When Kerri Murphy was 32, she underwent genetic testing for Lynch syndrome — a hereditary disorder that’s caused by a mutation in any of five genes that predisposes those who have it to several cancers. Her sister had tested positive for Lynch syndrome, and because they had lost their father to colon cancer, Murphy thought she should know if she had a predisposition to the disease, too.
“My father passed away from colon cancer at 48,” says Murphy, who lives in Rhode Island. “His mom had colon cancer, and a number of her siblings had it.”
So, Murphy wasn’t entirely surprised in 2012 when genetic testing revealed that she had Lynch syndrome. During discussions with a genetic counselor, Murphy learned she might face an increased risk not just of colon cancer, but also of cancers of the stomach, pancreas, kidneys, brain, uterus, skin and other sites. Because the gene mutation meant Murphy faced a high risk of developing endometrial or ovarian cancer, she opted to have a hysterectomy. In addition, Murphy, who is married with one son, undergoes a colonoscopy and skin exam every year, as well as an endoscopy to check her stomach every few years. So far, no cancers have been found.
“It’s a scary thing, but I feel fortunate that I know,” says Murphy, 38, who calls herself a “previvor.” “Knowing has quite possibly saved my life.”
Lynch syndrome is one of more than 50 genetic conditions that raise the risk of developing cancer, according to the National Cancer Institute. That list of hereditary cancer syndromes is growing rapidly as geneticists discover more gene mutations and link them to familial patterns of cancer diagnosis. At the same time, the cost of genetic testing is decreasing, running in the hundreds rather than thousands of dollars, making it feasible for healthy people to seek out testing and then pursue active surveillance plans — frequent colonoscopies or preventive surgeries, for example — if they are found to be at high risk.
“We know that all of these syndromes impact both men and women, and they can all be passed down to sons and daughters,” says Ellen Matloff, M.S., a certified genetic counselor and CEO of My Gene Counsel. “And they can increase the risk of several types of cancer.”
Inherited cancers are caused by mutations, or abnormalities, in genes, and account for about 5 to 10 percent of all cancer diagnoses, according to the American Cancer Society. Colorectal, breast and ovarian are the cancers most commonly linked to inherited gene mutations.
There are a few important factors that geneticists look for when deciding whether a healthy person, who has no personal history of cancer, should be screened for cancer-causing genes, and those are mostly related to family history. For example, if several family members have been diagnosed with kidney or specific types of cancers that seem to fit one of the hereditary syndromes, or if any relatives developed a disease such as breast or colon cancer before turning 50, you might be a good candidate for testing. Genetic counselors are particularly concerned about cancer in close relatives, such as parents or siblings. However, cancer in more distant relatives can also be important.
UNCOVERING CANCER-CAUSING GENES
“Had I known, I would have been able to be proactive and start getting colonoscopies very young.” SUSAN MCDEVITT, of her genetic predisposition to colon cancer. - PHOTO BY: ANGELA CHICOSKI
Lynch syndrome is one of the most complex genetic disorders because of the number of genes involved — MLH1, MSH2, MSH6, PMS2 and/or EPCAM. All these genes are involved in the process of DNA repair — an essential function, because the human genome is constantly at risk for mistakes in division, or DNA damage, that is repaired through several elaborate mechanisms. Mutations in each gene may infer a different risk, and this may also vary between families due to the effects of other genes. For example, people found to have mutations in the genes MLH1 and MSH2 face a lifetime risk of developing colon cancer that’s between 52 and 82 percent, compared with 4.8 percent for the general population, according to a section of the book “GeneReview,” posted online in 2004 by the National Center for Biotechnology Information. Women who have a mutation in those genes or in MSH6 also have a 25 to 60 percent lifetime risk of developing endometrial cancer, according the same resource.
As scientists learn more about Lynch syndrome, they’re realizing it’s more common than they initially believed. “Years ago it was called ‘rare,’ but now the estimate is that one out of every 279 people has it,” says Susan McDevitt, executive director of Lynch Syndrome International, a Madison, Connecticutbased organization that provides information and support to people diagnosed with the condition. McDevitt tested positive for the MSH2 mutation after surviving colon cancer in 2011. She opted for a hysterectomy. Now 50, McDevitt says she believes that she could have prevented her colon cancer if she had learned about her Lynch status earlier. “Had I known, I would have been able to be proactive and started getting colonoscopies very young,” she says.
Indeed, a benefit of knowing about a genetic predisposition to cancer is the chance to opt for earlier and more frequent surveillance than what is generally recommended, which will boost the chances of finding tumors in their earliest stages, when they can often be cured with surgery. For instance, the five-year survival rate for colon cancer diagnosed in stage 1 is about 92 percent. That rate drops to 11 percent in stage 4, when the cancer has already spread, according to the American Cancer Society.
Genetic testing for breast and ovarian cancers can also open up several options for prevention. Mutations in the genes BRCA1 and BRCA2 are well-known, but more than a half-dozen other genes have also been implicated in breast and ovarian cancer. Many of these genes are also involved in DNA repair — although they affect different repair mechanisms than those involved in Lynch syndrome. Meanwhile, scientists are learning more and more about which populations have the highest prevalence of BRCA mutations; like many other genetic traits, these tend to cluster in certain ethnic or geographic populations. For example, 1 in 400 to 800 men and women in the general population carry BRCA1 or BRCA2 mutations. That risk is higher in men and women of Ashkenazi Jewish descent, who face a 1 in 40 chance of having those mutations, according to the National Cancer Institute.
Diane Rose learned of her risk for breast and ovarian cancer from her father. It happened after his sister was diagnosed with ovarian cancer at 56 and entered into a study, during which she learned she carried the BRCA1 mutation. So, Rose, who lives in Oley, Pennsylvania, hopped in a car with her two brothers and her sister in 2006, and together they went to see a genetic counselor at Fox Chase Cancer Center in Philadelphia.
After hearing about the cancers on Rose’s father’s side of the family, which included several cases of colon cancer, the counselor had suggested that all four siblings undergo testing. Three tested positive for BRCA1, including Rose, who was 37 at the time. Rose was well aware that the mutation would increase her risk for breast and ovarian cancer, but she was surprised when the counselor suggested she undergo frequent screenings for melanoma and colon cancer. “I didn’t know the tie-in between the genes and other cancers,” says Rose, who is now vice president for volunteer programs at Facing Our Risk Of Cancer Empowered (FORCE), which provides resources to families affected by inherited cancers.
In fact, an increasing number of studies have found a link between the BRCA mutations and colorectal cancer. One study, published in 2013, tracked 7,015 women who tested positive for either BRCA1 or BRCA2 mutations, or both. Researchers found an increased risk for colon cancer among women under age 50 who had BRCA1 mutations. In studies examining the connection between both BRCA mutations and melanoma, there have been conflicting results, but the link is strong enough for many counselors to recommend yearly skin checks for carriers of either gene. And several recent studies suggest that men with either BRCA mutation may face a higher risk of prostate cancer, and both men and women with those mutations are at increased risk for pancreatic cancer.
For three years after she was diagnosed, Rose underwent frequent colonoscopies, mammograms and skin checks, and at age 40, she opted to have her ovaries and both breasts removed. It was a radical choice, but her cousin had been diagnosed with breast cancer at age 28, so Rose says she believed that the surgeries were necessary to reduce her risk. She made the choice with the help of counseling — a step she recommends for anyone considering getting tested for cancer genes. “This field is changing all the time. A genetic counselor will map out your whole family tree and tell you if you should have testing and which tests to have,” in addition to providing guidance about what actions to take based on the test results, Rose says.
THE ROLE OF COUNSELORS
Genetic counselors provide vital services at all stages of the testing process. They often recommend that testing start with members of the family who have been diagnosed with cancer, so the panel of potential genes can be narrowed down, says Mary Freivogel, M.S., a certified genetic counselor and president of the National Society of Genetic Counselors. But even if that’s not possible, genetic counselors can help patients choose the most appropriate tests based on family history. Then, they interpret the results and help establish an action plan for cancer risk reduction. They can also counsel those who have been tested on how to share the results with their family members.
One of the risks of having your genes tested is that you might end up with a “variant of unknown significance,” which means that, at the time of testing, it can’t be determined if a gene irregularity is harmful or benign. But the chances of getting an uncertain result from BRCA testing have dropped in recent years, says Allison Kurian, M.D., associate professor of medicine and of health research and policy at Stanford University School of Medicine, in California. “When we test genes in a lot of people, the rate of getting a variant of unknown significance goes way down,” Kurian says. That’s because, in mass testing, variants of unknown significance turn up more and more often, and can eventually be reliably linked to specific outcomes. “Our best estimate is that a great majority of variants of unknown significance are likely to turn out to be nothing,” he says, “and shouldn’t be a deterrent for most people.”
In February, Kurian published a survey in the Journal of the American Medical Association showing that about eight in 10 breast cancer survivors who are at high risk of having BRCA mutations want to have genetic testing, but only about half of them receive it. The most often cited reason was that their doctors didn’t recommend it. That’s why Kurian suggests that patients with cancer and others worried about their family risk take the initiative and seek out testing. “For patients who don’t have cancer, it’s an important conversation to initiate with their primary care practitioner,” she says.
As the field of cancer genetics evolves, more is being learned about the links between particular genes and specific tumor types. Another genetic disorder that raises the risk of breast cancer, for example, is Li-Fraumeni syndrome, which is most often caused by a mutation in TP53, a gene that normally acts to suppress tumors. Mutations in TP53 are less common than those in BRCA1 and BRCA2, and can cause early onset of a variety of cancer types, including brain tumors and soft tissue sarcomas, according to the Li-Fraumeni Syndrome Association. A rare type of stomach cancer called hereditary diffuse gastric cancer, as well as lobular breast cancer, have been linked to the gene CDH1. And some cases of the skin cancer basal cell carcinoma are genetic.
Surveillance and preventive surgeries are the standard options for healthy people found to carry a genetic risk for cancer. If you or a family member are diagnosed with cancer, the genetic data can be useful for selecting the treatments most likely to be effective. For example, a newer class of drugs called poly ADP ribose polymerase (PARP) inhibitors, which work by blocking an enzyme used by cancer cells to repair damage to their DNA, is showing promise in patients who have both inherited BRCA mutations and BRCA abnormalities in their tumors.
PARP inhibitors are also showing promise specifically in certain men with BRCA and other mutations, says Michael Walsh, a pediatrician, geneticist and hematologist/oncologist at Memorial Sloan Kettering Cancer Center in New York. In one trial of the PARP inhibitor Lynparza (olaparib) in 16 patients with prostate cancer who had the DNA-repair mutations, 14 patients responded well to the drug and median overall survival of about 14 months was nearly double that of patients without mutations. Lynparza has been approved in BRCA mutationassociated advanced ovarian cancer, and a randomized trial comparing this drug to chemotherapy in advanced BRCA-related breast cancer also demonstrated better results with Lynparza; a request for the drug’s approval for that indication will be submitted for FDA approval soon.
“We’re learning more about precision medicine and how (genetics) relates to treatment,” Walsh says. “It’s emerging.”