ARTICLE IN PRESS JID: YDLD [m5G;June 30, 2020;19:26] Digestive and Liver Disease xxx (xxxx) xxx Contents lists available at ScienceDirect Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld Oncology Is tumor testing efficiency for Lynch syndrome different in rectal and colon cancer? Monica Marabelli a , Sara Gandini b , Paola Raviele Rafaniello c , Mariarosaria Calvello a,∗ , Gianluca Tolva a , Irene Feroce a , Matteo Lazzeroni a , Elena Marino d , Matteo Dal Molin d , Cristina Trovato e , Aliana Guerrieri-Gonzaga a , Wanda Luisa Petz f , Massimo Barberis c , Lucio Bertario a , Bernardo Bonanni a a Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti, 435, 20141 Milan, Italy b Molecular and Pharmaco-Epidemiology Unit, Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti, 435, Milan, Italy c Division of Pathology, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti, 435, Milan, Italy d Clinical Genomics Laboratory Unit, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti, 435, Milan, Italy e Division of Endoscopy, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti, 435, Milan, Italy f Division of Gastrointestinal Surgery, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti, 435, Milan, Italy a r t i c l e i n f o Article history: Received 6 February 2020 Accepted 2 June 2020 Available online xxx Keywords: Lynch syndrome Tumor testing Immunohistochemistry (IHC) for MisMatch Repair (MMR) proteins MicroSatellite Instability analysis (MSI) a b s t r a c t Background: Tumor testing utility in Lynch syndrome (LS) diagnosis is established. Aims: Analyze the differences between tumor testing efficiency in rectal (RC) and colon cancer (CC). Methods: We performed immunohistochemistry (IHC) for MisMatch Repair (MMR) proteins (IHC-MMR) and MicroSatellite Instability analysis (MSI) on 482 unselected primary tumors: 320 CCs and 162 RCs. Samples had proficient-IHC, deficient-IHC or borderline-IHC (“patchy” expression). MSI-H borderline-IHC tumors were considered as likely MMR-deficient. Germline testing was offered to MMR-deficient patients without BRAF mutation or MLH1 promoter hypermetilation (MLH1-Hy). Results: We identified 51/482 (10.6%) MMR-defective tumors. Multivariable analysis demonstrated a sig- nificant correlation between tumor testing results with histotype, lymph-node involvement and tumor location. In particular, RC showed a lower MMR-deficiency rate than CC (p<0.0001). Interestingly, MLH1 loss was detected in 0% RCs and 76.1% CCs, with 80% of them showing BRAF mutation/MLH1-Hy. A germline variant was detected in 12 out of 18 patients (mutation detection rate of 66.7%). Conclusion: Tumor testing results showed molecular differences between CCs and RCs, in terms of MMR proteins expression, and presence of BRAF mutation/MLH1-Hy. MSH6 variants were the most frequent ones (50%). Although young age at diagnosis was associated with mutation detection (p = 0.045), 33.3% of LS patients were >50 years. © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. 1. Introduction Lynch syndrome (LS) is an autosomal dominant condition caused by a germline mutation in one of the DNA MisMatch Re- pair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) or by an EPCAM gene deletion resulting in MSH2 silencing [1]. LS is characterized by a relevant increased risk of developing tumors, particularly col- orectal cancer (CRC) and endometrial cancer (EC): it accounts for approximately 1–3% of all CRCs and 2% of ECs [2,3]. ∗ Corresponding author. E-mail address: mariarosaria.calvello@ieo.it (M. Calvello). Historically, the identification of individuals with LS has been based on clinical criteria (Amsterdam or Bethesda guidelines) [4]. However, sensitivity and specificity of these criteria has proven to be moderate [5,6]. Universal testing of all CRCs by IHC-MMR and/or by MSI is currently recommended as initial screening ap- proach to detect the syndrome, since MSI and loss of MMR protein expression are hallmarks of LS-associated tumors. Several studies on universal tumor screening have found that half of LS cases are diagnosed after age 50 and almost a quarter do not meet the Amsterdam criteria or revised Bethesda guidelines [7,8]. In addi- tion, clinical tools have been developed to quantify an individual’s probability of carrying a MMR gene mutation (e.g. MMRPro and PREMM5 Model), but also these models have limitations [9,10]. In light of these considerations, in 2015 the Lombardy region in https://doi.org/10.1016/j.dld.2020.06.002 1590-8658/© 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Please cite this article as: M. Marabelli, S. Gandini and P.R. Rafaniello et al., Is tumor testing efficiency for Lynch syndrome different in rectal and colon cancer? Digestive and Liver Disease, https://doi.org/10.1016/j.dld.2020.06.002