EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome

Abstract

EXECUTIVE SUMMARYAn original evidence review examined screening and diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) and the subsequent outcomes in a population of newly diagnosed cases of colorectal cancer (CRC). This supplementary evidence review focuses on five issues of further interest to the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG), as summarized below. Clarifying how to define the clinical disorder-Lynchsyndrome. In this supplementary review, Lynch syndrome refers to individuals with a predisposition to CRC and certain other malignancies as a result of a germline mismatch repair (MMR) gene mutation-including those with an existing cancer and those who have not yet developed cancer. This definition allows planned analyses of clinical validity and utility to be more straightforward. Several recent editorials and publications recommend that the ambiguous term HNPCC be abandoned and that this clarified definition of Lynch syndrome should be used instead. Removing family history from consideration as a preliminary test.A previous evidence review showed that screening performance of both the Amsterdam and the Bethesda criteria to identify individuals with Lynch syndrome were highly heterogeneous, possibly due to differences among the populations tested. In a general population, Amsterdam criteria are associated with relatively low sensitivity (28 -45%), but high specificity (99%), whereas Bethesda criteria are associated with higher sensitivity (73-91%), but at the cost of lower specificity (82-77%). Neither provides the necessary high sensitivity/specificity in a reliable and consistent manner. There are also gaps in knowledge relating to the time required to collect family history, the consistency with which it is collected, and the accuracy of the information. Inadequate evidence was available to determine the distribution of mutations in the MMR genes, but the limited data suggest 32% will be in MLH1, 38% in MSH2, 14% in MSH6, and 15% in PMS2. Adequate evidence was available to estimate sensitivity (69%) and specificity (point estimate of 100%) for identifying Lynch syndrome using a specific mutation in the BRAF gene among those with absent IHC staining for MLH1. An alternative to BRAF mutation testing might be direct testing of MLH1 methylation status, but this was not evaluated. Benefits and harms to probands and relatives with Lynchsyndrome. Between 2 and 12 first-degree relatives of probands (newly diagnosed CRC cases with Lynch syndrome, or index cases) can be contacted, based on resources and methodology. There was adequate evidence to document uptake of counseling among these firstdegree relatives who were contacted (52%) and subsequently targeted for MMR gene mutation testing (95% however, may be subject to family history bias. The U.S. Multisociety Task Force on Colorectal Cancer recommends colonoscopy every 1 or 2 years for first-degree relatives of individuals diagnosed with Lynch syndrome, and uptake among this group is about 80%. Th...

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…Diagnoses of Lynch Syndrome using clinical strategies, such as the Amsterdam criteria, have a lower sensitivity and specificity than those incorporating the use of MSI/MMR testing within the algorithm, such as the Bethesda guidelines (Gologan and Sepulveda, 2005;Jass, 2007;Peterlongo et al, 2003). Universal tumor screening further increases the sensitivity compared to selective testing strategies, with more at risk relatives undergoing genetic evaluation and receiving appropriate cancer surveillance (EGAPP, 2009;Palomaki et al, 2009;Snowsill et al, 2014). Strict, intensive life-saving cancer surveillance is recommended for any individual with Lynch syndrome .…”

“…A recent literature review and meta-analysis indicates the incidence of BRAF mutation in sporadic MLH1 MSI CRC to be 63.50% (95% CI: 46.98% -78.53%) (Parsons et al, 2012) Likewise most CRCs containing activated BRAF mutation have CIMP, whereas CIMP and the BRAF mutation are uncommon in Lynch syndrome-associated cancers (≤1%) (Lagerstedt Robinson et al, 2007). Thus, BRAF mutation analysis may offer an exclusion criterion for genetic testing in CRC (Lagerstedt Robinson et al, 2007;Palomaki et al, 2009). In contrast, the frequency of BRAF mutations in extra-colonic sporadic tumours is low and therefore BRAF testing is not useful in distinguishing sporadic dMMR extra-colonic tumours from those associated with Lynch syndrome, irrespective of methylation status (Kawaguchi et al, 2009).…”

“…A supplementary evidence review by the same group subsequently devised the new definition of Lynch syndrome as a hereditary predisposition to malignancy that is explained by a constitutional mutation in the MMR genes. HNPCC was replaced as it had been loosely applied to heterogeneous groups of families meeting limited clinical criteria (Palomaki et al, 2009). They also produced an economic modeling of programmatic costs and costs per Lynch syndrome detected using four different testing strategies in patients with CRC and their relatives.…”

Primary care providers’ cancer genetic testing-related knowledge, attitudes, and communication behaviors: A systematic review and research agenda

“…1,2 Recommendations exist for the use of genetic testing to identify pathogenic variants in highpenetrance genes including BRCA1/2, associated with hereditary breast and ovarian cancer, [3][4][5] and mismatch repair genes associated with hereditary nonpolyposis colorectal cancer (i.e., Lynch syndrome). [6][7][8] Such genetic testing can inform personalized cancer risk management strategies, including the use of cancer screening tests.…”

How do researchers manage genetic results in practice? The experience of the multinational Colon Cancer Family Registry

“…The lifetime CRC risk in individuals with LS is estimated to be up to 82 %, which is substantially higher than the general population CRC risk of 5 %. In 2009, the Evaluation of Genomic Applications in Practice and Prevention working group recommended screening all newly diagnosed CRC patients for LS by genetic testing, so that family members could be similarly tested and, if appropriate, offered early cancer detection interventions in order to decrease morbidity and mortality (Palomaki et al 2009). Specific cancer screening guidelines are available for early cancer screening and detection in such families (Järvinen et al 2000).…”