Abstract
Familial colorectal cancer type X (FCCTX) is a heterogeneous colorectal cancer predisposition syndrome that, although displays a cancer pattern similar to Lynch syndrome, is mismatch repair proficient and does not exhibit microsatellite instability. Besides, its genetic etiology remains to be elucidated. In this study we performed germline exome sequencing of 39 cancer-affected patients from 34 families at risk for FCCTX. Variant classification followed the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic/likely pathogenic variants were identified in 17.65% of the families. Rare and potentially pathogenic alterations were identified in known hereditary cancer genes (CHEK2), in putative FCCTX candidate genes (OGG1 and FAN1) and in other cancer-related genes such as ATR, ASXL1, PARK2, SLX4 and TREX1. This study provides novel important clues that can contribute to the understanding of FCCTX genetic basis.
Highlights
Familial colorectal cancer type X (FCCTX) is a heterogeneous colorectal cancer predisposition syndrome that, displays a cancer pattern similar to Lynch syndrome, is mismatch repair proficient and does not exhibit microsatellite instability
FCCTX and Lynch syndrome (LS) differ at the molecular level, because LS is caused by mismatch repair genes (MMR) MLH1, MSH2, MSH6, and PMS2 malfunctioning, presenting microsatellite instability (MSI—high—high microsatellite instability)
Likely pathogenic and pathogenic variants were confirmed by Sanger sequencing, the association of the variants identified with the FCCTX family history requires further validation by segregation analysis, and in other familial cancer cohorts
Summary
Familial colorectal cancer type X (FCCTX) is a heterogeneous colorectal cancer predisposition syndrome that, displays a cancer pattern similar to Lynch syndrome, is mismatch repair proficient and does not exhibit microsatellite instability. Familial colorectal cancer type X (FCCTX) can be considered a subgroup of LS Both are quite similar in their clinical presentation and characterized by several early onset nonpolyposis hereditary colorectal cancer cases in patients and family members from different generations[2]. Some genes have already been reported to be potentially associated with FCCTX, namely BMPR1A7, RPS208, SEMA4A9, SETD610, BRCA211, OGG112 and FAN113. A review by Nejadtagui and collaborators[15] pointed BRCA2, KRAS, APC, MGMT, BRAF, BMPR1A, RPS20, SEMA4A, and hypermethylation of at least one gene of the MMR system as potentially related to FCCTX. Despite these studies, no defined set of genes is conclusively associated with FCCTX. Histology Adenocarcinoma (NOS*) Unavailable Primary tumour location** Colorectal Endometrium Location (colorectal) Rectum Sigmoid Right colon Left colon Transversal colon Unavailable CRC differentiation level Poorly differentiated Moderately differentiated Well differentiated Unavailable CRC TNM stating I II (A, B, C) III (A, B, C) IV (A, B) Unavailable Status Follow up (following with no disease) Deceased Alive in treatment Loss of follow up Amount (%)
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