Prostate cancer risk doubles in patients with Lynch syndrome

Steven K. Clinton, MD, PhD

Because prostate cancer is the most common noncutaneous malignancy in men, it is not unusual for multiple first-degree relatives to be diagnosed within an aging population that is being screened. However, the identification of genes contributing to the risk of prostate cancer has been remarkably difficult and slow. We now appreciate that the hereditary breast and ovarian cancer (HBOC) syndrome associated with mutations in BRCA1 and BRCA2 genes enhances risk of male breast cancer and prostate cancer. However, the population-attributable risk for these rare genes is low, accounting for only a small proportion of the 240,000 new cases of prostate cancer each year in the United States.

The study by Raymond and colleagues has provided greater insight into the relationship between an inherited genetic condition called Lynch syndrome as a contributor to higher overall lifetime risk of prostate cancer, or development disease at an earlier age.

 Lynch syndrome was first identified as a component of inherited colon cancer and more recently as a contributor to endometrial, ovarian, stomach, bladder, pancreatic and brain cancers. Germline mutations occur in genes involved in mismatch repair, including MLH1, MSH2, MSH6 and PMS2.  Approximately one in 440 people are carriers for inherited mutations in DNA mismatch repair.

In this study of 198 Lynch syndrome families with more than 4,000 men monitored, the investigators observed a nearly twofold increased risk of prostate cancer compared with the general population. This finding may have implications for future screening efforts and cancer prevention research in order to detect curable cancers early and reduce the chance of developing advanced or lethal disease.

Jorge Garcia, MD

Prostate cancer remains the most common malignancy in men in North America. Despite major technical and therapeutic advances observed during the past decade — such as chemoprevention and early diagnosis — identification of populations at risk remains controversial. As it is the case for most solid tumors, the true etiology of this epithelial malignancy is not known. Well-established risk factors include age and ethnicity; however, dietary and genetic factors are less well understood.

Existing observational and epidemiological studies have demonstrated the importance of genetics in the pathogenesis of this disease. The data are unfortunately confounded by the intrinsic bias of population‐based studies, such as the Scandinavian twin pair study that suggested that a little bit less than 50% of the risk of prostate cancer could be explained by hereditary factors. Other relevant genomic studies have recently identified single nucleotide polymorphisms that can increase the risk of prostate cancer development but do not impact the overall prognosis of the disease. Similarly, other investigators have suggested that genetics interact with the environment. Examples of these include chronic viral infections (eg, XMRV virus) or low levels of oxidative enzymes, such as manganese superoxide dismutase.

It is also known that the presence of BRCA1 or BRCA2 mutations increase the risk of developing prostate cancer in men. Although alterations in these genes appear to correlate with more aggressive disease (ie, high Gleason Scores), the clinical utility of this information is not well defined. Other well-known genetic syndromes have been linked to prostate cancer; however, these studies are biased as most patients are identified through high‐risk genetic clinics where the estimates of cancer tend to be greater by definition.

The elegant study conducted by Raymond and colleagues continues to demonstrate the importance of a patient’s “makeup” and its association with cancer. As it is the case in Lynch syndrome, in addition to gastrointestinal and gynecological malignancies, tumors of the urinary tract have been associated with the germline mutations in the mismatch repair (MMR) genes that lead to this genetic syndrome.

Raymond’s study used modified segregation analysis to quantify the lifetime cumulative risk of prostate cancer for MMR mutation carriers recruited through high‐risk cancer genetics clinics. They studied probands and their first‐ through fourth‐degree relatives for 198 independent mutation‐positive Lynch syndrome families enrolled in two US familial cancer registries.

In the study, 97 of 4,127 prostate cancers were identified, with a cumulative lifetime risk of 6.3% at age 60 years. This risk is twofold higher than in the general population. Although this study can be utilized during patient counseling, it does not provide enough clinical information concerning tumor biology or overall disease outcome. In addition, it does not allow us to define the subset of patients who might benefit from early screening.

Taking into account the natural history or prostate cancer, including lead time bias and the lack of clear benefit for PSA screening, further genomic studies are required to further define the true clinical utility of genetic testing in prostate cancer.