American Society of Human Genetics

Prostate Tops List of Most Inheritable Cancers.

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One legacy that most men could do without is an inherited risk for prostate cancer, but a massive cohort study shows that for some men, genetic history hints at oncologic destiny.

Data on both identical (monozygotic) and fraternal (dizygotic) twins from the comprehensive birth-to-death registries in Denmark, Finland, Norway, and Sweden show that a man whose monozygotic twin has prostate cancer has a 32% risk for the disease himself, whereas a dizygotic twin whose brother has prostate cancer has only a 16% risk, said Jaakko Kaprio, MD, PhD, professor of genetic epidemiology at the University of Helsinki.

The estimated heritability of prostate cancer — the degree to which genes contribute to risk — was 58% (95% confidence interval, 52 – 63), which is the highest for any malignancy studied, Dr. Kaprio reported here at the American Society of Human Genetics 63rd Annual Meeting.

“These estimates for common cancers are greater than previously estimated. For rare cancers, such as testicular cancer, the concordance risk was substantial. We believe it provides an accurate estimate of familial risk prediction,” Dr. Kaprio toldMedscape Medical News.

Table. Cancers With Significant Heritability

Cancer Type Heritability Estimate, % 95% Confidence Interval
Prostate 58 52–63
Testicular 36 2–95
Breast 28 12–52
Kidney 23 11–42
Lung 25 12–44
Melanoma 39 8–81
Ovarian 28 15–47
Stomach 24 5–65
Uterine 24 14–87
Colon 16 2–63

The magnitude of the genetic contribution to prostate cancer found in this study is higher than the estimated 42% seen in a previous study of Nordic twins (N Engl J Med. 2000;343:78-85). Dr. Kaprio explained that this difference can be attributed to the fact that his team expanded the original cohort to include data from Norway, had 10 additional years of follow-up data, and had an aging cohort, with a resultant increase in incident cancers.

Dr. Kaprio’s team looked at data on 133,689 monozygotic and dizygotic pairs as part of the Nordic Twin Registry of Cancer. They used time-to-event analysis to estimate heritability and familial cancer risk.

What’s Going On?

This study raises important questions about the interplay between genetics and environment in cancer, said Richard Stevens, PhD, professor of cancer epidemiology at the University of Connecticut Health Center in Farmington.

“It’s a very strong study. The exciting thing about this study with prostate cancer is that it’s certainly saying something about mechanism that we don’t get,” he explained.

The study supports the presence of genetic polymorphisms in prostate cancer, and to a lesser degree breast cancer, that can cumulatively contribute to risk, he said.

“The specific polymorphisms we’re aware of — familial syndromes — account for very little breast cancer or prostate cancer. There are other genes where allelic variation and risk is moderate. There must be a lot of those genes with moderate risk; you put them together and it makes you more susceptible,” Dr. Stevens said.

Why a Lucky Few Can Eat to Their Heart’s Content.

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We all know people who seem to have been born with good genes—they may smoke, never exercise, or consume large amounts of bacon, yet they remain seemingly healthy. Now, researchers have found that individuals who carry a rare genetic mutation that controls the blood levels of certain fats, or lipids, are protected from heart disease. The result, reported here yesterday at the annual meeting of the American Society of Human Genetics, suggests that a drug mimicking this effect could prevent heart disease, a major killer.

Triglycerides are lipids that the body makes from unused calories in food and later burns as fuel. Doctors often monitor patients’ blood levels of these compounds because higher levels have been linked to a greater risk of heart disease.

One player in processing triglycerides is a protein called ApoC-III that is encoded by the gene APOC3. Five years ago, researchers discovered a mutation in APOC3 in 5% of the Amish population in Lancaster County, Pennsylvania. Those with this variant had unusually low levels of triglycerides after consuming a fat-laden milkshake. They also had only half as much ApoC-III protein in their blood, and they were less likely to develop calcification of coronary arteries, which can lead to coronary heart disease.

The Amish group was too small to allow researchers to directly link the genetic mutation to less heart disease, however. And it wasn’t clear whether the gene would show up in non-Amish people.

Now, researchers have found APOC3 mutations in the general U.S. population. They sequenced the protein-coding DNA, or exomes, of 3734 white and African-American volunteers, then combed through the data for genetic variants linked to triglyceride levels. A few people turned out to have either the Amish APOC3 mutation or one of three other variants in APOC3 that also disable this copy of the gene. When the team checked the DNA of a larger group of nearly 111,000 people, they found that about one in 200 carried one of the four APOC3 variants, reported Jacy Crosby of the University of Texas Health Science Center, Houston, who represented a large consortium called the National Heart, Lung, and Blood Institute Exome Sequencing Project.

The 500 or so people with one of these APOC3 variants not only had less ApoC-III in their blood and 38% lower triglyceride levels than the average person; they also had a 40% lower risk of coronary heart disease, whose effects include heart attacks. This result firms up the link between APOC3 and heart disease and also supports a possible prevention strategy, Crosby said: Reducing levels of the ApoC-III protein could potentially lower lipid levels and protect against heart disease. One such drug is already in clinical testing, she noted.

The new study “is exciting, but one has to be cautious” about whether such a drug will work, says geneticist Stephen Rich of the University of Virginia in Charlottesville. That’s because inhibiting ApoC-III late in life may not mimic being born with an APOC3 mutation, which protects for a lifetime, he says.