Population‐based screening for Lynch syndrome in Western Australia

Abstract

We showed earlier that routine screening for microsatellite instability (MSI) and loss of mismatch repair (MMR) protein expression in colorectal cancer (CRC) led to the identification of previously unrecognized cases of Lynch syndrome (LS). We report here the results of screening for LS in Western Australia (WA) during 1994-2012. Immunohistochemistry (IHC) for loss of MMR protein expression was performed in routine pathology laboratories, while MSI was detected in a reference molecular pathology laboratory. Information on germline mutations in MMR genes was obtained from the state's single familial cancer registry. Prior to the introduction of routine laboratory-based screening, an average of 2-3 cases of LS were diagnosed each year amongst WA CRC patients. Following the implementation of IHC and/or MSI screening for all younger (<60 years) CRC patients, this has increased to an average of 8 LS cases diagnosed annually. Based on our experience in WA, we propose three key elements for successful population-based screening of LS. First, for all younger CRC patients, reflex IHC testing should be carried out in accredited pathology services with ongoing quality control. Second, a state-or region-wide reference laboratory for MSI testing should be established to confirm abnormal or suspicious IHC test results and to exclude sporadic cases by carrying out BRAF mutation or MLH1 methylation testing. Finally, a state or regional LS coordinator is essential to ensure that all appropriate cases identified by laboratory testing are referred to and attend a Familial Cancer Clinic for followup and germline testing.Lynch syndrome (LS), formerly known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant condition caused by germline mutations in DNA mismatch repair (MMR) genes, most commonly MLH1, MSH2, MSH6, and PMS2.1,2 Tumours from LS cases have a defective DNA mismatch repair system, leading to ubiquitous small deletions and insertions in DNA repeat regions (microsatellites) resulting in microsatellite instability (MSI). MSI is almost always accompanied by the loss of expression of MMR proteins that can be readily detected using immunohistochemical (IHC) methods. These two molecular features are also observed in approximately 10% of sporadic (nonhereditary) colorectal cancer (CRC), meaning they are not completely specific markers for the presence of LS. However, sporadic microsatellite-unstable (MSI1) CRC contains mutations in the BRAF oncogene and often shows methylation of the MLH1 gene promoter, whereas MSI1 CRC from LS patients does not.3,4 Hence, the BRAF mutation and MLH1 methylation tests can be used to distinguish sporadic from LS-associated MSI1 CRC.In addition to CRC, LS is also associated with an increased risk of endometrial, small bowel, urothelial, gastric, ovarian, and other cancer types. Although some authors have reported that LS may be responsible for up to 3% of CRC, 5,6 population data derived from MSI screening suggested this

Current mismatch repair deficiency tumor testing practices and capabilities: A survey of Australian pathology providers

“…Ward et al . and Schofield et al . demonstrated less than optimal uptake of germline testing by patients after dMMR was identified in their tumor; therefore further research is required in identifying barriers and factors in uptake of germline testing.…”

“…Western Australia implemented state‐wide IHC and/or MSI screening in all newly diagnosed CRC occurring in < 60 years of age and annual LS cases detected increased fourfold . In South Eastern Sydney, all incident CRCs, regardless of patient age, were tested using MMR IHC supported by MSI and BRAF mutation testing.…”

Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome

“…Population-based studies of Lynch syndrome have shown that most MMR gene mutations are in MLH1 (35-40%) and MSH2 (44-48%), and far less frequent in MSH6 (8-10%) and PMS2 (2-8%) [Schofield et al, 2014;Steinke et al, 2014], but mutation frequency can be cohort dependent [Ward et al, 2013b]. Mutation "hotspots" do not occur in the MMR genes with the spectrum of constitutional mutations including missense [Belvederesi et al, 2006], nonsense [Yoon et al, 2009], frameshift [Caluseriu et al, 2001] and splicing mutations , exon deletions [van der Klift et al, 2005], and inversions [Wagner et al, 2002;Chen 2008;Rhees, et al 2014].…”

A Pragmatic Testing-Eligibility Framework for Population Mutation Screening: The Example of BRCA1/2

“…Furthermore, a surprisingly high fraction of unselected people may carry a medically actionable mutation (3)(4)(5). The confluence of these trends raises the possibility of population screening for medically actionable mutations (6,7). However, current medical guidelines generally recommend against genetic testing for persons without a family history suggesting the presence of a mutationrelated disease (2,8).…”