Study finds rules for cancer drivers
Cancer has come to be known as a “disease of the genome.” Any number of alterations to an individual’s genetic code – the sequence of As, Cs, Gs, and Ts that serve as our biological blueprint – has the potential to make a cell malfunction and proliferate into cancer tumors. Identifying the genetic changes that lead to cancer – and the rules that govern those changes – has been a key goal in the field of cancer genomics. It is a task made more challenging by the diversity of cancer types and the seemingly distinct biology of different types of cancers.
This week, researchers from the Genome Characterization Center (GCC) at the Broad Institute announced that they had identified some rules that apply across cancers for a specific type of genetic mutation – somatic copy number alterations (SCNAs). SCNAs are deletions or duplications of certain regions of the genome, and are some of the most common mutations that occur in cancer.
In the largest such study to date, the team looked at nearly 5,000 cancer samples from across 12 cancer types – including breast, bladder, and colon cancer, among others – for patterns in the occurrence of SCNAs. Their study, which appears in Nature Genetics, identified common ways in which these copy number changes are generated in cancer, and located specific genes and regions involved.
“Our goal was to find patterns that are universal across cancer,” said Matthew Meyerson, a senior associate member at the Broad and one of the study’s co-senior authors. “Finding these patterns across cancer types suggests that different cancers tend to result from similar or even the same underlying events, and therefore arise from many of the same pathways.”
The findings also serve as a database that researchers can draw from in future investigations.
“This paper gives researchers a large compendium of new genes and processes to look at that may play an essential role in individual cancers, enabling the research community to identify new causes and molecular pathways that may one day be targeted to treat cancer,” said Rameen Beroukhim, the lead investigator of the study and a co-senior author of the paper. Beroukhim is an associate member of the Broad, and an assistant professor at Dana-Farber Cancer Institute and Harvard Medical School.
The team found that, across cancer types, somatic copy number alterations adhered to the following rules:
Whole-genome doubling is associated with higher rates of every other type of copy number alteration. Whole-genome doubling is one of the major sources of copy number changes in tumors, occurring in about 37% of cancers. As the term suggests, it happens when the entire genome of an organism duplicates, so instead of producing the usual two of each chromosome, a person will produce four. The GCC study found that, in cancer, whole-genome doubling tends to trigger additional copy number alterations. The team found that the genes TP53 and CCNE1 – which had previously been linked to whole-genome doubling – were associated with these cancer-related events. They also found two new genes whose mutations contribute to the doubling of cancer genomes: PPP2R2A and PPP2R1A.
SCNAs that occur within chromosomes and those that occur at the ends of chromosomes are most likely caused by different mechanisms. The team found that copy number alterations that begin at the protective ends of chromosomes (called “telomeres”) tend to be longer than alterations that occur within chromosomes. The significant difference between these two types of SCNAs suggests that two distinct mechanisms are at work: one that causes copy number alterations that extend at the telomere, and a different one that can create internal, chromosomal copy number changes.
There are 140 regions of the genome that seem to be affected by somatic copy number alterations. Across all 12 cancer types examined in the study, these 140 regions were consistently altered. Of these regions, only 35 contained genes that were previously linked to cancer. The remaining regions house a large number of new candidate genes that may prove to be cancer drivers.
SCNAs can affect the epigenetic regulators that control how genes are expressed, contributing to cancer. Many of the 140 regions identified by the study are known to contain epigenetic regulators. These regulators modify how DNA is folded within the cell and what parts of the DNA’s genetic code can be read, which in turn affects how genes are expressed. This evidence suggests that some cancer patient populations may benefit from treatments that target these epigenetic regulators.
The GCC study was conducted as part The Cancer Genome Atlas (TCGA) Project, a national, multi-institution collaboration to characterize the genomes of over 20 types of cancer and to uncover the molecular basis of the disease. The Broad GCC site is one of six TCGA Genome Characterization Centers. Meyerson, who is one of the Broad GCC’s principal investigators, said the goal of the center is to provide copy number analysis of all of the tumors that are analyzed by TCGA.
“This paper is really the first report of that copy number analysis, systematically across cancer,” explained Meyerson, who is also an associate professor of pathology and medical oncology at Dana-Farber Cancer Institute. “It is the culmination of years of work in this area at the Broad, and the product of a data generation and analytical pipeline that is built upon a very long tradition of Broad research.”
Broad scientists Travis Zack and Steven Schumacher were the first authors of this paper. Other Broad researchers who contributed to the work include Scott Carter, Andrew Cherniack, Gordon Saksena, Barbara Tabak, Michael S. Lawrence, Cheng-Zhong Zhang, Jeremiah Wala, Craig Mermel, Carrie Sougnez, Stacey B. Gabriel, Bryan Hernandez, and Gad Getz (co-senior author).
Zack, T et. al. "Pan-cancer patterns of somatic copy number alteration." Nature Genetics DOI: 10.1038/ng.2760