Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome)

Abstract

Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.Electronic supplementary materialThe online version of this article (doi:10.1007/s10689-010-9408-8) contains supplementary material, which is available to authorized users.

Germline Mutations in Oncogene-Induced Senescence Pathways Are Associated With Multiple Sessile Serrated Adenomas

“…12 Attempts to model the genetics of this syndrome as monogenic among unrelated individuals, or as Mendelian through linkage analyses, have not been successful. 13, 14 The genetic basis for this disorder remains undefined, with the exception that mutations in MUTYH have been observed in only a small minority of cases that present with concomitant tubular adenomas. 15 …”

Family History of Colorectal Cancer in BRAF p.V600E-Mutated Colorectal Cancer Cases

“…In addition, multi-case families, with a predisposition to develop advanced serrated lesions (polyps and CRC) and a high frequency of CRC with the BRAF p.V600E mutation and variable levels of MSI (MSI-V), have been described(16). In a study of 11 such families, we have shown that 7 demonstrated linkage to the same region of chromosome 2q32.2-q35 (15) supporting a genetic predisposition to develop serrated neoplasia.…”

“…In addition to its occurrence in CRCs from individuals with no family history of CRC (7), the BRAF p.V600E mutation is frequently observed in the CRCs from multiple relatives within families with serrated neoplasia predispositions such as Jass syndrome (15, 16) and serrated polyposis(17). Previous studies have demonstrated a positive association of family history of both CRC and extracolonic cancers (ECCs) with risk of a BRAF -mutated CRC (11, 18, 19).…”

Familial Colorectal Cancer, Beyond Lynch Syndrome

“…48,49 Although biallelic MutYH mutations have been reported in some individuals meeting WHO criteria for serrated polyposis, 50 clinical genetic testing in these patients has been low yield. Studies in individual families have reported linkage to loci on chromosomes 1p 51 and 2q 52 ; however no definitive candidate genes have been identified.…”