Comparison Between Familial Colorectal Cancer Type X and Lynch Syndrome: Molecular, Clinical, and Pathological Characteristics and Pedigrees.

Yun Xu,Ye Xu,Cong Li,Yuqin Zhang,Fangqi Liu,Tian’An Guo,Congcong Zhu

doi:10.3389/fonc.2020.01603

Abstract

ObjectiveThis study aimed to compare the molecular, clinical, and pathological characteristics and pedigrees of familial colorectal cancer type X (FCCTX) with those of Lynch syndrome (LS) to provide a theoretical basis for the management of FCCTX.MethodsOverall, 46 cases of FCCTX and 47 LS probands and affected families were enrolled between June 2008 and September 2018 for this study. Multigene cancer panel tests that included 139 genes were performed for all patients, and variants in each group were described. The clinical, pathological, and pedigree characteristics were also compared between the two groups.ResultsIn total, 42 variants were detected in 27 (58.7%) cases in the FCCTX group, with BRCA1, BRCA2, POLE, POLD1, ATR, and ATM being the most frequently mutated genes. The mean onset age of colorectal cancer (CRC) was significantly older in the FCCTX group than in the LS group (53.57 ± 12.88 years vs. 44.36 ± 11.26 years, t = −9.204, p < 0.001). The proportion of patients with rectal cancer was also higher in the FCCTX group than in the LS group [43.5% (20/46) vs. 10.6% (5/47), χ2 = 12.823, p = 0.005]. Within a median follow-up time of 53.9 ± 37.0 months, the proportion of patients who developed metachronous CRC was significantly higher in the LS group than in the FCCTX group [34.0% (16/47) vs. 13.0% (6/46), χ2 = 5.676, p = 0.017]. When comparing pedigrees, older age at cancer onset and rectal cancer clustering were observed in the FCCTX families. A higher prevalence in male patients was also observed in the FCCTX families.ConclusionFCCTX is an entity distinct from LS, but its genetic etiology remains unknown. A larger multigene panel would be recommended for determining the underlying pathogenic variants. Considering the pathology and moderate penetrance of the CRC link to FCCTX, less stringent surgical treatments and colonoscopy surveillance would be preferable. Rectum preference is a typical feature of FCCTX. Colonoscopy surveillance in FCCTX families could be less intensive, and more attention should be given to male members.

Highlights

Heredity is a major influencing factor for the occurrence of colorectal cancer (CRC), and approximately 20–30% of CRC patients have a family history of the disease [1]
Of the 93 patients, 47 identified with pathological variants (PV) of the mismatch repair (MMR) gene were classified as the Lynch syndrome (LS) group, and 46 who met the Amsterdam criteria (AC) and showed a pMMR profile were classified as the familial CRC type X (FCCTX) group
In patients identified with PVs in MMR genes, the results of IHC MMR staining were consistent with those of gene detection

Summary

Introduction

Heredity is a major influencing factor for the occurrence of colorectal cancer (CRC), and approximately 20–30% of CRC patients have a family history of the disease [1]. Lynch syndrome (LS) is a dominantly inherited condition characterized by a significantly increased risk for CRC, being the primary etiology in 2–5% of all CRC cases [2, 3]. LS is recognized by the Amsterdam criteria (AC), which is formulated according to history-based diagnostic algorithms [5]. Research has shown that a considerable number of families that fulfill the AC neither manifested defects in the MMR protein nor carried PV in MMR genes. It was suggested that this hereditary condition should be considered as a different clinical and genetic entity and was designated as familial CRC type X (FCCTX) [6]

Methods

Results

Discussion

Conclusion