The Genetics of Breast and Ovarian Cancer

What are the genes associated with hereditary breast and ovarian cancers?

Mutations in at least five genes predispose women to breast cancer: mutations on BRCA1, BRCA2, p53 (associated with Li-Fraumeni Syndrome), CD1 (associated with Cowden Syndrome), and possibly ATM (ataxia telangiectasia mutated). Research will probably uncover other genes as well. We all carry every one of these genes, mostly in their normal form. They can mutate in hundreds or even thousands of ways, some alterations are unique to a given family. Mutations often crop up at "hot spots"¡Xareas of the gene where scientists have found more than one genetic flaw.

Women who inherit a mutated form of the genes BRCA1 or BRCA2 have as much as a 90% lifetime chance of developing breast cancer, and as much as a 60% chance of developing ovarian cancer during their lifetime. Researchers reckon that these genes account for 5% to 10% of all such cancers, as well as an excess number of colon and prostate cancers¡Xabout three times as many as occur in the general population. When linked to BRCA1 and BRCA2, breast and ovarian cancers strike early¡Xin a woman's 40s on average as opposed to her 60s as you might expect with sporadic forms of these diseases. Mutations in BRCA2 also are associated with rare male breast cancer.

In October 1996, investigators at The Memorial Sloan-Kettering Cancer Center reported that a specific alteration in the BRCA2 gene is just as common as a BRCA1 mutation among Jewish
women of Eastern European descent, a group that includes more than 90% of the 6 million Jews living in the United States. However, the risk of breast cancer in this ethnic group is more than three times higher in women who inherit the BRCA1 mutation compared to those who inherit the BRCA2 mutation.

Location of the BRCA1 gene on chromosome 17. HBC = hereditary breast cancer

The study's lead author, Kenneth Offit, MD, expressed surprise, saying he expected the cancer risk of the two faulty genes to be about the same. According to Dr. Offit, about one in every 50 Ashkenazi Jews carries one of the two altered genes, "a frequency that is quite high," he says. The new estimates predict that, compared with the general population, the risk of early-onset breast cancer (before age 42) is 31 times greater in Ashkenazi women with the BRCA1 error, and 9 times greater than in those with the BRCA2 error.

Location of the BRCA2 gene on chromosome 13. HBC = hereditary breast cancer

In their normal guise, BRCA1 (found on chromosome 17) and BRCA2 (found on chromosome 13) appear to act as tumor suppressor genes. So far, investigators have found more than 100 different mutations in BRCA1. One common gene flaw, especially among Ashkenazi Jews: what researchers call the "185delAG" gene. Translation: At codon number 185, the chemical bases adenine and guanine have been deleted. This DNA error cripples the gene's ability to code for a protein that places a brake on unchecked cell growth. In similar fashion BRCA2 can mutate in many ways; one variety is the "6174delT" mutation in which thymine has quit the scene at codon
number 6174. Beyond that, researchers know few details.

Ironically, and oddly, a small study at the University of Pennsylvania recently showed that ovarian cancer patients with mutated BRCA1 genes lived longer than other such patients without the altered gene. And in Scandinavia, women with altered BRCA1 genes exhibited somewhat less deadly forms of breast cancer.

During the late 1960s and early 1970s, Henry Lynch, MD, and his colleagues at Creighton University and the National Cancer Institute, first described a hereditary breast-ovarian cancer syndrome. By studying the Hall family (see Chapter 7), and many others, Dr. Lynch was able to verify how both breast and ovarian cancer fit into an autosomal dominant inheritance pattern. In certain members of the Hall family, patients were diagnosed with both types of cancer; in other cases a mother with ovarian cancer produced daughters who developed breast or ovarian cancer or both. Likewise, some mothers with breast cancer gave rise to daughters with breast or ovarian cancer or both.

What other risk factors predispose patients to breast and ovarian cancers?

Certainly, the more first-degree relatives struck by cancer, the higher one's chances of contracting the disease. But often it takes more than wayward genes alone to create tumors.

Risk factors for breast cancer include:

• Early menstruation (before age 12) or late menopause (after age 55)
• First pregnancy after age 30 or nulliparity
• Tallness (linked to a slightly higher risk for premenopausal
• breast cancer) and obesity (linked to a higher risk for breast cancer after age 50)
• Alcohol consumption
• Use of estrogen (still controversial)

Also under study: the connection between breast cancer and high-fat diet; smoking; lack of exercise; exposure to pesticides, engine exhausts, contaminants in food and water; abortion; miscarriage; choosing not to breast-feed.

Risk factors under investigation for ovarian cancer include:

• High-fat diet
• Use of talc (an asbestos-related product that can reach the ovaries through the cervix) in the genital area
• No pregnancies or infertility
• Use of fertility-stimulating drugs that induce ovulation and create more disruption to ovarian tissue

Can prophylactic surgeries prevent hereditary breast and ovarian cancers?

Even though some women have taken this step, we need more research to answer that question definitively. It seems logical: remove the ovaries, for instance, and you cut out the cancer risk. The problem: ovarian tissue derives from the same embryonic cells as the peritoneum. Among women who opt for oophorectomy, 3% to 5% contract an ovarian cancer-like pathology in the peritoneal tissue. But that risk must be viewed in perspective and compared with the 40% to 66% lifetime ovarian cancer risk for a BRCA1 mutation carrier.

Removing the ovaries before natural menopause creates an abrupt loss of estrogen production. That can lead to such side effects as dry vagina as well as an increased lifetime risk for osteoporosis and heart disease. Hormone replacement therapy (both estrogen and progestin) could ease these side effects. But controversy remains on whether estrogen increases the risk for breast cancer.

Unfortunately, early detection of ovarian cancers has proved exceedingly difficult, even with high-tech transvaginal ovarian ultrasound and the CA-125 blood test. In most cases, by the time doctors detect the disease it has progressed to an inoperable, incurable stage. Once women understand the limitations of available screening techniques, some may view prophylactic oophorectomy as a more acceptable choice.

According to studies conducted at The University of Texas M.D. Anderson Cancer Center, prophylactic mastectomies appear to offer greater protection against cancer than oophorectomies. Among 3,000 patients with a family history of breast cancer who had had preventive mastectomies, only 1% of the 800 highest risk patients developed the disease after surgery. While surgeons cannot remove all the breast tissue, it appears that with less tissue left behind, less chance remains for disease to evolve.

Of course, physicians have found more success in screening for breast cancer than ovarian cancer. Mammography tends to work better among women over 50 whose fattier breasts yield their inner landscape more readily. But the x-rays cannot always detect cancers early enough in younger women whose denser breast tissue can cloak tiny tumors. Despite that, Dr. Lynch recommends that women at inordinately high risk for hereditary breast cancer begin screening at age 25, repeating the procedure every other year through age 35, and then annually thereafter. Such caution is warranted, he says, because so many of these women will contract breast cancer in their mid-40s. And for those facing heritable disease, prophylactic surgery starts to look like an option, if an uncertain one