Study shows the combined effect of inherited and acquired mutations on cancer development

The common belief that tumors arise via activation of a few genes that "drive" cancer development is unsupported by a widespread investigation into those genes and others in three large patient genetic databases, according to a study led by Yale Cancer Center (YCC) researchers. The findings were published online today in the Journal Nature Communications.

The pattern the Yale team uncovered shows that cancer develops due to combined effects of many gene variants originating both as the germline mutations, or inherited alterations in genes, and somatic mutations, changes that genes acquire after birth and over a lifespan. Some inherited germline variants do increase the risk of developing cancer, but additional somatic mutations are required for cancer to develop, usually in the third or fourth decade of life. Somatic mutations are random mutations that build up in cells as a person ages, and can substantially increase due to environmental effects, such as sunlight, cigarette smoking, diet, and exposure to various carcinogens.

In the new study, scientists found the proportion of germline variants to somatic mutations is linked to the age of cancer onset. Cancers that occur before age 50 -; which account for half of all cases -; have a greater degree of germline variations relative to somatic mutations. Likewise, investigators report that as people 50 and older age, their cancer is characterized by increasing levels of somatic mutations compared to germline variants. Thus, in younger people, a diagnosis of cancer is caused by a greater contribution of germline alterations, and late-onset cancer cancers are more dependent on acquired somatic mutations, said the researchers.

The strange thing about cancer driver genes, which had long been thought to be necessary and sufficient for cancer development, is that they do not seem to exist. There is always some additional genetic abnormality that is also required for a 'cancer driver' to manifest its transforming effect.

Our work suggests to us that genes commonly considered 'cancer drivers' may be more appropriately called 'cancer enablers' because, under the right constellation of other genomic events, they enable transformation of a normal cell into cancer. In short, we hypothesize that the combined effect of other co-occurring somatic mutations and inherited germline variants together conspire to bring about cancer development."

Lajos Pusztai, M.D., D.Phil., professor of medicine (medical oncology), co-director of the Genetics and Genomics Research Program at YCC, and senior author of the study

This new understanding of cancer could have profound implications for prevention and treatment, according to the researchers. Instead of targeting just one or several "cancer drivers" in a given cancer type, effective cancer control may require a broader analysis of individual patient genomes and treatment that is specifically aligned with both germline and somatic mutations.

In this study, including postdoctoral fellow Tao Qing, Ph.D., the investigators analyzed three different large data sets -; The Cancer Genome Atlas (TCGA), the Pancancer Analysis of Whole Genomes (PCAWG) and the United Kingdom's Biobank (UKBB). The team is currently working on a "cancer gene affectedness score" that could be calculated for an individual and would sum up the combined effect of all deleterious germline variants. the researchers said this score could be used as new personalized cancer risk measure.

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