A subset of cancers arises in individuals who are born with rare sequence variants that significantly alter their cancer risk. The discovery of such variants, like those in the BRCA1– and BRCA2 genes, has led to improved early cancer detection and the development of targeted therapies, ultimately reducing the cancer burden and improving prognosis of those carrying these mutations. Scientists at Amgen deCODE genetics department with other coworkers have discovered six novel genes with rare germline variants that associate with cancer risk. The findings are published today in Nature Genetics under the title “Gene-based burden tests of rare germline variants identify six cancer susceptibility genes”.
In this investigation, the researchers analyzed three large genetic datasets from individuals of European descent, including 130,991 cancer patients and 733,486 controls. Through a gene-based burden association analysis across 22 different cancer types, they found four novel genes associated with a risk of developing cancer: the autophagy-involved ATG12 for colorectal cancer, the thyroglobulin (TG) gene for thyroid cancer, the pro-apoptotic BIK for prostate cancer and CMTR2 for both lung cancer and cutaneous melanoma. The relative increase in cancer risk conferred by these variants was substantial (90-295%); additionally, the researchers found the first genes with rare variants that are associated with a decreased risk of cancer.
Specifically, loss of Aurora kinase B gene (AURKB) was found to protect against any cancer type. Aurora B inhibitors are already available for cancer therapy: barasertib, tozasertib, BRD-7880 and TAK-901 are already available and have completed phase I/II clinical trials. Similarly, loss of PPP1R15A (coding the Gadd-34 protein) was associated with 53% lower risk of breast cancer indicating that inhibition of PPP1R15A may be a therapeutic option for breast cancer. Gadd-34 is a DNA damage-inducible protein, that is involved in cellular resistance to drugs and ionizing radiations. An inhibitor of this protein is already known, Sephin-1, which is being investigated in misfolded protein-associated conditions.
This investigation overall revealed new insight into the biological mechanisms involved in cancer predisposition that will hopefully lead to better screening and treatment strategies.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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