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Genome Advance of the Month

Massively parallel sequencing:
Taking an all-at-once approach to genetic testing in cancer

By Jonathan Max Gitlin
Science Policy Analyst
From right to left: Ming Lee, Sunday Stray, Elizabeth Swisher, Anne Thornton, Chris Pennil, Anneka Wickramanayake, Mary-Claire King, Siliva Casadei, Katy Pennington, Tom Walsh.
From right to left: Ming Lee, Sunday Stray, Elizabeth Swisher, Anne Thornton, Chris Pennil, Anneka Wickramanayake, Mary-Claire King, Siliva Casadei, Katy Pennington, Tom Walsh

Cancers are inherently genomic diseases. Mutations in genes prevent cells from knowing when to stop dividing, and this uncontrolled and inappropriate growth results in tumors. This can happen for many different reasons.

Some cancers are caused by our interaction with our environment. Too much exposure to the sun's ultraviolet light can cause skin cancer, and exposure to tobacco smoke can result in lung cancer.

Other cancers run in families. Rather than a mutation occurring in an individual cell at some point during a person's life, faulty copies of a gene that normally protects against cancer can be inherited from a parent and passed on to future generations.

The most well-known example of genes that cause inherited cancers are called BRCA1 and BRCA2, which are associated with breast and ovarian cancers. Women with a family history of these diseases commonly have their BRCA genes tested for disease-causing mutations. But inherited BRCA mutations are not the whole story when it comes to inherited cancers. Mutations in other, tumor suppressor genes can also be passed down through generations, but these are rarely screened for, a legacy of the cost and time needed to sequence genes (until very recently), among other reasons.

Now, however, thanks to the breathtaking decrease in the time and cost needed to analyze genes, scientists are taking a broader approach by sequencing and analyzing multiple cancer-causing genes at once. This Genome Advance of the Month details exactly such an approach, developed at the University of Washington School of Medicine in Seattle.

Unlike previous monthly genome advance reports that have featured whole genome or whole exome sequencing, this approach, described in the Proceedings of the National Academy of Sciences by Tom Walsh, Ph.D., and colleagues, uses next-generation sequencing platforms targeted at just 21 genes known to be tumor suppressors. The team used this approach, which they've called BROCA after the 19th century scientist, Paul Broca (and possibly as a play on words, or acronyms, for BRCA), to analyze blood samples from 360 women undergoing surgery for ovarian, peritoneal or fallopian tube cancers.

They discovered that 24 percent of the women had an inherited mutation in at least one of the genes that would result in a loss of its tumor suppressing function. Two thirds of these were in BRCA1 and BRCA2; but they also detected mutations in genes that previously hadn't been associated with inherited ovarian cancer. The team also found that 30 percent of women with an inherited mutation had no family history of breast or ovarian cancer among parents, siblings, or grandparents, and 35 percent of these patients were diagnosed with their cancers after the age of 60.

This means that screening efforts that only focus on young women with family histories of breast or ovarian cancers would not detect mutations and increased cancer risk among older women and those with no history of these cancers. This may also mean that the medical community will need to consider genetic screening of women without an immediate family history of breast or ovarian cancers. However, there are dangers associated with screening programs that are too broad (e.g. patients receiving procedures they don't need, which may overburden the health care system), as well as screening programs that are too narrow in scope.

Unfortunately, there are no plans to introduce the BROCA test commercially at the moment, as the BRCA genes are subject to patent protection. In the United States, only Myriad Genetics, Inc., has the license to sequence BRCA genes in the context of cancer diagnostics, at least until the patents expire in 2015 (depending upon the outcome of an ongoing legal challenge to Myriad's patents, which is expected to reach the U.S. Supreme Court some time in 2012). However, the University of Washington has applied the approach of screening a panel of tumor suppressor genes to create a test that looks for inherited mutations in colon cancer, called ColoSeq, which it began offering on November 1, 2011.

Read the study: Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A, Norquist B, Pennington KP, Garcia RL, King M-C, Swisher EM. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proceedings of the National Academy of Sciences, 108(44):18032-18037. 2011. [PubMed]

Last updated: April 30, 2011