Ambitious Plan to Sequence Large Number of Cancer Genomes

Zosia Chustecka

April 09, 2009

April 9 — An ambitious plan to sequence large numbers of cancer genomes is underway, under the auspices of the International Cancer Genome Consortium (ICGC).

Although the proposal has already stirred up some controversy and will be expensive, the scientists involved argue that this is a "deliverable project that will comprehensively elucidate central questions relating to the nature of human cancer."

These new insights will in turn lead to new therapies, the scientists predict. "The clinical and translational implications of such a body of work are profound," they write in a review article published in the April 9 issue of Nature.

Work is already underway, says senior author Andy Futreal, PhD, codirector of the Cancer Genome Project at the Wellcome Trust Sanger Institute, in Hinxton, Cambridgeshire, United Kingdom. "There are several groups, including ours, that have sequenced handfuls of cancer genomes and are now scaling up these efforts."

The ICGC was begun in earnest in April 2008, Dr. Futreal told Medscape Oncology. It is endeavoring to coordinate and minimize the duplication of efforts by following the pattern of international collaboration that characterized the Human Genome Project. The aim is "to generate a resource of high quality so that we only have to do it once, empowering cancer research with a lasting legacy for the future."

Somatic Mutations at the Root of All Cancers

All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes in the cancer cell, known as somatic mutations. The very first of these naturally occurring human cancer-causing sequence changes was identified in 1982 (in the HRAS gene in bladder cancer); since then, another 100,000 have been reported.

"Early data suggest that cancers may harbor several tens of thousands of somatic mutations in their genomes," Dr. Futreal commented. Given this, over the next 5 to 10 years, depending on technological advances, several hundred million somatic mutations will be revealed by the large-scale complete sequencing of cancer genomes, he predicts.

The project will focus on 50 classes of cancer, including those with the highest global incidence and mortality. Initial efforts are being directed at breast cancer (several types), gastric cancer, pancreatic cancer, liver cancer, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and cancers of the oral cavity, he said.

"To some extent, we cannot predict what will be found," the scientists admit. But they hope that among the findings will be "further druggable cancer genes," to add to those that have already been discovered and have given rise to successful targeted therapies. These include the mutated ABL gene in acute myeloid leukemia and the activated KIT gene in gastrointestinal stromal tumors — both of which are targeted with imatinib (Gleevec, Novartis). They also include ERBB2 (also known as HER2), which is commonly amplified and overexpressed in breast cancer and is targeted by trastuzumab (Herceptin, Genentech/Roche).

There is also hope that the project will "generate new insights into the genetic patterns that underpin disease phenotype, prognosis, drug response, and chemotherapy resistance." In the future, such data may drive individualized therapeutic decision-making, through the ability to predict prognosis, to choose therapeutic regimens known to have efficacy for the particular genetic subtype of cancer, to sensitively monitor response to therapy, and to identify rare subclones harboring drug-resistance mutations before therapy is even initiated, they write.

"We will be generating the complete catalog of mutations that have contributed to the development of thousands of human cancers," Dr. Futreal elaborated.

"This set of mutated genes will themselves be targets for drug development in a proportion of cases, and will inform on critical pathways that are commonly subverted in human cancer, thus pointing toward opportunities for therapeutic intervention," he continued. "In addition, this compendium of mutations will provide more accurate molecular classification of cancers and novel markers for diagnostic development and monitoring of treatment responses."

The researchers have disclosed no relevant financial relationships.

Nature. 2009;458:719-724.