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All in the family: Heredity and prostate cancer

(This article was first printed in the March 2003 issue of the Harvard Men's Health Watch. For more information or to order, please go to http://health.harvard.edu/men.)

At the most basic level, all cancers are genetic. The unrestrained growth that characterizes malignant cells depends on defects in deoxyribonucleic acid (DNA), the cells’ genetic master code. DNA is a complex molecule, and errors creep in all the time. In most cases, the cell can correct its own defects, but when repairs fail, important diseases — including cancer — can develop.

Although all cancers depend on genetic abnormalities, not all defects are hereditary; while some are indeed passed down from generation to generation, others are acquired in the course of a lifetime. And even when DNA abnormalities are present at birth, they don’t necessarily cause illness in the years ahead. In fact, most cancer genes can’t ignite malignancies unless they are aided by additional assaults on health, such as exposure to radiation or toxins.

Although prostate cancer is the most common internal malignancy in men, it has taken years for scientists to recognize that heredity plays an important role in causing it. And researchers are just now uncovering the actual genetic defects that predispose men to prostate cancer; it’s important progress that can help warn certain men of an increased risk. And while the benefits of screening are unproven, men with a hereditary predisposition to prostate cancer may choose to undergo prostate-specific antigen (PSA) screening 5–10 years earlier than at the usual age of 50 (see HMHW, July 2001). And they may also decide to change their lifestyles in ways that may prevent an inherited prostate cancer gene from doing its work (see HMHW, March and May 2001).

The impact of heredity

There is no doubt that prostate cancer runs in families. The link was first suspected in 1956, but it wasn’t demonstrated clearly until the early 1970s. Since then, at least a dozen studies have provided confirmation. Most depend on a well-established technique called the case control method. It involves identifying men with prostate cancer and then surveying their families to learn how many relatives also have the disease. At the same time, researchers investigate the families of an equal number of age-matched men who do not have prostate cancer.

By comparing the prevalence of prostate cancer in the relatives of the cancer patients and in those of the healthy men, scientists can establish a relative risk ratio. For example, if prostate cancer is twice as likely to develop in men with family histories of the disease as in men whose families are free of it, the relative risk would be 2.0. In other words, having prostate cancer in the family would double a man’s risk of developing the disease.

Although many studies agree that having a relative with prostate cancer is a risky business, they disagree on just how risky; estimates range from relative risks as low as 1.7 to as high as 8.7. There is, of course, a big difference between a 70% and an 870% increase in risk. The discrepancies can be resolved, in part, by reading the fine print. The impact of family history is greatest when close relatives have the disease, when multiple relatives have been afflicted, and when the disease has been diagnosed at an early age.

All in all, a man who has a father or brother with clinically diagnosed prostate cancer is one and a half to three times more likely to develop the disease than a man with no family history. Grandfathers, uncles, and cousins have a much smaller impact — but a man with many affected relatives is at highest risk, particularly if the disease has been diagnosed before the age of 60. The table below shows an estimate of how these factors affect risk.

Family history and prostate cancer risk
Family history	Estimated relative risk	Estimated lifetime risk
No prostate cancer	—	8%
Father diagnosed after age 60	1.5%	12%
One brother diagnosed after age 60	2.0%	15%
Father diagnosed before age 60	2.5%	20%
One brother diagnosed before age 60	3.0%	25%
Two relatives with prostate cancer	4.0%	30 %
Three or more relatives with prostate cancer	5.0%	35%–45%
Relative risk = Increase in risk in comparison to men with no family history of prostate cancer Lifetime risk = Overall chance of developing prostate cancer during a man’s lifetime Source: Bratt, O. Journal of Urology 2002, vol. 168, p. 907.

Nature vs. nurture

Families share more than genes; they may also have common environmental exposures, dietary patterns, exercise habits, socioeconomic status, and educational levels. When prostate cancer runs in a family, is it due to genetic factors or lifestyle influences, to nature or nurture?

Scientists turned to a unique resource, the Scandinavian twin registries, which contain medical and demographic data on 44,788 pairs of Swedish, Danish, and Finnish twins. The subjects include both monozygotic twins, who are genetically identical, and dizygotic twins, who are no closer genetically than siblings who are not twins. In addition, the registry includes twins who were raised in the same household as well as those who were separated early in life. By comparing the incidence of cancer in each category of individuals, the researchers were able to calculate the relative importance of hereditary and environmental factors for 11 different types of cancer.

The study found that heredity makes only a minor contribution to most malignancies. But prostate cancer, breast cancer, and colorectal cancer were the exceptions. In each disease, heredity was very important indeed — and it had a greater impact on prostate cancer than on the other hereditary tumors. In all, the scientists calculated that 42% of the risk of prostate cancer depends on inherited factors; for colorectal and breast cancers, the figures are 35% and 27%, respectively.

Other cancers

It is clear that a family history of prostate cancer boosts a man’s risk of developing the disease — but does a family history of other malignancies also increase his risk for prostate cancer?

Yes — in some cases, at least. The link is strongest for breast cancer. Researchers from the American Cancer Society tracked 480,802 men who were free of cancer when the study began in 1982. During the next 17 years, 3,141 men died of prostate cancer. Among men with no family history of prostate cancer, those with a family history of breast cancer were more likely to die from prostate cancer than those without breast cancer in a relative.

The overall risk was very modest, but it was more appreciable among men younger than 65 whose relatives were diagnosed with breast cancer before age 50 (a 65% increase in risk) and among Jewish men (a 73% increase). And while a much smaller Swedish study found no link between hereditary prostate cancer and most malignancies, it raised the possibility of an association between prostate cancer and cancers of the stomach and kidney as well as the breast.

Which genes?

Each human being has more than 30,000 individual genes; only a handful contribute to prostate cancer.

After years of intensive study, scientists in Sweden and the U.S. identified the first prostate cancer gene in 1996. With a logic that’s sometimes missing in medical terminology, they called it hereditary prostate cancer 1 (HPC1). The gene, which is located on chromosome 1, is responsible for about 3% of all prostate cancers. In all, about 1 in every 500 American men carries HPC1.

A second prostate cancer gene, HPC2, was discovered in 2000. Found on chromosome 17, HPC2 is subject to at least three distinct mutations; the two more common abnormalities confer only a modest increase in risk, but the rare type may send a man’s risk soaring to 200 or even 300 times normal. In all, HPC2 accounts for 4%–5% of prostate cancer cases.

Because no single genetic abnormality accounts for most cases of prostate cancer, it is highly likely that many genes share the responsibility. In addition to HPC1 and HPC2, other suspect genes include MSRI (a gene that also increases cardiac risk), ELAC2, the androgen receptor gene, RNASEL, and two genes on the sex chromosomes, one on the X, the other on the Y. Finally, the breast cancer genes, BRCA1 and BRCA2, appear to have a role in prostate cancer; in particular, a specific BRCA2 mutation (13q) may quadruple a man’s risk for prostate cancer.

Every man should try to improve the lifestyle factors that may contribute to prostate cancer. Although none of the interventions has proven effective, men with an inherited strike against them may be wise to change their ways before the final proof is in. Nutrition is the crucial element, and reducing saturated fat is the most important preventive measure. There is also good evidence to support a high intake of tomatoes and other vegetables, soy, whole grains, fish, and nuts and seeds. Men at high risk might also decide to get lots of vitamin D while avoiding a high intake of calcium. Although foods appear more protective than supplements, selenium and possibly vitamin E may also help. Finally, although the evidence is mixed, regular exercise may confer some benefit.

Even if prevention fails, early diagnosis may help. Measuring the amount of PSA in a man’s blood is the best way to detect prostate cancer in its earliest, most curable form. The test is simple and inexpensive, but it’s controversial, both because of erroneous results and because doctors don’t know if early detection will lead to a longer life, much less a better quality of life (see HMHW, July 2001). Although the 2002 report of the U.S. Preventive Services Task Force does not endorse PSA screening, the American Cancer Society (ACS) and the American Urological Association (AUA) recommend that doctors discuss the pros and cons of PSA screening with their patients, then offer annual testing starting at the age of 50. But for men at increased risk, including men with family histories of the disease and African Americans, they suggest starting the discussion at 40 (AUA) or 45 (ACS).

Family first

Prostate cancer is a worry for all men, regardless of their family history. Still, it’s important to retain perspective, remembering that only 3 of every 100 American men will die from the disease. Remember, too, that prostate cancer is just one example of a malady that can run in families; others include coronary artery disease, high blood pressure, stroke, colon cancer , obesity, and diabetes. Of course, not every man in an affected family will develop the disease, and every man can take steps to improve his odds. That’s why it’s important for you to look at your family tree, keeping track of the branches that are diseased as well as the healthy ones.