Lynch syndrome is a hereditary disorder caused by a mutation in a mismatch repair gene in which affected individuals have an increased risk of developing colorectal cancer, endometrial cancer, and various other types of aggressive cancers. The syndrome is named after its discoverer, Henry T. Lynch, MD, director of Creighton University’s Hereditary Cancer Center. It’s estimated that about 3 of every 100 colon cancers are caused by Lynch syndrome, making it the most common inherited cause for colon cancer.
Hereditary cancers were not actively researched until the second half of the last century. There is documentation that physicians acknowledged family cancer clusters during the 1800s; however, it wasn’t until the late 1950s and early 1960s that statistics were used in cancer research to establish the existence of hereditary cancers.
Dr Lynch was a pioneer in the study of cancer and genetics in the 1960s, when cancer incidence was largely attributed to environmental causes. His use of statistics to prove genetic links to certain cancer types was unique from other researchers at that time. His early cancer research significantly influenced how physicians and researchers treat and study hereditary cancers today. Dr Lynch demonstrated Mendelian inheritance patterns for a previously unrecognized form of colon cancer (hereditary nonpolyposis colorectal cancer, now known as Lynch syndrome), and for the hereditary breast-ovarian cancer syndrome, which he subsequently helped link to the BRCA1 and BRCA2 genes. In addition, he provided some of the first findings of hereditary malignant melanoma and prostate and pancreatic cancers. The purpose of his work has been to enable physicians to more quickly and accurately identify high-risk patients, leading to earlier and more effective surveillance, management, and treatment.
Today, based on worldwide estimates, it is projected that over 600,000 individuals have the defective gene; however, less than 5% of them have been diagnosed. Part of Dr Lynch’s vision is a network to serve those with Lynch syndrome that includes genetic testing, a registry, treatment centers, and ongoing surveillance for early prevention. To this end, he helped establish Lynch Syndrome International, a nonprofit organization founded in 2009 to raise public awareness and support for individuals afflicted with the syndrome. It was our great pleasure to interview Dr Lynch about his contributions to the field of oncology, particularly in genetics.
Thank you for speaking with us, Dr Lynch. We’d like you to describe the process that led to the discovery of Lynch syndrome.
Dr Lynch: I developed an interest in genetics early in my medical training, particularly as it related to cancer. Many individuals with an extensive family history of colon cancer were diagnosed with familial adenomatous polyposis (FAP), a hereditary colon cancer that produces hundreds to thousands of polyps. However, some patients diagnosed with FAP did not have symptoms characteristic of the syndrome; the typical numerous polyps were not present in the first family I studied. I suspected another hereditary cancer might exist.
Does the research of Lynch syndrome have implications for other research models/strategies?
Dr Lynch: Yes, our research has extremely important implications for preventive as well as other clinical translational research models/strategies.
Is there a research strategy specific to Lynch syndrome?
Dr Lynch: The research strategy for the Lynch syndrome revolves around issues related to its diagnosis and ultimate management strategies. Its clinical importance relates to the fact that it is by far the most common hereditary colorectal cancer syndrome and extracolonic cancer syndrome problem. These often result in extremely important clinical/preventive cancer syndrome issues.
Does Lynch syndrome resemble other disease states in terms of disease process, patient selectivity, or progression? In other words, is there any analog for gaining an understanding of it?
Dr Lynch: Lynch syndrome, in fact, has strong similarities to disease processes relevant to patient selectivity and cancer progression. There are multiple clinical analogs revolving around the need for a comprehensive family history and ultimately genetic testing, when appropriate, in the search for cancer-causing mutations and design of preventive opportunities.
What has been the greatest significance of the discovery and management of Lynch syndrome on cancer and/or personalized medicine research?
Dr Lynch: The most significant issue, by far, in terms of its diagnosis and management pertains to the need for its personalized medical research contributing to a reduction in morbidity and mortality when compliance is adhered to.
How has the discovery and clinical usage of diagnosis of Lynch syndrome changed morbidity and mortality outcomes of the various cancers it concerns?
Dr Lynch: Discovery and clinical usage of diagnosis of Lynch syndrome has definitely changed morbidity and mortality outcomes. We have profound evidence of this in the study of countless families throughout the United States, South America, and Europe, where we have been highly privileged to have been involved clinically and genetically with physicians in multiple specialties; medical genetics, surgery – particularly surgical oncology and colorectal surgery – gastroenterology, and gynecologic oncology.
How aware of and responsive to Lynch syndrome are practicing oncologists?
Dr Lynch: Well, it’s more fitting to ask if the patients are aware, and their response. We find that our patients have been partially responsive to the preventive implications of Lynch syndrome and the advice given by their family doctors as well as practicing oncologists. However, this only happens when the patients are adequately educated and have constant encouragement.
Which factors tend to limit, and which increase, awareness and management of Lynch syndrome?
Dr Lynch: As part of our goals at the Hereditary Cancer Center, we strive to promote awareness and preventive management. Compliance is hopefully magnified through our genetic counselor and physician interventions. Awareness and management is based on many years of our intensive research, with attempts to come up with what is best for a particular patient.
Factors that limit increased awareness and management of Lynch syndrome revolve around physician interest and willingness to learn about the syndrome and provide its diagnostic and preventive implications to high-risk patients in their practices. Other factors that limit increased awareness and management revolve around limited interest on the part of the patient and willingness of insurance companies to help cover the cost, which can be very high in the case of the sine qua non for diagnosis, namely the search for the cancer-causing germline mutation.
How would you describe awareness and management of the syndrome at Creighton?
Dr Lynch: This has been done admirably well, in my opinion, in our academic setting. The preventive measures we use, particularly colonoscopy, with initiation at age 25 and repeated every other year to age 40 and then annually thereafter, have been successful. Implications for prophylactic hysterectomy and bilateral salpingo-oophorectomy, in collaboration with colleagues at the MD Anderson Cancer Center, in Houston, Texas, have been successful.
Does any particular stakeholder group – practicing oncologists at the academic centers or community centers, payers, patients, etc – stand out as more, or less, cognizant of Lynch syndrome and its management? Put differently, where do healthcare disparities for Lynch syndrome tend to occur regarding patient risk stratification, diagnosis, treatment, patient management/follow-up, and payer coverage/reimbursement?
Dr Lynch: The stakeholder groups, including practicing oncologists and academic centers, have worked very hard to get insurance companies’ support for its costly management. Healthcare disparities for Lynch syndrome enter the picture and may be a particular hazard for ethnic and racial factors, particularly those involving African Americans and patients of Latino background. These issues must be resolved.
Are medical directors and pharmacy directors at health plans sufficiently informed about Lynch syndrome to provide proper coverage of its care?
Dr Lynch: Our experience indicates that medical and pharmacy directors have, for the most part, not been sufficiently informed about Lynch syndrome to the extent that they can reasonably provide proper coverage of its diagnosis and management.
While Lynch syndrome increases risk for some cancers, it does not for others. What accounts for the absence of risk for developing certain cancers?
Dr Lynch: Lynch syndrome increases the risk for multiple primary cancers, particularly cancer of the colorectum, endometrium, ovary, among other extracolonic cancers. So far as we can determine, its risk for so-called environmental cancers, inclusive of head and neck and lung cancer, has not been an exceptionable problem. However, we have no knowledge at this time about the absence of risk for developing certain cancers.
How would you briefly describe the pathogenesis, pathophysiology, and clinical sequelae of Lynch syndrome in terms relevant to practicing oncologists? Do clinicians understand the science behind Lynch syndrome, or just its impact on outcomes?
Dr Lynch: Our pathology colleagues, among other specialists, have been working very hard at attempts to understand the pathogenesis, pathophysiology, and clinical sequelae of Lynch syndrome in terms that can be most useful to practicing oncologists. Understanding the science of the Lynch syndrome has been emerging, particularly at the molecular genetics level, but we have a long way to go in order to have its impact more fully explained on clinical outcomes.
Where is Lynch syndrome trending in terms of clinician recognition, diagnosis, and management? How has this progressed over the past 5 years?
Dr Lynch: The Lynch syndrome has been increasing significantly in its clinical recognition, diagnosis, and management, and it has progressed favorably over the past 5 years in diagnosis. This is in contrast to my initial discovery of the Lynch syndrome in 1962, when I was a second-year medical resident at the University of Nebraska College of Medicine. Clearly, there was no editorial concern about what I was attempting to publish. Attention to the syndrome throughout the world and the lack of believability of my work was truly profound. Over the years interest gradually increased, but at a slow pace. It began to emerge relevant to mounting evidence supporting the existence of Lynch syndrome. However, it wasn’t until the early 1990s when linkage analysis and other technology emerged in support of the diagnosis of Lynch syndrome. Substantial evidence emerged rapidly following the discovery of germline mutations giving evidence for its existence.
Thank you so much for your time today, and our best to you in your continued pursuit of making a difference in the lives of those with Lynch syndrome.