Scientists identify six genes linked to cancer risk, revealing insights into cancer predisposition that may enhance screening and treatment.
Study: Gene-based burden tests of rare germline variants identify six cancer susceptibility genes. Image Credit: romakhan3595/Shutterstock.com
A study recently published in Nature Genetics identifies four genes associated with increased cancer risk and four genes with rare variants associated with reduced cancer risk.
Background
A fraction of cancers have been found to develop in individuals with germline pathogenic variants in genes associated with increased cancer risk. Germline variants identified in the BRCA1 and BRCA2 genes have significantly improved early-stage cancer detection and targeted drug development.
Genetic variants associated with high cancer risk are rare because of the strong negative selection. Whole-genome sequencing is effective in identifying variants predicted to cause a loss of function of a gene.
This type of analysis in founder populations, such as the Icelanders, has been found to facilitate the discovery process. The founder effect allows negatively selected variants to become more common than those in more outbred populations.
In this study, scientists screened for rare germline variants associated with cancer risk in three large genetic datasets, including 130,991 cancer cases and 733,486 controls from Iceland, Norway, and the United Kingdom.
Important observations
The scientists conducted gene-based rare variant burden associations with 22 cancer sites across three large genetic datasets.
The analysis identified 34 genes associated with cancer risk, including previously unidentified rare variants in six genes.
Genes associated with reduced cancer risk
The study found that heterozygous loss of PPP1R15A is associated with a 53% lower risk of breast cancer. PPP1R15A encodes a key regulatory protein of the integrated stress response pathway, which is activated in response to various stress factors.
Activation of the integrated stress response pathway is associated with a global downregulation of protein synthesis and selective activation of stress-responsive genes to maintain homeostasis. However, a continuous stress response may trigger cell death.
The integrated stress response pathway plays a dual role in cancer by serving as both a tumor suppressor and a promotor. Studies investigating the activation of integrated stress response pathways as a therapeutic strategy have produced mixed results.
While some studies have shown reduced proliferation and metastasis of breast cancer cells following PPP1R15A inhibition, some have found that cancer cells may utilize the integrated stress response pathway to promote survival and growth.
The current study reported that loss of germline PPP1R15A protects against breast cancer, which supports the tumor-suppressive role of the integrated stress response pathway.
Similar to PPP1R15A, the study found that loss of AURKB was associated with a 16% lower risk of any cancer, irrespective of cancer sites. AURKB encodes aurora kinase B, which acts as a key regulator of mitosis.
Aurora kinase B has been found to be overexpressed in various cancers. Several clinical trials have been conducted to explore the anti-cancer effects of small molecule inhibitors targeting this protein.
Genes associated with increased cancer risk
The study identified rare coding variants in BIK that were associated with an increased risk of prostate cancer. BIK is a member of the BH3-only proapoptotic group of proteins.
Existing evidence indicates that BIK acts as a tumor suppressor in several human tissues. The current study showed that BIK is highly expressed in prostate tissues and that loss of function variants in BIK are exclusively associated with prostate cancer risk.
Similar to prostate cancer, an increased risk of colorectal cancer was found to be associated with loss of function variants in ATG12. ATG12 encodes autophagy-related 12 (ATG12) protein that plays an important role in the autophagy process.
Existing evidence indicates that autophagy acts as a tumor suppressive process at the early cancer stage; however, at the advanced cancer stage, autophagy helps cancer cells survive and metastasize.
Besides autophagy, ATG12 regulates cell death by inactivating pro-survival Bcl-2 proteins. Ectopic expression of ATG12 has been found to induce colon cancer cell death. These observations collectively highlight the tumor-suppressive role of ATG12 in colorectal cancer.
The study further identified loss of function variants in CMTR2 that were particularly associated with increased risk of lung adenocarcinoma and cutaneous melanoma. CMTR2 was found to be associated with cancer sites that have strong environmental risk factors, such as smoking for lung cancer and ultraviolet radiation for skin cancer.
CMTR2 is a methyltransferase that acts as a key regulator of gene expression. Several studies have shown tumor suppressive activities of CMTR2.
TG was the fourth gene identified in the study to be associated with an increased risk of thyroid cancer. TG encodes thyroglobulin, which is the precursor of thyroid hormone.
Previous studies have shown that both missense and nonsense variants in the TG gene are associated with several benign thyroid conditions.
Study significance
The study identifies four genes with rare variants, namely BIK, CMTR2, TG, and ATG12, which are associated with a significantly increased risk of cancer.
The study also identifies two genes, namely AURKB and PPP1R15A, which are associated with reduced cancer risk.
Overall, the study findings emphasize autophagy, apoptosis, and cell stress response as a focus point for developing new therapeutics.
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