Bad genes do not inevitably bring on disease

Experts at a day-long Jerusalem symposium on genetic breast cancer tell carriers how they can fight and win.

Genes 311 (photo credit: Judy Siegel-Itzkovich)
Genes 311
(photo credit: Judy Siegel-Itzkovich)
Cancer has emerged beyond heart disease to become the most common cause of death in Israel, making the risk of contracting some type of malignancy during extended lifetimes more likely. Most cancers are triggered by environmental and lifestyle or unknown causes. But a minority are hereditary, triggered in carriers by defective genes that disrupt the gentle balance between those that encourage controlled division of cells and others that activate wild division of cells.
Hereditary cancer syndromes that have been discovered in recent years include familial adenopolyposis (which begins as polyps in the digestive system); hereditary non-polyposis colorectal cancer; Li Fraumeni Syndrome (appears in a number of organs at a young age); retinoblastoma (in the eye and bone tissues); Von-Hippel-Lindau syndrome (kidney and intestinal cancers); Cowden’s syndrome (breast, ovarian and thyroid); and multiple endocrine neoplasia (parathyroid and other glands, pancreas and other organs).
Yet the most prevalent and well-known causes of hereditary cancer are the BRCA1 and BRCA2 mutations, which can cause breast and/or ovarian cancer in women (BRCA2 can cause breast and prostate cancer in men as well). Late last month, Jerusalem’s Shaare Zedek Medical Center and the Israel Cancer Association sponsored an all-day symposium in the hospital’s auditorium on BRCA genes for families at risk, but some doctors and nurses attended as well. It was presided over by Prof. Ephrat Levy-Lahad, head of the medical center’s medical genetics unit, who is an expert in the field.
Most malignancies, said Levy-Lahad, are not due to heredity. In general, about 10 percent of breast cancer and 5% of ovarian cancer cases are contracted by carriers of defective genes. One in 40 Ashkenazi Jews carry defective BRCA genes in each of their cells, and these mutations explain 10% of breast cancers and 40% of ovarian cancers in this group. There are three common known mutations among Ashkenazi Jews and one in Jews of Iraqi origin, but others in non-Jews around the world. “Thus it is relatively easy to check for these in relevant populations and know if they are at higher risk,” she said, “and that is what is done in Israel.”
There apparently are more defective genes that cause these two types of cancers, but many haven’t yet been discovered.
The discoverer of BRCA1’s existence (in 1990), Prof. Mary-Claire King, is a close friend and colleague of Levy-Lahad. King, a lauded human geneticist and American Cancer Society professor at Seattle’s University of Washington, studies the genetics and interaction of genetics and environmental influences on disorders such as breast and ovarian cancer, HIV and inherited deafness; she also showed that humans and chimpanzees are 99% genetically identical and applied genomic sequencing to identify the missing, dead and unidentified. In a recent article, King noted that about a dozen genes are associated with inherited breast cancer and reported a test that can incorporate all of them.
But genetics isn’t everything, noted Levy- Lahad at the symposium. “In one family with carriers of the same mutation, some women will get the disease when young, some when they are old and some not at all. There are environmental influences as well. At the cell level, not every carrier gets cancer because of tumor suppressor genes. One can have one healthy gene and one sick gene.”
Why do the health funds not check every member for all cancer genes? Levy-Lahad noted that genome sequencing is possible from a small sample of blood or saliva.
“There are private labs in Israel that today offer sequencing of BRCA genes for NIS 8,000, but the costs continue to drop dramatically.”
In the US, an individual’s whole genome of 3 billion DNA base pairs (permutations of combinations of thymine, guanine, adenine and cytosine) on 23 pairs of chromosomes can be sequenced for $20,000, but the US National Institutes of Health estimate that by 2015, it will drop to only $1,000, and there are predictions of even lower costs.
The Shaare Zedek geneticist noted that individuals found to be carriers can make personal decisions – such as undergoing frequent medical checkups, having their children tested and even undergoing prophylactic breast and/or ovary removal to minimize their risk of eventual cancer. She personally believes that genome sequencing should provided as part of the health basket for people who had breast/ovarian cancer or a family history of the disease – and eventually, all women of a certain age.
“In the next few years, more women will have genetic tests, and more genes will be tested for. We have a lot of information now, but the risks and mechanisms for the disease are not yet understood enough. What we learn from genes can lead to more effective treatment,” she said.
It is possible for women to undergo testing for the defective gene from age 19, but Levy- Lahad said her unit prefers to wait to 25 or 30, as “before, it has no clinical implications.
We sit with a woman and talk to her on whether she wants to know or not. There are women who prefer not to. Psychological aspects are involved in the decision.
Although individuals can find out whether they are BRCA carriers, there is no test today that can say whether that means they will actually get breast or ovarian cancer or when they will get it.”
Dr.Michal Braun, a psychooncologist who is a consultant to Shaare Zedek, said she has worked with many BRCA carriers – both women and men – over the last 13 years. “There are those who came to us who already have cancer in the family, while there are those who have been found negative but refuse to believe that they are not carriers.”
Braun recalled a single woman from a family in which all the women died of breast cancer.
“She was raised in a home with only men. She didn’t get tested and found it impossible to understand how any woman could live beyond 40. Not being a carrier was not an option for her. She believed in determinism and lack of choice and felt all had been decided in advance.”
The woman came to Braun at 35, after both her mother and grandmother had died of breast cancer. “She was sure she would be diagnosed and would die – and that cancer was infectious.”
After insisting that she was “like” her mother, she received psychological treatment to separate from her. Finally, she married, had a child, was tested and found not to be a carrier.
Some older women undergo a test for BRCA for their daughters’ sakes. But it is complicated, said Braun. Carriers may feel guilt for handing the disease down to the next generation. “It can create a feeling of hopelessness, loneliness, shame, depression, anger, fear and anxiety. But in the long term, after being tested, women are usually satisfied.”
Some women who are found to be carriers decide to have their breasts and/or ovaries removed prophylactically. This may give them a sense of empowerment, as this means in most cases that they have escaped the disease.
Yet it is complicated.
Surgeon Dr. Moshe Carmon of the hospital’s breast unit said there are a small number of women who come for prophylactic mastectomy because they were told they had a BRCA carrier in the family. Others have a significant family history of breast cancer or have been diagnosed with a tumor. “There are also women with a family history, but their test results show they are not carriers.
Some want to have their breasts removed to escape the disease.”
He noted that cancer tissue from biopsies is saved, by law, for 20 years, so if a person has died, it can still be tested to find out if she was a carrier. Mammography is often not used alone to diagnose breast cancer. In some cases, an MRI (magnetic resonance instrument) scan is used as well, especially in younger women in which the mammogram is less sensitive. If a woman has the cancer, genetic analysis may be used to decide what type of chemotherapy to give without any connection to the tumor size, said Carmon. “There are parameters today that tell us how aggressive a tumor is. If we know the tumor is genetic, we can integrate breast removal with prevention by removing the ovaries as well.”
DR. PNINA Mor, a Shaare Zedek nurse and midwife with a doctorate on defining the needs of healthy breast cancer mutation carriers, helped establish at the hospital the NOGA clinic ( for healthy carriers of defective BRCA genes in 2007. “The clinic was the immediate result of my doctoral work.” NOGA, which in Hebrew means “radiance” and is also the acronym for Women at High Risk, is the only one of its kind in the country.
“To undergo all the annual screening needed – a mammogram, clinical breast exams, MRIs, CA125 blood tests for ovarian cancer, a pelvic ultrasound – would take 22 days a year at a variety of facilities to which they would be referred by their health fund.
This is exhausting. So we offer all the tests in one place, condensing the screening regime to two days a year.”
NOGA received funding from the Jack and Elisa Klein Foundation in the US, and the services, including psychological support for women, are free if not covered by their health fund. Breast imaging and biopsies, if necessary, are conducted at the HALA nonprofit comprehensive breast center in Jerusalem’s Givat Shaul neighborhood.
After that, the women come to Shaare Zedek for the pelvic ultrasound and blood testing and can meet with a genetic counsellor. At present, 300 women from around the country come to the integrative outpatient clinic once a year.
“They hear about it from word of mouth,” said Mor. “If someone actually has cancer, she is referred to all kinds of experts, but if she’s a healthy carrier, there is nobody else who coordinates it.”
Maccabi Health Services is the only health fund so far to finance the testing for its members, but Mor hopes others will follow.
“Women at high risk for breast and ovarian cancer because of BRCA1 and BRCA2 mutations are often confused by conflicting advice from different specialists. To address this need, we also conduct periodic joint consultations with the patients to ensure that care is coordinated.”
Suspicious breast lesions have so far been detected in 29 women, all of whom underwent biopsies, and revealing breast cancer in eight women aged 32 through 53. Fortunately, all breast cancers were detected at early stages. In one case, the woman reported uncharacteristic symptoms (vague breast irritation), and while the initial imaging was negative, she was rescreened two months later at the staff’s insistence, and a tumor was found.
Preventive removal of the ovaries is recommended to carriers who have completed their families, and many carriers have undergone this operation. In a 54 year old, curable ovarian cancer was diagnosed at an early stage during what was intended to be preventive surgery. Early ovarian cancer is practically impossible to detect, and without this surgery this woman would have likely been diagnosed later with an advanced malignancy, Mor recalled. Five younger women have undergone in-vitro fertilization after preimplantation genetic diagnosis (PGD) to choose BRCA-free embryos and stop the mutation from being transferred to the next generation.
Julia Grinshpun-Cohen, a genetic counselor at NOGA, said that women found to be carriers may want to preserve their privacy and not tell close relatives, even though the findings are relevant to their health. Some might say: “I know my sister. She wouldn’t want to know the truth. Or my daughter is single; I will tell her when it is relevant.”
How does one go about telling the family? “If communications in the family are generally good, you can sit and talk,” said Grinshpun- Cohen. “But it’s not so in all families. There are those who don’t meet a lot. Some insist on sending an anonymous letter via the hospital, without saying who is the carrier. But it certainly isn’t pleasant to get such a letter. By law, we can inform relatives anonymously even if the carrier refuses to say anything.”
Shaare Zedek medical ethicist and pediatric neurologist Prof. Avraham Steinberg said it was not mandatory to “tell every person everything, as sometimes it can cause damage. Ethically, one can hide information if does not have the potential to bring any benefit.” However, he also noted that according to Jewish law, carriers must make sure that relatives who may be at risk receive this information. “There is also the matter of how you give information.” Only recently has this issue of how one gives sensitive information begun to be taught in medical school.