Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family.

Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1, a gene associated with breast and ovarian cancer and RNF43, a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998-2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43:c.988 C > T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO2019) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing.

BACKGROUND: Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones. METHODS: We performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants. RESULTS: We identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer. CONCLUSIONS: Identification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.

Familial Colorectal Cancer Type X.

The genetic background is unknown for the 50-60% of the HNPCC families, who fulfill the Amsterdam criteria, but do not have a mutation in an MMR gene, and is referred to as FCCTX. This study reviews the clinical, morphological and molecular characteristics of FCCTX, and discusses the molecular genetic methods used to localize new FCCTX genes, along with an overview of the genes and chromosomal areas that possibly relate to FCCTX. FCCTX is a heterogeneous group, mainly comprising cases caused by single high-penetrance genes, or by multiple low-penetrance genes acting together, and sporadic CRC cases. FCCTX differs in clinical, morphological and molecular genetic characteristics compared to LS, including a later age of onset, distal location of tumours in the colon, lower risk of developing extracolonic tumours and a higher adenoma/carcinoma ratio, which indicates a slower progression to CRC. Certain characteristics are shared with sporadic CRC, e.g. similarities in gene expression and a high degree of CIN+, with significanly increased 20q gain in FCCTX. Other molecular characteristics of FCCTX include longer telomere length and hypomethylation of LINE-1, both being a possible explanation for CIN+. Some genes in FCCTX families (RPS20, BMPR1A, SEMA4A) have been identified by using a combination of linkage analysis and sequencing. Sequencing strategies and subsequent bioinformatics are improving fast. Exome sequencing and whole genome sequencing are currently the most promising tools. Finally, the involvement of CNV's and regulatory sequences are widely unexplored and would be interesting for further investigation in FCCTX.

Differential expression of CK20, ß-catenin, and MUC2/5AC/6 in Lynch syndrome and familial colorectal cancer type X.

BACKGROUND: Hereditary non-polyposis colorectal cancer comprises Lynch syndrome and familial colorectal cancer type X (FCCTX). Differences in genetics, demographics and histopathology have been extensively studied. The purpose of this study is to characterize their immunoprofile of markers other than MMR proteins. METHODS: We compared the expression patterns of cytokeratins (CK7 and CK20), mucins (MUC2/5 AC/6), CDX2 and ß-catenin in Lynch syndrome and FCCTX. RESULTS: Differences were identified for CK20 and nuclear ß-catenin, which were significantly more often expressed in FCCTX than in Lynch syndrome (p < 0.001), whereas MUC2, MUC5AC and MUC6 were overexpressed in Lynch syndrome tumors compared with FCCTX tumors (p = 0.001, < 0.01, and < 0.001, respectively). We observed no differences in the expression patterns of CK7 and CDX2. CONCLUSIONS: In summary, we identified significant differences in the immunoprofiles of colorectal cancers linked to FCCTX and Lynch syndrome with a more sporadic-like profile in the former group and a more distinct profile with frequent MUC6 positivity in the latter group.

The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems.

Semaphorins were originally identified as axon guidance cues that regulate the functional activity of axons in the nervous system. In addition, accumulating evidence indicates that semaphorins have multiple functions in physiological and pathogenic processes, including vascular development, tumor progression, and immune responses. Sema4A is a semaphorin expressed in immune cells, and is thus termed an "immune semaphorin." Sema4A has 4 types of receptors: Plexin D family, Plexin B family, Tim-2, and Nrp-1. Recent studies suggest that Sema4A plays critical roles in many processes including cell-cell interactions, immune-cell activation, differentiation, and migration. In other studies, Sema4A is also associated with carcinogenesis and retinal systems. In this review, we summarize current knowledge regarding the biology of Sema4A in relation to angiogenesis, immune responses, colorectal cancer, and the retina.

Update on Hereditary Colorectal Cancer.

In the past two decades, significant advances have been made in our understanding of colorectal (CRC) tumors with DNA mismatch (MMR) repair deficiency. The knowledge from molecular and genetic alterations in a variety of clinical conditions has refined the disease terminology and classification. Hereditary non-polyposis colorectal cancer (HNPCC) encompasses a spectrum of conditions that have significant phenotypic overlapping that makes clinical diagnosis a challenging task. Distinguishing among the HNPCC disorders is clinically important, as the approach to surveillance for patients and their at-risk family members differs according to risks for colonic and extracolonic cancer associated with each syndrome. Prospective and next-generation studies will provide valuable clinical information regarding the natural history of disease that will help differentiate the Lynch syndrome mimics and guide diagnosis and management for heterogeneous conditions currently grouped under the category of familial CRC. The review is intended to present and discuss the molecular nature of various conditions related to MMR deficiency and discusses the tools and strategies that have been used in detecting these conditions.

Clinicopathological differences between familial colorectal cancer type X and sporadic cancer in an isolated area of spain.

AIM: Very few studies have compared the epidemiological characteristics of patients with familial colorectal cancer Type X (FCCTX) with those of sporadic colorectal cancer (S-CRC). The aim of this study was to compare clinicopathological characteristics and survival between FCCTX and S-CRC in patients from a historically isolated geographical region. METHOD: A retrospective study was carried out of patients with S-CRC and FCCTX treated in the Canary Islands. Family and personal history of colorectal cancer (CRC) were recorded, together with genetic (microsatellite instability), immunohistochemical and clinical variables. RESULTS: Forty-eight (10.6%) of 451 patients were classified as FCCTX and the remaining 403 (89.4%) as S-CRC. Age at the diagnosis of tumour was significantly lower in FCCTX than in S-CRC (64.06 ± 12.65 years vs 69.13 ± 10.80 years; P = 0.01; Z = -2.48). Patients with FCCTX had a larger number of synchronous tumours (P = 0.09). Recurrence was significantly higher in FCCTX than in S-CRC (18.7% vs 8.6%; P = 0.01). Survival correlated significantly with the number of first-degree and second-degree relatives with CRC (P = 0.04; OR: 1.368, 95% CI: 1.01-1.84, and P = 0.04; OR: 1.363, 95% CI: 1.08-1.65) and with the total number of cases of CRC in the immediate family (P < 0.01; OR: 1.377, 95% CI: 1.17-1.61). Recurrence-free time was significantly lower in patients with FCCTX (log-rank = 0.01). CONCLUSION: Significant differences were found in several demographic and clinicopathological variables between patients with FCCTX and patients with S-CRC. These included increased tumour presentation under the age of 50 years and a higher recurrence rate in patients with FCCTX, suggesting an increased risk of CRC in this group.