; Radiation Oncology
- Record Identifier
- 9984549557202771
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