Clearer Picture of PMS2-Associated Lynch Syndrome Is Emerging

The term Lynch syndrome is used to refer to the hereditary cancer predisposition caused by germline heritable mutations in any one of the family of mismatch repair genes, including MLH1, MSH2 (as well as indirect inactivation of MSH2 via EpCAM mutation), MSH6, and PMS2. Mutations in any of these genes lead to a significant increase in colorectal and endometrial cancer risk, and this commonality in phenotype supports the use of the blanket term Lynch syndrome. However, it has also long been recognized that phenotype varies on the basis of which gene has been disrupted. In particular, the lifetime colorectal, endometrial, and other cancer risks associated with MSH6 and PMS2 seem to be lower than those associated with MLH1 and MSH2. Historically, Lynch syndrome cancer risks and screening recommendations were described mainly on the basis of MLH1 and MSH2 families, because these genes are the most common causes of Lynch syndrome. Acknowledging the heterogeneity within Lynch syndrome, more recent National Comprehensive Cancer Network guidelines have started to provide specific screening recommendations on the basis of the gene affected. The specific phenotype caused by germline PMS2 mutations has been difficult to characterize, both because these mutations are less common than other mismatch repair gene mutations and because, for a long time, the technical difficulties of PMS2 genetic testing caused by the presence of pseudogenes limited the clinical availability of this testing. Thankfully, PMS2 clinical genetic testing is now widely available, and as more individuals with PMS2 mutations are identified, the importance of understanding this phenotype will continue to grow. The largest previous PMS2 study, by Senter et al, estimated cancer penetrance on the basis of 39 families, and this study provided important guidance regarding the management of PMS2-associated Lynch syndrome. In the article that accompanies this editorial, ten Broeke et al provide a significant contribution to the literature regarding PMS2-associated Lynch syndrome. Through the collaborative efforts of cancer genetics specialists in the Netherlands, Denmark, Spain, Sweden, Norway, and Germany, the authors were able to analyze a relatively large sample of 98 PMS2 families that included a total of 2,548 family members and 377 proven mutation carriers. Cancer penetrance estimates that are based on high-risk families who are identified through cancer genetics clinics can be plagued by ascertainment bias that will tend to overestimate risk; whether and to what extent this issue has been addressed is key to the quality of any such study. The study by ten Broeke et al acknowledges and adjusts for this possibility by using a modified segregation analysis model to calculate colorectal and endometrial cancer risks. The authors found a 19% lifetime colorectal cancer risk for men with PMS2 mutations, and an 11% colorectal cancer risk and a 12% endometrial cancer risk for women with PMS2 mutations. These risks are significantly higher than general population risks, but also quite a bit lower than the commonly quoted MLH1and MSH2-associated risks of 60% or greater. Age at colorectal cancer diagnosis in this study ranged from 26 to 86 years (including six individuals who were diagnosed before age 30 years), with a mean age of 47 years in probands and 58 years in family members. Age at endometrial cancer diagnosis ranged from 35 to 81 years, with a mean age of 55 years (no difference between probands and family members). The authors also observed increased risks of other Lynch syndrome–associated cancers, including small bowel, ovarian, and renal pelvis. In addition, the breast cancer standardized incidence ratio was 3.8 (95% CI, 1.9 to 6.8), similar to that found in other recent studies that have suggested that Lynch syndrome might be a low to moderate penetrance risk factor for breast cancer. However, the clinical significance of this finding continues to be unclear for a number of reasons, including small numbers of cases, the possibility of screening bias, and lack of data regarding how this risk factor interacts with other established breast cancer risk factors, including family history. The authors then consider the question of how these cancer risks should best be managed. Standard (MLH1 and MSH2 based) Lynch syndrome screening recommendations include colonoscopy every 1 to 2 years beginning at age 20 to 25 years, awareness of endometrial cancer symptoms, consideration of endometrial cancer screening such as annual endometrial biopsy (with an acknowledgment of the limited data available on efficacy), and consideration of risk-reducing total hysterectomy/bilateral salpingo-oophorectomy (RRTHBSO) when childbearing is complete. Current National Comprehensive Cancer Network recommendations alter this slightly for MSH6 and PMS2, recommending colonoscopy beginning at age 25 to 30 years. ten Broeke et al propose PMS2-associated Lynch syndrome screening guidelines, including deferring colonoscopy until age 30 years. They recommend endometrial cancer screening beginning at age 30 to 35 years, consisting of transvaginal ultrasound and/or endometrial biopsy, and advise against RRTHBSO, citing low endometrial cancer–associated mortality noted in a study of Finnish families with Lynch syndrome. Although we appreciate the authors’ contribution to our understanding of the cancer risks associated with PMS2 mutations, we JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 4 FEBRUARY 1 2015