Germline Alterations in Patients With IBD-associated Colorectal Cancer. Issue 3 (4th August 2021)

• Record Type: Journal Article
• Authors: Biscaglia, Giuseppe; Latiano, Anna; Castellana, Stefano; Fontana, Rosanna; Gentile, Annamaria; Latiano, Tiziana; Corritore, Giuseppe; Panza, Anna; Nardella, Marianna; Martino, Giuseppina; Bossa, Fabrizio; Perri, Francesco; Mazza, Tommaso; Andriulli, Angelo; Palmieri, Orazio
• Is Part Of: Inflammatory bowel diseases. Volume 28:Issue 3(2022)
• Page Start: 447
• Page End: 454
• Publication Date: 2021-08-04
• Subjects: Crohn's disease -- ulcerative colitis -- colorectal cancer -- genetics; Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izab195
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Background: Patients with inflammatory 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 investigates germline alterations in patients with IBD-associated CRC. Methods: We profiled 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 identified pathogenic variants, likely pathogenic, or variants with unknown significance in 18 patients (72%). Six patients (24%) carried pathogenic or likely variants (IARC class 5 or 4). Of the identified 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 significantly shorter in carriers of 4 or 5 IARC variants (7 years; range 0–21; P = .002) and in those with variants with unknown significance (12 years; range 0–22; P = .005) compared with patients without or with only benign variations (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 significantly earlier than in patients with benign or unidentified variants. The screening for these genes could identify IBD patients requiring a more intensive endoscopic surveillance for earlier detection of dysplastic changes.