DNA-Repair Genes and Prostate Cancer

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Years of research demonstrate beyond doubt that cancer often runs in families-that is, the risk for being diagnosed with a malignancy is influenced by the genes we inherit from our parents. Prostate cancer is highly heritable, meaning that a man’s genetic profile greatly affects his odds of developing the disease.

In fact, researchers recently discovered that defects, or mutations, in certain genes that normally play a maintenance role in the body increase the risk for metastatic prostate cancer, the variety that’s hardest to treat. This research has important implications for men with advanced prostate cancer-and for their families as well.

The role of DNA-repair genes

A major advance in technology called DNA sequencing is helping scientists learn more about how genes that are passed from parent to child affect the risk for many different diseases. Genes are segments of DNA, the substance that carries a cell’s operating instructions. DNA frequently sustains damage, which can be caused by environmental influences, such as tobacco smoke or overexposure to the sun. DNA can also be damaged by “errors” that occur when cells divide and replicate themselves. Both types of damage can eventually cause mutations, which, in turn, may increase the risk for disease.

Gene defects that occur in germ cells (sperm or egg cells) pass from one generation to the next and are known as germline, or inherited, mutations. Defects that occur in all other cells after conception are called somatic, or acquired, mutations. Fortunately, our cells also have a variety of genes that can repair DNA; they carry instructions for producing proteins that can fix or undo much genetic damage. Ironically, DNA-repair genes themselves can develop mutations. If that happens, DNA damage may go unrepaired, leading to mutations that promote cancer. Unfortunately, DNA-repair gene mutations can also be inherited.

DNA-repair genes and prostate cancer

Certain inherited mutations in DNA-repair genes are known to increase the risk for prostate cancer. Until recently, however, scientists had primarily studied the link between these mutations and localized prostate cancer-that is, cancer that has not metastasized, or spread beyond the gland to other organs. A better understanding of the genetic makeup of metastatic prostate cancer-the kind that spreads rapidly and is challenging to treat-could prove highly valuable.

Current methods for screening men for prostate cancer “overdiagnose” the disease, since they don’t distinguish between harmless tumors that will never metastasize and those that will become lethal. A genetic test that could identify men with prostate cancer that’s likely to metastasize could help ensure that they receive prompt, aggressive, and targeted treatment, while sparing unnecessary biopsies and therapies for men with tumors that are likely to remain indolent and never cause harm.

To better understand the role of inherited DNA-repair gene mutations in prostate cancer, researchers analyzed data on the DNA of 692 men with metastatic disease. The data were obtained from studies conducted at several different medical centers in the United States and the United Kingdom. Men were included in the analysis regardless of a family history of cancer or age at diagnosis-factors commonly associated with inherited cancer risk. Each man had provided a sample of his saliva, inner cheek cells, or blood, which researchers used to perform DNA sequencing in search of mutations occurring in 20 DNA-repair genes linked to an increased risk of various forms of cancer, including prostate cancer.

The study, published in The New England Journal of Medicine in 2016, found that nearly 12 percent of the men had at least one inherited DNA-repair gene mutation. To put that figure in perspective, the researchers compared their findings to an earlier study of men with localized prostate cancer, which found that only 4.6 percent had inherited DNA-repair gene mutations. An examination of a large database of more than 53,000 cancer-free men found that just 2.7 percent had these gene mutations. In other words, men with aggressive prostate cancer were more than twice as likely as men with localized prostate cancer to have inherited a DNA-repair gene mutation and more than four times as likely as cancer-free men in the general population.

Guiding therapy decisions

The results of this investigation suggest that a test for inherited DNA-repair gene mutations might one day be used to identify men who require early and frequent screening for prostate cancer. It would also help determine which men diagnosed with prostate cancer would require prompt treatment (meaning they would not be candidates for active surveillance, or close monitoring).

The findings also suggest that men with metastatic prostate cancer should undergo genetic testing, because the results could guide treatment decisions. Doctors now know that men with metastatic disease who carry these inherited mutations respond to certain treatment approaches.

A family affair

Another reason for men with metastatic prostate cancer to undergo genetic testing: The results could serve as a sentinel, providing close family members with important information about their own cancer risk. While men in the 2016 New England Journal of Medicine study who had germline DNA-repair mutations did not necessarily have a family history of prostate cancer, their first-degree male relatives (fathers, brothers, sons) would nonetheless benefit from knowing that they share a genetic profile that increases their risk for an aggressive form of the disease. For instance, such knowledge might prompt those men to pursue more frequent screening.

Moreover, 71 percent of men with inherited DNA-repair mutations in that study had close relatives with certain other malignancies, particularly breast, ovarian and pancreatic cancers. That’s no surprise, since certain gene mutations are known to increase the risk for several forms of cancer. By far the most common mutation found among the men in this study was a defect in the DNA-repair gene BRCA2, which made up 44 percent of all mutations. BRCA2 mutations are closely associated with breast, ovarian, and prostate cancer. Another DNA-repair gene, BRCA1, represented 7 percent of the mutations in this study. If a woman knows that her father, brother, or son carries germline BRCA1 or BRCA2 mutations, she may choose to pursue more aggressive cancer screening, too.

Ask your doctor if you are a candidate for genetic testing. The National Comprehensive Cancer Network (NCCN) has recently issued guidance on when such testing may be appropriate.