NEW YORK – By focusing on rare variants found in the germline genetic sequences from individuals with or without cancer, a team led by investigators at Amgen subsidiary Decode Genetics and the University of Iceland unearthed half a dozen previously unappreciated cancer susceptibility genes using sequence data for hundreds of thousands of European ancestry individuals with or without a prior cancer diagnosis.
For the study, published in Nature Genetics on Tuesday, researchers at Decode Genetics, the University of Iceland, and other centers in Iceland and beyond brought together genotyping, targeted sequencing, or whole-genome sequencing data for 130,991 individuals diagnosed with cancer, searching for rare germline variants that differed from those found in 733,486 cancer-free control individuals.
The participants were enrolled through studies performed in Iceland, the UK, and Norway, and represented individuals with 22 distinct cancer types.
By bringing in gene burden analyses, the team highlighted 34 cancer risk-related genes, including six previously unappreciated genes associated with increased or decreased risk of specific cancer types.
"Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis, and cell stress response as a focus point for developing new therapeutics," co-first and co-corresponding author Erna Ivarsdottir, with Decode Genetics/Amgen, and her colleagues reported.
Along with cancer risk genes identified in the past, for example, the researchers uncovered four genes linked to increased risk of prostate, colorectal, thyroid, or lung cancer and cutaneous melanoma. In particular, they saw ties between prostate cancer and rare germline variants in an apoptosis-related gene called BIK, as well as thyroid cancer-associated variants in the TG gene.
In addition, the team found that rare germline alterations in a gene called ATG12, which has been implicated in autophagic processes, were overrepresented in colorectal cancer cases, whereas the risk of lung cancer and cutaneous melanoma ticked up in individuals carrying rare germline changes in the CMTR2 gene.
Loss-of-function alterations and missense genetic variants in the TG gene were also implicated in benign thyroid conditions such as hypothyroidism in the team's subsequent phenome-wide association analysis involving some 4,000 phenotyped cancer cases and controls.
In two remaining new genes uncovered in the cancer-related germline analyses, meanwhile, the team highlighted rare variants in the PPP1R15A and AURKB genes that appeared to have protective effects, dialing down the risk of developing breast cancer or cancer overall, respectively.
"We found that heterozygous loss of PPP1R15A is associated with 53 percent lower risk of breast cancer, and the carriers were, on average, older than noncarriers when diagnosed with breast cancer," the authors reported.
That, in turn, pointed to an apparent tumor suppressor role for an "integrated stress response" (ISR) pathway previously implicated in the growth or suppression of cancer, depending on the broader context, the researchers explained. They noted that the latest results suggest some forms of ISR inhibition may curb or combat breast cancer development.
"Overall, our study demonstrates the power of large-scale whole-genome sequencing in the search for cancer-associating genes and potential therapeutic targets," the authors concluded.