Association of CHEK2 Low-Risk Variants with Cancer Phenotypes

Academic Background

The CHEK2 gene (OMIM 604373) is one of the susceptibility genes for breast cancer. Monoallelic pathogenic variants (PVs) in CHEK2 are associated with an increased risk of breast, colorectal, kidney, and thyroid cancers. However, there is limited research on the phenotype of biallelic CHEK2 variants, particularly low-risk (LR) variants such as p.I157T, p.S428F, and p.T476M. These low-risk variants are relatively common in the population, but their cancer risk in a biallelic state remains poorly understood. Therefore, this study aims to explore the relationship between biallelic low-risk variants in CHEK2 and cancer phenotypes, especially in comparison to monoallelic variants and wild-type (WT) individuals.

Source of the Paper

This paper was co-authored by Brittany L. Bychkovsky, Nihat B. Agaoglu, Carolyn Horton, and others, affiliated with multiple research institutions including Dana-Farber Cancer Institute, Harvard Medical School, and Ambry Genetics. The paper was published on January 2, 2025, in JAMA Network Open, titled “Double CHEK2 Pathogenic and Low-Risk Variants and Associated Cancer Phenotypes.”

Study Design and Methods

Study Design

This study is a retrospective observational cohort study involving individuals who underwent genetic testing at a diagnostic laboratory (Ambry Genetics) between July 1, 2012, and September 30, 2019. A total of 36,821 individuals were included, of whom 3,783 (10.3%) carried CHEK2 pathogenic or low-risk variants. The primary objective was to compare the cancer phenotypes of individuals with biallelic low-risk variants (2 LR variants) and those with one pathogenic variant and one low-risk variant (1 PV + 1 LR variant) against wild-type, monoallelic low-risk, and monoallelic pathogenic variant carriers.

Study Population and Sample

The study population consisted of 36,821 individuals who underwent multi-gene panel testing, of whom 92.1% were female, with a median testing age of 53 years. Individuals with pathogenic variants in other genes were excluded. The study categorized individuals with CHEK2 variants into the following groups: - Wild-type (WT): 33,034 individuals - Monoallelic low-risk variant (single LR variant): 1,566 individuals - Monoallelic pathogenic variant (single PV): 2,167 individuals - Biallelic low-risk variants (2 LR variants): 13 individuals - One pathogenic variant and one low-risk variant (1 PV + 1 LR variant): 20 individuals - Biallelic pathogenic variants (2 PVs): 21 individuals

Data Analysis

Statistical analysis was performed using R software (version 4.0.4). Cancer incidence, multiple primary cancers, breast cancer, and bilateral breast cancer rates were calculated for different genotype groups. Two-sided statistical tests were used, with a significance level set at p < 0.05.

Results

Cancer Incidence

The study found that individuals with biallelic low-risk variants (2 LR variants) had a cancer incidence (76.9%) similar to that of wild-type (69.8%) and monoallelic low-risk variant carriers (70.9%). However, individuals with one pathogenic variant and one low-risk variant (1 PV + 1 LR variant) had a higher cancer incidence (95.0%) compared to monoallelic pathogenic variant carriers (76.8%), although the difference was not statistically significant.

Multiple Primary Cancers

The incidence of multiple primary cancers was highest in individuals with biallelic pathogenic variants (47.6%), followed by those with one pathogenic variant and one low-risk variant (35.0%), biallelic low-risk variant carriers (30.8%), monoallelic pathogenic variant carriers (14.6%), wild-type individuals (13.8%), and monoallelic low-risk variant carriers (12.8%).

Breast Cancer

Breast cancer incidence was highest in individuals with biallelic pathogenic variants (100%), followed by those with one pathogenic variant and one low-risk variant (86.7%), monoallelic pathogenic variant carriers (67.1%), biallelic low-risk variant carriers (60.0%), monoallelic low-risk variant carriers (57.5%), and wild-type individuals (52.7%). A similar trend was observed for bilateral breast cancer.

Discussion and Conclusions

Discussion

This study suggests that CHEK2 low-risk variants (p.I157T, p.S428F, and p.T476M) may exhibit higher cancer penetrance when co-occurring with pathogenic variants. However, individuals with biallelic low-risk variants did not show a higher cancer risk compared to monoallelic low-risk variant carriers. This finding indicates that low-risk variants may act as modifiers in conjunction with other genetic or environmental factors.

Conclusions

The study concludes that biallelic low-risk variants in CHEK2 do not exhibit higher cancer penetrance than monoallelic low-risk variants. However, low-risk variants may increase cancer risk, particularly for breast cancer and multiple primary cancers, when co-occurring with pathogenic variants. These findings have significant implications for genetic testing laboratories and genetic counseling, especially in family planning and cancer screening.

Highlights of the Study

1. Broad Study Population: The study included over 36,000 individuals, covering various CHEK2 variant types, providing new insights into the cancer risk associated with low-risk variants.
2. Modifier Role of Low-Risk Variants: The study found that low-risk variants may increase cancer risk when co-occurring with pathogenic variants, offering a new direction for future cancer risk assessments.
3. Clinical Applications: The results have important implications for genetic testing laboratories and genetic counseling, particularly in family planning and cancer screening.

Limitations of the Study

Despite the large scale of the study, the number of individuals with biallelic CHEK2 variants was relatively small, which may affect the statistical power of the results. Additionally, the study population was predominantly White, which may limit the generalizability of the findings. Future studies with larger and more diverse populations are needed to further validate these results.

This report provides a detailed overview of the study on the association between CHEK2 low-risk variants and cancer phenotypes, covering the background, methods, results, and clinical implications. The findings offer important insights for future cancer risk assessments and genetic counseling.