DNA sequencing technologies are uncovering unprecedented amounts of information about the genes that drive cancer. Memorial Sloan Kettering’s Robert and Kate Niehaus Center for Inherited Cancer Genomics is taking advantage of those advances to discover more genes that make a person more likely to develop the disease. This knowledge about the cancer-related mutations that run in families could lead to new methods of screening and prevention.
The Niehaus Center is using data from the MSK-IMPACT™ test — which looks for cancer genes in patients’ tumor samples as well as in their normal tissue — in addition to other advanced genomic techniques. Physician-scientist Michael Walsh, a member of the Niehaus Center research team who recently came to MSK from St. Jude Children’s Research Hospital in Memphis, is seeking to expand these kinds of studies to MSK’s pediatric patients. His efforts build on work previously initiated by Niehaus Center leader Kenneth Offit and cancer geneticists Zsofia Stadler and Vijai Joseph.
Dr. Walsh was co-first author on a paper published with his St. Jude colleagues last month in the New England Journal of Medicine that looked at more than 1,000 pediatric patients treated for cancer at a number of different hospitals. The study found that 8.5 percent of patients with pediatric cancer had mutations in their germline DNA that increased their predisposition to cancer. These mutations were present in their cells at birth and could be passed to subsequent generations. More than half of all patients with these mutations had no family history of hereditary cancers.
“Normally, patients with pediatric cancer are referred to genetics specialists only if their cancer or their family history fits certain criteria,” Dr. Walsh says. “These findings suggest that we should reconsider this approach and look at all pediatric cancer patients to determine whether other family members may have an increased cancer risk. However, given the ethical issues and limited understanding of clinical utility, such an approach requires caution and infrastructure in place to handle the weight of this information.”
Dr. Offit and Mark Robson, the Niehaus Center’s clinical director, have initiated a multi-institutional study called PROMPT, which addresses some of the crucial concepts around the anticipated shift in how genetic testing is conducted.
In the NEJM study, the investigators sequenced the genomes of patients with pediatric cancers to look for mutations in their germline DNA that were associated with a predisposition to cancer. They found that 95 of the 1,120 patients studied had inherited mutations in 21 different genes, a rate that was much higher than expected. The highest frequencies were found in patients with bone tumors, adrenal cortical tumors (cancers of the adrenal glands), neuroblastoma (a type of tumor that starts in nerve cells), and retinoblastoma (an eye tumor), at 16.7%; central nervous system tumors, at 9%; and leukemia, at 4.4%.
A number of patients had mutations in the BRCA1 and BRCA2 genes, which are associated with an increased risk of breast cancer and ovarian cancer in adults but have not previously been linked to pediatric cancers. The investigators don’t yet know if this association is unrelated or whether these mutations are driving pediatric cancers. Other mutated genes that were found already had been associated with certain inherited childhood cancers, but were thought to be much less common than the new research suggests.
Dr. Offit collaborated with members of the St. Jude team on two earlier studies that found previously unknown mutations in inherited forms of childhood acute lymphoblastic leukemia. In families known to carry those gene mutations, prospective parents who are using in vitro fertilization to get pregnant can seek genetic testing before embryos are implanted to look for defects.Back to top
Keeping Research in the Family
Dr. Walsh says there may be several reasons why so many patients who carried mutations for cancer — including more than half of those in the current study — had no family history of the disease. Some of the mutations may have been de novo, which means that they occurred when the embryo was first dividing and therefore were not inherited from either parent. (But like inherited cancers, these mutations are still found in all cells in the body.) In other cases, the family history may be incomplete. “It’s also possible that family members may carry the genes as well but have not yet developed cancer,” he says, “or that the mutations are not completely penetrant — meaning additional factors are required for cancer to develop.”
“The field of genetics is changing so rapidly,” says Dr. Walsh. “Right now there are three types of results from these genetic studies: The findings may be positive or negative for known cancer genes, or they may have significance that is not known at this time. As new information comes up and we learn more about cancer genes, it will be increasingly important to stay in touch with these families so that we can reach out to them as we learn more.”
“This is why long-term follow-up with these families is so important,” adds Dr. Walsh, who conducted much of the research in the NEJM paper while he was still at St. Jude. “I came to MSK because I wanted to play a role in taking care of whole families that have these predispositions to cancers, not just the kids. Much of the knowledge we expect to gain through this research will apply to entire families.”Back to top