Mutational Landscape Identified in 12 Major Cancer Types

Gene mutations and their significance across major types of cancer

Examining 12 major types of cancer, scientists at Washington University School of Medicine in St. Louis have identified 127 repeatedly mutated genes that appear to drive the development and progression of a range of tumours. The discovery sets the stage for devising new diagnostic tools and more personalised cancer treatments. The research findings are published October 17 in Nature.

The study shows that some of the same genes commonly mutated in certain cancers also occur in seemingly unrelated tumours. For example, a gene mutated in 25% of leukaemia cases in the study also was found in tumours of the breast, rectum, head and neck, kidney, lung, ovary and uterus.

Based on the findings, the researchers envision that a single test that surveys errors in a swath of cancer genes eventually could become part of the standard diagnostic workup for most cancers. Results of such testing could guide treatment decisions for patients based on the unique genetic signatures of their tumours.

New insights into cancer are possible because of advances in genome sequencing that enable scientists to analyse the DNA of cancer cells on a scale that is much faster and less expensive today than even a few years ago. While earlier genome studies typically focused on individual tumour types, the current research is one of the first to look across many different types of cancer.

According to a senior author Li Ding, PhD, of The Genome Institute at Washington University, many oncologists and scientists have wondered whether it's possible to come up with a complete list of cancer genes responsible for all human cancers.

The new research analysed the genes from 3,281 tumours of the breast, uterus, head and neck, colon and rectum, bladder, kidney, ovary, lung, brain and blood. In addition to finding common links among genes in different cancers, the researchers also identified a number of mutations exclusive to particular cancer types.

Looking at a large number of tumours across many different cancers gives the researchers the statistical power they need to identify significantly mutated genes. They occur frequently in some cancers and rarely in others but are nevertheless thought to be important to cancer growth. The research was conducted as part of The Cancer Genome Atlas Pan-Cancer effort, funded by the National Cancer Institute and the National Human Genome Research Institute, both at the USA National Institutes of Health (NIH).

While the average number of mutated genes in tumours varied among the cancer types, most tumours had only two to six mutations in genes that drive cancer. This may be one reason why cancer is so common, the researchers said.

The scientists, which included co-first authors Cyriac Kandoth, PhD, and Michael McLellan, both at Washington University, along with collaborator Benjamin Raphael, PhD, from Brown University, were also able to identify genes that have a significant effect on survival.

TP53, an already well-known cancer gene, occurred most commonly across the different tumour types. It was found in 42% of samples and routinely was associated with a poor prognosis, particularly in kidney cancer, head and neck cancer and acute myeloid leukaemia.

Another gene, BAP1, also was linked with an unfavourable prognosis, especially in patients with renal and uterine cancer.

However, mutations in the breast cancer gene BRCA2 were associated with improved survival in ovarian cancer, while errors in IDH1 were linked to an improved prognosis in gliobastoma, a particularly aggressive brain tumour, and in other cancer types.

Research to find additional cancer genes is ongoing at Washington University's Genome Institute, one of the large-scale genome sequencing centers supported by NIH, and at other academic institutions. Identifying a more comprehensive list of cancer genes could provide the backdrop to improve the diagnosis of cancer and to guide treatment decisions.

Ding, an assistant professor of medicine, also is a research member of the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.

This work was supported by the National Cancer Institute grants R01CA180006 and PO1CA101937, and National Human Genome Research Institute grants R01HG005690, U54HG003079 and U01HG006517, and National Science Foundation grant IIS-1016648.

Reference

Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013, 502: 333–339 doi:10.1038/nature12634