Inflammatory Bowel Diseases, 2022, 28, 447–454 https://doi.org/10.1093/ibd/izab195 Advance access publication 4 August 2021 Original Research Articles - Basic Science Received for publications: May 28, 2021. Editorial Decision: July 11, 2021 © The Author(s) 2021. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com Germline Alterations in Patients With IBD-associated Colorectal Cancer Giuseppe Biscaglia, MD,* Anna Latiano, BsC,* , Stefano Castellana, PhD, † Rosanna Fontana, BsC,* Annamaria Gentile, TLSB,* Tiziana Latiano, TLSB,* Giuseppe Corritore, TLSB,* Anna Panza, PhD,* Marianna Nardella,* Giuseppina Martino,* Fabrizio Bossa, MD,* Francesco Perri, MD,* Tommaso Mazza, PhD, †, Angelo Andriulli, MD,* and Orazio Palmieri, BsC* , From the *Division of Gastroenterology, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy † Unit of Bioinformatics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy Address correspondence to: Giuseppe Biscaglia, MD, Division of Gastroenterology, IRCCS, Fondazione Casa Sollievo della Sofferenza, viale Cappuccini 1, 71013 San Giovanni Rotondo, Italy (giuseppe.biscaglia@gmail.com). Background: Patients with infammatory bowel diseases (IBD), both ulcerative colitis (UC) and Crohn’s disease (CD), are at risk of developing a colorectal cancer (CRC). No information is available on the contribution of patients’ genetic background to CRC occurrence. This study investi- gates germline alterations in patients with IBD-associated CRC. Methods: We profled a panel of 39 genes potentially involved in cancer predisposition and searched for germline variants in IBD patients with CRC or high-grade dysplasia. Results: After clinical exclusion of genetic cancer syndromes, 25 IBD patients (4 CD and 21 UC) with CRC or high-grade dysplasia were studied. After excluding variants with low likelihood of pathogenicity (classes 1 or 2 according the International Agency for Research on Cancer [IARC]), the panel identifed pathogenic variants, likely pathogenic, or variants with unknown signifcance in 18 patients (72%). Six patients (24%) carried pathogenic or likely variants (IARC class 5 or 4). Of the identifed variants, 4 encompassed the APC region, 3 the MLH1 gene, and the remaining ones the MSH2, MSH3, monoallelic MUTYH, EPCAM, BRCA1, CHEK2, POLD1, POLE, CDKN2A, and PDGFRA genes. Four patients carried at least 2 variants in different genes. Duration of IBD was signifcantly shorter in carriers of 4 or 5 IARC variants (7 years; range 0–21; P = .002) and in those with variants with unknown signifcance (12 years; range 0–22; P = .005) compared with patients without or with only benign vari- ations (23.5 years; range 15–34). Conclusions: In silico analysis and sequence-based testing of germline DNA from IBD patients with CRC or high-grade dysplasia detected 24% of variants positioned in pathogenic classes. In patients with type 3, 4, and 5 variants, the onset of high-grade dysplasia or CRC was signifcantly earlier than in patients with benign or unidentifed variants. The screening for these genes could identify IBD patients requiring a more intensive endoscopic surveillance for earlier detection of dysplastic changes. Key Words: Crohn’s disease, ulcerative colitis, colorectal cancer, genetics Introduction Patients with infammatory bowel diseases (IBDs) and co- lonic localization are at a higher risk of developing colorectal cancer (CRC), usually referred as IBD-associated or colitis- associated CRC (CA-CRC). 1 The cumulative risk increases over time from the initial diagnosis of IBD, with an esti- mated value of 0.02% to 2% at 10 years, and 5% to 18% at 20 years. 2–6 Although the cumulative risk in the affected patients has declined in the last years, CRC remains the most fearsome complication of IBD, accounting for 10% to 15% of deaths. 1,7 Chronic infammation is assumed to play a key role in the cancer pathogenesis by inducing a chronic, persistent DNA damage in the colonic mucosa. 8 It has been hypothesized that enhanced oxidative stress damaging the genes involved in the cell cycle may be the initial step in the carcinogenetic pro- cess, 9 leading to a specifc pathway, “dysplasia-cancer.” 8 As matter of fact, the recently reported decline in IBD-associated CRC incidence 10,11 has been attributed to the better utiliza- tion of medical therapy and overall immunosuppressant and immunomodulant agents, which are considered to be more effective in the control of the infammation. 12 However, even in patients with a long-standing IBD, CRC occurs only in a minority of cases. This fnding could suggest the presence of a genetic component that, besides infammation, may predis- pose to CRC development. The concept of genetic predispos- ition to CRC in IBD patients is also suggested by other 2 lines of evidence: a familial recall of CRC by some patients, and an animal model showing that after the administration of colitis-inducing agents, genetically engineered cancer-prone mice were more likely to develop CA-CRC than wild-type animals. 13 With the intent to minimize such a risk, efforts have been directed to control infammation and attain an early diag- Downloaded from https://academic.oup.com/ibdjournal/article/28/3/447/6339340 by guest on 14 November 2023