How do we approach the goal of identifying everybody with Lynch Syndrome

Lynch syndrome (LS) is the most common inherited cause of colorectal (CRC) and endometrial cancer. We here define LS as an individual with a germline deleterious mutation in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 or EPCAM [1]. Presently, most people diagnosed with LS have already had colorectal (CRC) endometrial (EC) or other LS-associated cancers; however, among all existing carriers of LS the majority has not (yet) had cancer. LS is currently seriously under-diagnosed. A recent study [2] of stages III and IV CRC patients in the Kaiser Permanente healthcare system found that family history documentation varied from site to site with 3 sites documenting family history on <70 % of cases and 4 sites documenting family history in over 85 % of cases. Despite the fact that in those with a documented family history, 61 % had a relative with cancer and 20 % of these had CRC in at least one first degree relative, <5 % of the population received any Lynch syndrome testing [2]. There are essentially three different approaches that can be taken to identify individuals with Lynch syndrome: (1) The current approach which is to educate providers about Lynch syndrome and then expect that they take a family history from their patients and refer appropriate patients for a cancer genetics evaluation; (2) screen all newly diagnosed CRC and EC patients for Lynch syndrome at the time of diagnosis; or (3) screen the general public for Lynch syndrome either at birth or in early adulthood. Since it is clear that the current approach is not sufficient alone, we discuss the latter two approaches here. The WHO principles of screening are used to decide when a condition should be included in a population-based screening effort [3]. These criteria are as follows: The condition should be an important health problem. The natural history of the condition should be understood and there should be a detectable risk factor, disease marker, latent period or early symptomatic stage. There should be a simple, safe, precise and validated test. The test should be acceptable to the population. There should be an agreed policy on the further diagnostic evaluation of individuals with a positive tests result and on the choices available to those individuals. There should be an effective treatment or intervention for patients identified through early detection, with evidence of early treatment leading to better outcomes than late treatment. There should be agreed upon evidence-based policies covering which individuals should be offered treatment and the appropriate treatment to be offered. There should be evidence from high quality randomized controlled trials that the screening program is effective in reducing mortality or morbidity. There should be evidence that the complete screening program (test, diagnostic procedures, treatment/intervention) is clinically, socially and ethically acceptable to health professionals and the public. The opportunity cost of the screening program (including testing, diagnosis and treatment) should be economically balanced in relation to expenditure on medical care as a whole. We will make the case that LS meets these criteria and therefore, should be considered for some sort of population-based screening approach. At this time, we believe that this screening should be targeted to individuals diagnosed with a LS-associated cancer and their at-risk relatives. However, as new testing techniques emerge and the costs decrease, it is possible that it may be a better approach to screen unaffected individuals either in the newborn setting or in early adulthood as has been suggested previously [4]. Of course, in addition to these active population-based screening approaches, we still support the traditional approach whereby healthcare providers take their patients’ family histories and refer patients (both affected and unaffected) for genetic evaluation when LS is suspected.