Germline Variants in DNA Interstrand-Cross Link Repair Genes May Contribute to Increased Susceptibility for Serrated Polyposis Syndrome

Serrated polyposis syndrome (SPS) is characterized by the development of multiple colorectal serrated polyps and increased predisposition to colorectal cancer (CRC). However, the molecular basis of SPS, especially in cases presenting family history of SPS and/or polyps and/or CRC in first-degree relatives (SPS-FHP/CRC), is still poorly understood. In a previous study, we proposed the existence of two molecular entities amongst SPS-FHP/CRC families, proximal/whole-colon and distal SPS-FHP/CRC, according to the preferential location of lesions and somatic events involved in tumor initiation. In the present study, we aimed to investigate these distinct subgroups of SPS patients in a larger cohort at the germline level and to identify the genetic defects underlying an inherited susceptibility for these two entities. Next-generation sequencing was performed using multigene analysis with a custom-designed panel in a Miseq platform in 60 SPS patients (with and without/unknown FHP/CRC). We found germline pathogenic variants in 6/60 patients (<i>ATM</i>, <i>FANCM</i>, <i>MITF</i>, <i>RAD50</i>, <i>RAD51C</i>, and <i>RNF43</i>). We also found variants of unknown significance (VUS), with prediction of probable damaging effect in 23/60 patients (<i>ATM</i>, <i>BLM</i>, <i>BRCA1</i>, <i>FAN1</i>, <i>ERCC2</i>, <i>ERCC3</i>, <i>FANCA</i>, <i>FANCD2</i>, <i>FANCL</i>, <i>MSH2</i>, <i>MSH6</i>, <i>NTHL1</i>, <i>PALB2</i>, <i>PDGFRA</i>, <i>PMS2</i>, <i>PTCH1</i>, <i>RAD51C</i>, <i>RAD51D</i>, <i>RECQL4</i>, <i>TSC2</i>, <i>WRN,</i> and <i>XRCC5</i> genes). Most variants were detected in gene coding for proteins of the Fanconi Anemia (FA) pathway involved in the DNA Interstrand-Cross Link repair (ICLR). Notably, variants in ICLR genes were significantly more frequent in the proximal/whole-colon than in the distal subgroup [15/44 (34%) vs 1/16 (6%), <i>p</i> = 0.025], as opposed to the non-ICLR genes that were slightly more frequent in the distal group [8/44 (18%) vs. 5/16 (31%), <i>p</i> > 0.05]. Germline defects in the DNA-ICLR genes may contribute to increased serrated colorectal polyps/carcinoma risk in SPS patients, particularly in proximal/whole-colon SPS. The inclusion of DNA-ICLR genes in the genetic diagnosis of SPS patients, mainly in those with proximal/whole-colon lesions, should be considered and validated by other studies. In addition, patients with germline defects in the DNA-ICLR genes may be more sensitive to treatment with platinum-based therapeutics, which can have implications in the clinical management of these patients.