Linkage Analysis in Familial Non-Lynch Syndrome Colorectal Cancer Families from Sweden

Abstract

Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies.

Exome sequencing in one family with gastric- and rectal cancer

“…Previous linkage studies have identified several candidate regions on different chromosomes, but the only one in the present study, which resembles any of the published regions, is 9q [ 6 , 7 , 14 , 39 – 41 ]. The region identified in the present study (the variants in the genes OR13C8, EPB41L4B, SEC16A and NOTCH1 ), is just proximal to that region on 9q.…”

Familial colorectal cancer type X: genetic profiles and phenotypic features

“…46 Current understanding suggests that the risk alleles identified are insufficient to independently account for FCCTX, but a combination of moderate and low-risk alleles could contribute to the familial aggregation. 4,[39][40][41][42]47 Genomic and epigenetic profiles of FCCTX-associated colorectal cancer Deranged DNA methylation is inversely associated with the MSI and the CpG island methylation phenotypes (CIMP) and has been demonstrated in 30-40% of colorectal cancers. [48][49][50][51][52] Hypomethylation in long interspersed nucleotide element-1 (LINE-1) has been linked to familial CRC, including FCCTX, and is thought to interfere with chromosomal segregation and thereby enhance chromosomal instability (CIN).…”

Genetic analyses supporting colorectal, gastric, and prostate cancer syndromes

“…In the linkage analysis, the genetic analyses were performed as described, 16 although this time 45 families with at least one case of PrC or GC were used and subdivided into three different analysis groups: all 45 families were analyzed in one CRC, PrC, and GC syndrome group, 32 families in the CRC and PrC syndrome groups, and 22 families in the CRC and GC syndrome groups (see Table 1). The analysis was executed twice for all three groups.…”