Universal Screening For Lynch Syndrome Research Articles

Comparison of immediate germline sequencing and multi-step screening for Lynch syndrome detection in high-risk endometrial and colorectal cancer patients.

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome with a significantly increased risk of colorectal and endometrial cancers. Current standard practice involves universal screening for LS in patients with newly diagnosed colorectal or endometrial cancer using a multi-step screening protocol (MSP). However, MSP may not always accurately identify LS cases. To address this limitation, we compared the diagnostic performance of immediate germline sequencing (IGS) with MSP in a high-risk group. A total of 31 Taiwanese women with synchronous or metachronous endometrial and colorectal malignancies underwent MSP which included immunohistochemical staining of DNA mismatch repair (MMR) proteins, MLH1 promoter hypermethylation analysis, and germline sequencing to identify pathogenic variants. All patients who were excluded during MSP received germline sequencing for MMR genes to simulate IGS for the detection of LS. Our findings indicate that IGS surpassed MSP in terms of diagnostic yield (29.0% vs. 19.4%, respectively) and sensitivity (90% vs. 60%, respectively). Specifically, IGS successfully identified nine LS cases, which is 50% more than the number detected through MSP. Additionally, germline methylation analysis revealed one more LS case with constitutional MLH1 promoter hypermethylation, bringing the total LS cases to ten (32.3%). Intriguingly, we observed no significant differences in clinical characteristics or overall survival between patients with and without LS in our cohort. Our study suggests that IGS may potentially offer a more effective approach compared to MSP in identifying LS among high-risk patients. This advantage is evident when patients have been pre-selected utilizing specific clinical criteria.

Using a multistep approach with multidisciplinary team to increase the diagnosis rate of Lynch syndrome-associated colorectal cancer after universal screening: a single-center study in Japan

Backgrounds: This study aimed to evaluate the changes in the rates of genetic counseling and genetic testing as well as the diagnosis rate of Lynch syndrome (LS)-associated colorectal cancer before and after multistep approach with multidisciplinary team in Japanese.MethodsIn September 2016, we started universal screening for LS by mismatch repair protein immunohistochemistry and prospectively collected the records. Following patient interviews, we started multistep approach with multidisciplinary team (MA) in January 2020. MA consists of six surgeons, one genetic counselor, one medical geneticist, and six pathologists. MA is set up to compensate for patients’ lack of knowledge about genetic diseases and make case selection for elderly colorectal cancer patients with deficient mismatch repair (dMMR). MA is designed as a system that could be performed by a small number of medical genetic specialists. A total of 522 patients were included during the study duration, 323 and 199 patients in the pre-MA (P-MA) and MA groups, respectively.ResultsThe frequency of dMMR in all patients was 10.0%. The patient interview results indicated a significant lack of patient education regarding genetic diseases. The rates of genetic counseling and genetic testing was significantly higher in MA group than in P-MA group (genetic counseling: MA 34.6% vs. P-MA 7.7%, p = 0.04; genetic testing: MA 30.8% vs. P-MA 3.8%, p = 0.02). Moreover, the diagnosis rate of LS-associated colorectal cancer was significantly higher in MA group (2.5%) than in P-MA group (0.3%) (P = 0.03). In addition, MA could be performed without problems despite the small number of medical and human genetics specialists.ConclusionsMA has achieved appropriate pickup of suspected hereditary colorectal cancer patients and complemented the lack of knowledge about genetic diseases. The introduction of MA increased LS-associated colorectal cancer after universal screening. MA is an appropriate LS screening protocol for Japanese patients who lag behind in medical and human genetics education.

EE513 Economic Evaluation of Universal Lynch Syndrome Screening Protocols Among Newly Diagnosed Patients with Endometrial Cancer

Between 2%-6% of endometrial cancer (EC) cases are attributable to Lynch syndrome (LS). Although universal tumor screening for LS among patients with EC is recommended by professional societies, implementation remains suboptimal. Our objective is to compare the relative performance, costs, and efficiency of different LS screening protocols among newly diagnosed EC patients from a U.S. healthcare system perspective.

Universal screening for Lynch syndrome in operated colorectal cancer by immunohistochemistry: a cohort of patients in Liaoning province, China.

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome worldwide. Due to the decreasing family size in Liaoning province. The Bethesda and Amsterdam II criteria have lower sensitivity and specificity and are not suitable for the local population. Immunohistochemistry screening for mutations in DNA mismatch repair (MMR) in newly diagnosed colorectal cancer can improve the detection rate of LS. All newly diagnosed colorectal cancer patients who underwent surgery between January 2018 and June 2020 at Cancer Hospital of China Medical University and Shengjing Hospital of China Medical University from Liaoning China were included retrospectively, and the ratio of universal LS screening by immunohistochemistry, MMR protein deficiency (dMMR) ratio, MLH1 loss, MSH2 loss, MSH6 loss, and PMS2 loss was analyzed. The clinicopathological characteristics of patients with pMMR and dMMR were analyzed. A total of 7019 colorectal cancer patients underwent surgery and 4802 (68.41%) patients were screened by immunohistochemistry for MMR, 258 (5.37%) cases were reported to have a loss of MMR expression. In the dMMR group, a higher number of patients were under 50 years old, more tumors were located at the right colon, less patients have lymph node metastasis, more tumors were stage II, and histological types of mucinous carcinoma or signet ring carcinoma were more common, compared with the pMMR group. Only 2.71% dMMR patients meet Amsterdam criteria II, 2.71% of patients meet Revised Bethesda guidelines, and 17.83% meet Chinese LS criteria. Twenty-five dMMR patients were confirmed by next-generation sequencing and five families were confirmed as Lynch family. These data imply that universal screening for LS by immunohistochemistry may be effective in Liaoning province.

A Focused Clinical Review of Lynch Syndrome

Lynch syndrome (LS) is an autosomal dominant condition that increases an individual's risk of a constellation of cancers. LS is defined when an individual has inherited pathogenic variants in the mismatch repair genes. Currently, most people with LS are undiagnosed. Early detection of LS is vital as those with LS can be enrolled in cancer reduction strategies through chemoprophylaxis, risk reducing surgery and cancer surveillance. However, these interventions are often invasive and require refinement. Furthermore, not all LS associated cancers are currently amenable to surveillance. Historically only those with a strong family history suggestive of LS were offered testing; this has proved far too restrictive. New criteria for testing have recently been introduced including the universal screening for LS in associated cancers. This has increased the number of people being diagnosed with LS but has also brought about unique challenges such as when to consent for germline testing and questions over how and who should carry out the consent. The results of germline testing for LS can be complicated and the diagnostic pathway is not always clear. Furthermore, by testing only those with cancer for LS we fail to identify these individuals before they develop potentially fatal pathology. This review will outline these challenges and explore solutions. Furthermore, we consider the potential future of LS care and the related treatments and interventions which are the current focus of research.

597P Endometrial carcinoma and mismatch repair deficiency: Clinical association and universal screening for Lynch syndrome

Endometrial carcinoma (EC) is characterised by a high rate of DNA Mismatch Repair deficiency (dMMR). Testing for dMMR might have implications for EC prognosis and is part of Universal Screening (US) for Lynch syndrome (LS) diagnosis. However, this is not widely implemented yet, and LS is still underdiagnosed. For these reasons, we aimed to evaluate dMMR prevalence, its association with clinicopathological variables and its role for LS diagnosis for EC patients. This is a monocentric retrospective study on 368 consecutive EC cases (stages I-IV). From 2013 to 2020 they underwent surgery and immunohistochemistry (IHC) analysis for dMMR. We collected age, date of surgery, tumor histotype, grading, FIGO stage at diagnosis, lymphovascular invasion (LVSI), and survival status. We then assessed the proportion of dMMR patients on the entire cohort. Major outcome were OS and RFS in the dMMR patients compared to MMR proficient cases (pMMR). Among the dMMR cases, we reported those who underwent genetic testing and had LS. dMMR was found in 91/368 EC patients (25%). 84 had endometroid histotype, 7 other histotypes (92% vs 8% p= 0.010), 50 had G2 nuclear grading vs 19 G1 and 22 G3 (55% vs 21% vs 24%; p=0.005). As compared to pMMR at a 4-year follow-up an unfavorable trend in OS and RFS was observed for patients with dMMR (4 y OS 82% vs 74% p=0.115, 4 y RFS 70% vs 54% p-value=0.153). In multivariate analysis, age (p<0.001), histotype and grade (p<0.001), stage (p=0.003) and LVSI (p=0.010) were independently associated to OS. dMMR only showed a trend in worse OS (p=0.10). Among the 91 patients with dMMR, only 5 underwent genetic counseling (GC)(6.6%): LS was diagnosed in 1 patient (20%) with loss of MSH2/MSH6 expression. This is the largest Italian cohort of US for LS. dMMR prevalence was 25%, mainly associated with endometrioid type, G2 grading and a worse 4 y OS, as compared to pMMR cases, consistent with the literature. Unfortunately, oncologists' compliance with US for LS is still very poor, with a 6.6% GC referral. This should be implemented according to international guidelines, to increase LS diagnosis, reduce mortality in relatives and incidence of second cancers in survived patients.

221 Lynch Syndrome - Do We Really Screen for It?

Abstract Aim Firstly, assess the compliance of our Trust with the DG27 NICE Guidelines (2017) recommending universal screening of patients with Colorectal Cancer (CRC) for Lynch Syndrome (LS), using Immunohistochemistry or Microsatellite Instability testing. Secondly, provide a cost estimate for the Trust to implement universal screening for LS. Method Retrospective data collection for all CRC resection specimens reported by the Trust's Pathology Lab in 2019, and check of pathology reports, Clinic letters, and lab results through the Trust's electronic system for screening for LS. Cost estimates were calculated using information from the Histopathology Department and similar Audits by other NHS Trusts. Results From the 361 colorectal resection specimens examined at the Trust's Pathology lab, 340 were not screened for LS (NICE Guidelines compliance = 5.8%). Of the 21 screened, 12 patients did not have LS, and for 9 screening was not completed. By categorising the patients into groups by age, location of cancer, and presence of synchronous or metachronous cancers, we found that there was no consistent rationale behind screening (i.e., patients with phenotypical characteristics traditionally related to LS were not screened). We estimated that universal LS screening would cost the Trust approximately £25,000 annually. Conclusions There is extremely poor compliance with the NICE Guidelines in a Trust with one of the highest numbers of CRC resections annually. Even the Amsterdam Criteria are not used to screen patients for LS. Screening could change the surgical and oncological management of the patients and also suggest different surveillance and prophylaxis for the affected family members.

A Scoring Model and Protocol to Adapt Universal Screening for Lynch Syndrome to Identify Germline Pathogenic Variants by Next Generation Sequencing from Colorectal Cancer Patients and Cascade Screening.

Simple SummaryLynch syndrome (LS) is an autosomal-dominantly inherited form of cancer predisposition dominated by colorectal cancer (CRC). LS is caused by germline pathogenic variants (PV) occurring in known mismatch repair genes. For effective cascade screening, it is critical to identify PV for LS predisposition. When limited resources are available, next generation sequencing (NGS) of an entire cohort of colorectal cancer (CRC) patients, even those under 50 or 60 years of age, places a huge burden on the system. Here, we present an innovative LS ascertainment and follow-up program that includes LS molecular analysis, PV screening with NGS technology, and cascade screening. The goal is to improve LS ascertainment in light of the growing burden of early-onset CRC, particularly in low- and middle-income countries.Identification of germline pathogenic variants (PV) predisposing to Lynch syndrome (LS) is an important step for effective use of cascade screening of extended at-risk lineages, leading to reduced morbidity and mortality due to colorectal cancer (CRC). As a general rule, however, next generation sequencing (NGS, either of gene panels or whole exomes) is relatively expensive and unaffordable for general clinical use. In resource-poor settings, performing NGS testing on an entire cohort of CRC patients, even if limited to those under 50 or 60 years of age, still places an enormous burden on limited resources. Although family history can be a good indicator for LS testing, identifying at-risk family members and offering cascade screening may not benefit many patients/probands without an obvious family history. This article presents a novel program called Modified Ascertainment and follow-up Program (MAP) with a scoring model for LS ascertainment and molecular screening by NGS with diagnosis confirmation of PV and cascade screening. The goal is to improve LS ascertainment in light of the growing burden of early-onset CRC, particularly in low- and middle-income countries. Through MAP, judiciously applied molecular genetics will improve identification of PV predisposing to LS and cascade screening.

Initial screening by immunohistochemistry is effective in universal screening for Lynch syndrome in endometrial cancer patients: a prospective observational study.

Few prospective reports of universal screening for Lynch syndrome exist for patients with endometrial cancer. In this study, we performed immunohistochemical staining for DNA mismatch repair-related genes (MLH1, MSH2, MSH6 and PMS2), to determine the extent to which Lynch syndrome can be diagnosed in endometrial cancer patients through universal screening. We recruited 116 consecutive patients assumed to have uterine corpus malignancy from October 2019 to February 2021 in a prospective observational study. We performed immunohistochemical for mismatch repair-related proteins on samples from 100 patients who had surgicopathologically confirmed diagnoses of endometrial cancer. Samples with missing immunohistochemical results for any of the proteins had subsequent universal screening tests for microsatellite instability, DNA methylation of the MLH1 promoter region and mismatch repair genetics. We identified 19 (19.0%) patients with lost results for any of the proteins. All 19 patient samples had subsequent screening tests. We identified the microsatellite instability-high phenotype in 84.2% (16/19) of these patients and MLH1 methylation in 57.9% (11/19). Mismatch repair genetic testing detected two pathological variants, in MSH2 and MSH6, which indicated that the prevalence of Lynch syndrome was 2.0% in our cohort. Two cases of unclassified variant (MSH6) and one case of benign variant (PMS2) were also detected. Initial screening by immunohistochemical is an effective method in universal screening for Lynch syndrome in endometrial cancer patients.

Universal Screening for Lynch Syndrome Compared with Pedigree-Based Screening: 10-Year Experience in a Tertiary Hospital.

Universal screening for Lynch syndrome (LS) refers to routine tumor testing for microsatellite instability (MSI) among all patients with colorectal cancer (CRC). Despite its widespread adoption, real-world data on the yield is lacking in Korean population. We studied the yield of adopting universal screening for LS in comparison with pedigree-based screening in a tertiary center. CRC patients from 2007-2018 were reviewed. Family histories were obtained and were evaluated for hereditary nonpolyposis colorectal cancer (HNPCC) using Amsterdam II criteria. Tumor testing for MSI began in 2007 and genetic testing was offered using all available clinicopathologic data. Yield of genetic testing for LS was compared for each approach and step. Of the 5,520 patients, tumor testing was performed in 4,701 patients (85.2%) and family histories were obtained from 4,241 patients (76.8%). Hereditary CRC (LS or HNPCC) was present in 69 patients (1.3%). MSI-high was present in 6.9%, and 25 patients had confirmed LS. Genetic testing was performed in 41.2% (47/114) of MSI-high patients, out of which 40.4% (19/47) were diagnosed with LS. There were six additional LS patients found outside of tumor testing. For pedigree-based screening, Amsterdam II criteria diagnosed 55 patients with HNPCC. Fifteen of these patients underwent genetic testing, and 11 (73.3%) were diagnosed with LS. Two patients without prior family history were diagnosed with LS and relied solely on tumor testing results. Despite widespread adoption of routine tumor testing for MSI, this is not a fail-safe approach to screen all LS patients. Obtaining a thorough family history in combination with universal screening provides a more comprehensive 'universal' screening method for LS.

Results of an immunohistochemistry-based universal screening strategy for Lynch syndrome in patients with colorectal cancer treated in a public hospital from Latin-America

BackgroundThere is limited evidence regarding the implementation of an immunohistochemistry-based universal screening for Lynch Syndrome (LS) in Latin America. The aim of this study was to evaluate the results of a universal screening strategy in colorectal cancer in a public hospital from Latin-America. MethodsSingle center prospective study including patients who underwent colorectal resection for CRC between March 1, 2016 and March 1, 2017. Mismatch Repair status (MMR) based on immunohistochemistry (IHC) was obtained. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for revised Bethesda and modified Amsterdam II criteria. Kaplan-Meier analysis was performed for overall and relapse free survival. Results65 patients were enrolled (35 women). Median age 58 years (22-88). Main tumor location was left colon (48%). Nineteen patients (29%) had positive Bethesda Criteria. Eight patients (12%) with MMR deficiency were detected by IHC: 5 MLH1/PMS2, 2 MSH2/MSH6 and 1 MSH6. The sensibility and specificity for Bethesda Criteria to assess MMR loss were 50% and 73.8%, respectively. Among the patients with MLH1 loss, one patient had a mutated BRAF and two MLH1 promoter hypermethylation. Of the five eligible patients for genetic study, one did not present mutations, three corresponded to a variable of uncertain significance and one had a pathogenic variant of MSH2. The 5-year overall survival was 63.1% without any difference according MMR status. ConclusionsDespite the barriers in public health from Latin America, higher detection rates of patients who should undergo germline sequence study for LS supports the implementation of a universal LS screening strategy.

Swiss cost-effectiveness analysis of universal screening for Lynch syndrome of patients with colorectal cancer followed by cascade genetic testing of relatives

BackgroundWe estimated the cost-effectiveness of universal DNA screening for Lynch syndrome (LS) among newly diagnosed patients with colorectal cancer (CRC) followed by cascade screening of relatives from the Swiss healthcare...

Real-world outcome of universal screening for Lynch syndrome in Japanese patients with colorectal cancer highlights the importance of targeting patients with young-onset disease.

Despite the recommendations of the latest guidelines, the practical efficacy of universal screening for identifying Lynch syndrome (LS) among patients with colorectal cancer (CRC) may be limited in the real world due to infrequent referrals and the difficulties of genetic testing. Thus, the present study aimed to retrospectively analyze the results of universal screening of patients with CRC at a referral hospital in Japan. Immunohistochemistry was performed for mismatch repair proteins [including DNA mismatch repair protein MSH6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), DNA mismatch repair protein Msh2 (MSH2) and DNA mismatch repair protein Mlh1 (MLH1)] and BRAF V600E mutation. Tumors that showed the following were considered to indicate LS and patients with such tumors were designated as genetic testing candidates (GTCs): i) Loss of MSH6/MSH2; ii) loss of MSH6 alone; iii) loss of PMS2 alone; and iv) loss of PMS2/MLH1 with negative BRAF V600E. MLH1 methylation and BRAF V600E mutation were analyzed in deficient mismatch repair (dMMR) tumors retrospectively. The frequency of dMMR and GTCs in an independent cohort of patients with young-onset CRC were also investigated. Universal screening revealed dMMR tumors, GTCs and LS probands in 7.3, 3.9 and 0.4%, respectively, of 463 patients with CRC. Although dMMR tumors were observed in both younger (<50 years) and older (≥60 years) patients, the GTCs were enriched in younger individuals. Evaluation of mismatch repair status in an independent cohort confirmed the high rate of GTCs in patients with young-onset CRC. The low detection rate of LS demonstrated in this study questions the implementation of routine universal screening in regions with low prevalence of LS. Considering the enrichment of GTCs in young-onset CRCs, age-restricted strategies may be simple and efficient practical alternatives to universal screening in the real world.

Endometrial cancer in Lynch syndrome.

Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS-associated endometrial cancer (LS-EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and PMS2. The clinicopathologic features of LS-EC include early age of onset, lower body mass index (BMI), endometrioid carcinoma and lower uterine segment involvement. There has been significant progress in screening, diagnosis, surveillance, prevention and treatment of LS-EC. Many studies support universal screening for LS among patients with EC. Screening mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR-immunohistochemistry (MMR-IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing and gene sequencing. The effectiveness of endometrial biopsy and transvaginal ultrasound (TVS) for clinical monitoring of asymptomatic women with LS are uncertain yet. Preventive strategies include hysterectomy and bilateral salpingo-oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin. Recent research has revealed the benefits of immunotherapy for LS-EC. The NCCN guidelines recommend pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) EC.

P18-2 Clinical usefulness of universal screening for Lynch syndrome in gynecological cancer of a single-center investigation

Reportedly, Lynch syndrome (LS) accounts for 2-3% of endometrial and colorectal cancer. Although clinical screening, Amsterdam or Bethesda criteria are used to identify patients at risk of LS, these screening tools are limited by their low sensitivity.

Universal Screening for Lynch Syndrome in Uterine Cancer Patients: A Quality Improvement Initiative

(Abstracted from Gynecol Oncol 2021;160:169–174) The Society of Gynecologic Oncology (SGO) recommends systematic clinical screening for Lynch syndrome through immunohistochemistry (IHC) testing of tumors identified in patients younger than 60 years or of any age and a thorough review of personal and family history. Testing targets expression of mismatch repair genes MLH1, MLH2, PMS2, and MSH6 to evaluate microsatellite instability.

Evaluating the clinical utility of universal screening to identify Lynch syndrome in stage III/III colorectal cancer patients: A prospective observational study in Japan.

41 Background: Universal screening for Lynch syndrome (LS) by identifying deficient DNA mismatch repair (MMR) in the tumor tissue of all new colorectal cancer (CRC) patients is widely accepted. The population prevalence of LS is approximately 3% in Western countries, whereas it is approximately 0.7% in Japan. In addition, the number of relatives diagnosed per proband is 3.6 in Western countries, whereas there are even fewer diagnoses per proband in Japan. To address the issue of LS remaining largely underdiagnosed in Japan, we prospectively evaluated the clinical utility of universal screening of LS in CRC patients. Methods: From March 2016 to August 2019, all consecutive new cases of stage II/III CRC underwent immunohistochemistry (IHC) screening for MMR using MLH1, MSH2, MSH6, and PMS2 antibodies. The patients negative for both MLH1 and PMS2 (MLH1-/PMS2-) were subjected to reflex testing for BRAF V600E mutation. Patients with both MLH1-/PMS2- and BRAF negative (cohort A, n = 14) and those with other IHC patterns (cohort B, n = 13) were referred for genetic counseling (GC) and genetic testing (GT). Furthermore, relatives of probands with confirmed LS were referred for GC/GT if they were willing. Results: Overall, 591 pts were enrolled in this study. Patient background were as follows: &gt; 70 y/o, 35%; right-sided/left-sided colon/rectum, 24%/24%/53%; and cStage II/III, 65%/35%. Of 591 patients, 40 (6.8%) had MMR deficiency. Of 27 patients with MLH1-/PMS2-, 24 underwent BRAF reflex testing; only 10 of these patients tested positive for mutation. Of 27 patients recommended for GC, 25 were referred for GC and 22 for GT, which revealed 12 LS cases (2%, mutation genes:MLH1/PMS2/MSH2; 4/2/6). The frequency of LS diagnosis with respect to patient background was as follows: &gt; 70/≤70 y, 1.0/2.6%; right-sided/left-sided colon/rectum, 5.8/0/1.3%; and cStage II/III, 2.6/1.0%. Interestingly, only 3 (25%) of 12 patients who underwent GC/GT in cohort A had LS compared with 9 (90%) of 10 patients in cohort B ( p= 0.004). Moreover, among 11 relatives of 5 families who were willing to undergo GC/GT, six (55%) had LS, of whom two were first-degree relatives (33%), one was a second-degree relative (50%), and three were third-degree relatives (100%). Conclusions: This study showed that universal screening of LS in CRC patients is significantly useful in Japan. Furthermore, implementing a reflex testing strategy demonstrated high adherence to guidelines and the appropriateness of our referrals for GC/GT.

Comparison of universal screening in major lynch-associated tumors: a systematic review of literature.

Lynch syndrome (LS) is associated with an increased lifetime risk of several cancers including colorectal (CRC), endometrial (EC), ovarian (OC), urinary (UT) and sebaceous tumors (ST). The benefit for universal screening in CRC and EC is well known. However, this benefit in other major lynch-associated tumors is unclear. We performed a systematic review of all published articles in the MEDLINE database between 2005 to 2017 to identify studies performing universal screening for LS in unselected CRC, EC, OC, UT and ST. All cases with MSI-H (instability in two or more markers) or missing one or more proteins on IHC testing were considered screening positive. Cases with MLH1 promoter hypermethylation or BRAF mutation positive were considered to have somatic mutations. A total of 3788 articles were identified in MEDLINE yielding 129 study arms from 113 studies. The overall pooled yield of universal LS screening and germline mismatch gene mutation was significantly different across the major LS-associated tumors (Mann Whitney test, p < 0.001). The pooled screening yield was highest in ST [52.5% (355/676), 95% CI 48.74-56.26%] followed by EC [22.65% (1142/5041), 95% CI 21.54-23.86%], CRC [11.9% (5649/47,545), 95% CI 11.61-12.19%], OC [11.29% (320/2833), 95% CI 10.13-12.47%] and UT [11.2% (31/276), 95% CI 7.48-14.92%]. ST also had the highest pooled germline positivity for mismatch repair gene mutation [18.8%, 33/176, 95%CI 13.03-24.57], followed by EC [2.6% (97/3765), 95% CI 2.09-3.11], CRC [1.8% (682/37,220), 95% CI 1.66-1.94%], UT [1.8%(3/164), 95% CI - 0.24-3.83%] and OC [0.83%(25/2983), 95% CI 0.48-1.12%]. LS screening in EC yielded significantly higher somatic mutations compared to CRC [pooled percentage 16.94% [(538/3176), 95%CI 15.60-18.20%] vs. 5.23% [(1639/26,152), 95% CI 4.93-5.47%], Mann Whitney test, p < 0.0001. Universal LS testing should be routinely performed in OC, UT and STs in addition to CRC and EC. Our findings also support consideration for IHC and somatic mutation testing before germline testing in EC due to higher prevalence of somatic mutations as well as germline testing in all patients with ST. Our results have implications for future design of LS screening programs and further studies are needed to assess the cost effectiveness and burden on genetic counselling services with expanded universal testing for LS.

Universal screening for Lynch syndrome in uterine cancer patients: A quality improvement initiative

ObjectiveTo determine the feasibility and effectiveness of a quality improvement initiative (QI) to adopt universal screening for Lynch syndrome in uterine cancer patients at an institution that previously employed age-based screening. MethodsPrior to the initiative, tumors of patients with uterine cancer diagnosed at age ≤ 60 years were screened for mismatch repair deficiency (MMR) and microsatellite instability (MSI). The QI process change model adopted universal testing of all uterine cancer specimens and implemented provider training, standardized documentation, and enhanced use of the electronic medical record (EMR). We compared screening rates, results of screening, follow up of abnormal results, and final diagnoses from the pre- and post-implementation periods. ResultsPre- and post-implementation screening rates for women age ≤ 60 years at the time of diagnosis were 45/78 (57.7%) and 64/68 (94.5%), respectively. The screening rate for all patients with uterine cancer increased from 73/190 (38.4%) to 172/182 (94.5%). The rate of abnormal screening results increased from 15/190 (7.9%) to 44/182 (24.0%) cases. Genetics referral rates among screen positives increased from 3/15 (20.0%) to 16/44 (36.4%). Germline diagnoses increased from 2/190 (1.1%) with two Lynch syndrome diagnoses to 4/182 (2.2%) including three Lynch syndrome diagnoses and one BRCA1 germline diagnosis. The number of patients errantly not screened decreased from at least 32 patients to 3 patients after the intervention. ConclusionsAdherence to screening guidelines significantly improved after interventions involving provider education, optimal use of the EMR, and simplification of screening indications. These interventions are feasible at other institutions and translatable to other screening indications.

Implementation of Universal Colorectal Cancer Screening for Lynch Syndrome in Hispanics Living in Puerto Rico.

Colorectal cancer is the leading cause of cancer death in Puerto Rico and third among Hispanics in the USA. Up to 2-4% of colorectal cancer cases are a result of Lynch syndrome (LS), a hereditary cancer syndrome caused by a germline mutation in at least one of the DNA mismatch repair genes. The objective of this study was to determine the prevalence of LS in colorectal tumors during the first 15-months after the implementation of universal tumor-based screening for LS in Puerto Rico. A total of 317 colorectal tumors were evaluated in a large private pathology laboratory from September 2014 to December 2015. Clinical characteristics were obtained from the pathology reports. Unadjusted and adjusted logistic regression models were used to estimate the magnitude of association (odds ratio [OR] with 95% confidence intervals [CI]) between absent MMR protein expression and patient characteristics. Most cases (93.4%) were analyzed by immunohistochemistry; 11.8% (35 of 296) had deficient mismatch repair protein expression. While 29 of the 317 cases were subjected to PCR-based microsatellite instability analysis of which 10.3% (3 of 317) had microsatellite instability. In total, 11.0% of the tumors were reported MMR deficient. These tumors were more likely from females and more likely localized in the proximal colon compared to those with proficient MMR expression. Our data is consistent with the results from other studies including US Hispanics, where approximately 10% of Hispanic individuals with colorectal cancer have microsatellite instability. Our results support universal tumor-based screening for LS among Hispanics in accordance with National Comprehensive Cancer Network guidelines.