Cancer clues. Sequencing tumor DNA can find changes that drive cancer cell growth.
Cancer researchers who have spent the last 7 years compiling a catalog of mutations in patients' tumors are now talking about what they should do next.
This week, researchers at the National Cancer Institute (NCI) unveiled a project on their wish list: a much broader survey of 10,000 tumors per cancer type
that would aim to pin down very rare cancer genes.
Next year, NCI will wind up The Cancer Genome Atlas (TCGA), a huge project piloted in 2006 that is systematically searching tumors for genetic changes
involved in cancer. More than 150 cancer researchers have divvied up the work of sequencing about 500 tumor samples for each of some 20 cancer types
(10,000 samples in total) at a cost of more than $375 million. TCGA has
verified known cancer genes and found new genetic changes driving some cancers; although the project has been criticized as too costly, many researchers think it
has been worthwhile.
So what next? On Monday at a meeting of NCI's Board of Scientific Advisors (BSA), NCI cancer geneticists Louis Staudt and Stephen Chanock sketched out one
idea that emerged from a recent TCGA workshop (starts at 116:00 on video). Staudt
explained that because tumors are often riddled with mutations that aren't involved in cancer, it is difficult to pick out those that matter. Even some
known cancer genes for lung adenocarcinoma, one of the most intensively studied cancers, haven't popped out in cancer genome surveys. To find rare cancer
genes, researchers need to sequence many more samples, he said.
Staudt then described what he called "The 10K Concept." The idea is to sequence 10,000 tumor samples for each of several common cancers, such as breast and
prostate. This should be enough to find mutations that occur in as few as 1% of samples, Staudt said. The project would also attempt to link an individual
patient's genetic results with clinical outcome and lifestyle factors such as smoking, which TCGA didn't do.
Finding the 10,000 tumors for each cancer may be easier than it sounds, Staudt said. One reason is that researchers recently realized that tumor biopsies
preserved in paraffin, the most common method, can be used for sequencing and gene expression studies. That is a "game changer," according to Staudt. Until
now, TCGA researchers thought they had to use frozen samples, which are much scarcer.
The project would also save money by gathering tumor samples from completed clinical trials and observational studies, as well as by piggybacking on
planned studies. For example, a new NCI lung cancer trial called ALChEMIST will test 7000 patients' tumors to find the 16% with two specific mutated genes;
only those patients will continue in the treatment part of the study. But biopsies from all 7000 patients could be part of a 10,000 lung cancer genomes
project, Staudt said.
Staudt acknowledged that with NCI facing a 5% budget cut, it isn't a great
time to suggest a large new research project. And several BSA members spoke skeptically of the "diminishing returns" from more cancer genomes. Bruce
Stillman, president of Cold Spring Harbor Laboratory in New York, said that although he was a "strong proponent" of TCGA, scaling up to 10,000 tumors per
cancer "is not very sensible at the moment." Stillman pointed out that the discovery of the breast cancer risk genes BRCA1 and BRCA2 inspired
a push to find more familial breast cancer genes that didn't yield much. Instead, NCI should focus on learning more from the data already gathered by TCGA,
such as exploring biological pathways, Stillman suggested.
Staudt told ScienceInsider that NCI doesn't have a price tag yet for the 10,000 cancer genomes proposal. It is just one of several being considered
to follow the TCGA; its fate will depend on NCI's other priorities, he said. He cautioned that it's only in the discussion stage. "This is not yet a
'project.' It is a concept that may or may not morph into a project," he said.