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Evolutionary Analysis Reveals Number, Nature of Mutations Under Positive Selection in Cancer

NEW YORK (GenomeWeb) – By analyzing genomic data for thousands of tumors, a team from the UK and Belgium has concluded that as few as one mutation and as many as 10 can spur cancer development, depending on the cancer type and genes affected.

Researchers from the Wellcome Trust Sanger Institute, the University of Cambridge, and elsewhere took a molecular evolution-informed approach to examine positive and negative selection patterns — along with the alterations driving cancer formation — in more than 7,600 tumors. Their findings, published online today in Cell, indicate that many mutations are tolerated and not subjected to negative selection, while positive selection plays a prominent role in cancer formation.

When the team focused on cancer driver mutations falling in protein-coding sequences in the tumor collection, it found that four substitution mutations are typically subjected to positive selection in cancer, on average. Still, the number of driver mutations under positive selection varied dramatically between the 29 cancer types considered, ranging from one or fewer coding mutations per thyroid or testicular tumor to almost 10 tumor drivers in cancer types such as colorectal cancer or endometrial cancer.

The research shows that "across cancer types a relatively consistent small number of mutated genes is required to convert a single normal cell into a cancer cell, but that the specific genes chosen differ according to cancer type," Sanger Institute Director Michael Stratton, a co-author on the study, said in a statement.

For their analyses, he and his colleagues established models for narrowing in on driver mutations under selection in data for 7,664 tumors assessed for the Cancer Genome Atlas project and five healthy tissues, flagging instances of enhanced or diminished mutation across a given gene, gene set, or exome.

By considering the ratio of non-synonymous to synonymous mutations and other features in available genomic profiles for the tumors, the team quantified the effects of positive and negative selection in the cancer types.

Diving into the positively selected genes, in particular, offered a glimpse at the number of driver mutations as well as the genes that are most often affected. There, the researchers identified almost 200 mutated genes under positive selection in cancer — a collection that included known cancer contributors and genes not previously implicated as cancer driver candidates.

"There is already much insight into the most important genes involved in cancer; but there are many more genes yet to be discovered," first author Iñigo Martincorena, a researcher at the Sanger Institute, said in a statement. "We will need to bring together even larger numbers of cancers studied by DNA sequencing, into the tens of thousands, to find these elusive genes."