Abstract
An in-depth analysis has produced the most comprehensive portrait to date of the myriad genomic alterations involved in breast cancer. In sequencing the whole genomes of 560 breast cancers and combining this information with published data from another 772 breast tumors, the research team uncovered several new genes and mutational signatures that potentially influence this disease.
An in-depth analysis led by the Wellcome Trust Sanger Institute in Cambridge, UK, has produced the most comprehensive portrait to date of the myriad genomic alterations involved in breast cancer. Several new genes and mutational signatures that potentially influence this disease have also been uncovered.
The research team sequenced the whole genomes of 560 human breast cancers, along with matching normal tissue. They found a mutational mess: Overall, almost 3.5 million base changes, more than 370,000 small insertions or deletions, and nearly 78,000 genomic rearrangements were detected, varying considerably in number among individual tumors.
Next, the researchers combined their sequencing information with published genomic data from another 772 breast cancers and, through statistical probing, identified a total of 93 recurrently altered breast cancer genes. Most were known players, but five—MED23, FOXP1, MLLT4, XBP1, and ZFP36L1—had not previously been associated with the disease. Nine, including PTEN and ARID1B, derived some of their role in breast cancer from recurrent genomic rearrangements, the team noted. They also found that the 10 most frequently altered genes, including TP53 and PIK3CA, accounted for 62% of breast cancer drivers.
“This tells us most of the common drivers have already been found for breast cancer,” says lead author Serena Nik-Zainal, MD, PhD. “A study of 10,000 tumors might yield a few more rare genes, but is unlikely to change much, if any, of this disease's genomic landscape.”
Daniel Hayes, MD, director of breast oncology at the University of Michigan in Ann Arbor, who was not involved with this work, concurs. “It's doubtful that we'll find anything truly different with further explorations,” he says, “so we ought to focus on therapeutically targeting breast cancer's recurrent abnormalities.” Hayes called the analysis “an enormous undertaking, like TCGA [The Cancer Genome Atlas] on steroids.”
Nik-Zainal's group used a mathematical approach to extract 12 breast cancer mutational signatures characterized by distinct base changes—five were known, five more had been reported in other cancers, and two were new. They also found six mutational signatures marked by genomic rearrangements; one was associated with BRCA1 or BRCA2 deficiency, and another with ER-positive disease. They explored these signatures further in a second, simultaneously published study.
“There's been skepticism about whether mutational signatures are real or simply artifacts of mathematics,” Nik-Zainal says. “We learned that the ones we found are related to different processes like DNA replication, transcription, and chromatin organization. It's evidence that they're true pathophysiological patterns of things going wrong in the cell.”
To Clifford Hudis, MD, chief of breast medicine at Memorial Sloan Kettering Cancer Center in New York, NY, Nik-Zainal's group has “boosted the theory that cancer is often a disease of mutations.” Breast cancer is challenging, he adds, because “it hasn't yielded to the simple view that only a narrow set of genetic changes are involved.” Hudis also says that the findings “require some external validation with an independent dataset.”
“There are no immediate clinical implications,” Hayes says. “It's a bit like the Oxford dictionary—a monumental document, but not one you'd read cover to cover. Rather, with this analysis, the breast cancer ‘dictionary’ is now pretty well-defined, and this will help researchers figure out future experiments without reinventing the wheel each time.” –Alissa Poh
