Genome-wide linkage analyses of hereditary prostate cancer families with colon cancer provide further evidence for a susceptibility locus on 15q11–q14

Abstract

The search for susceptibility loci in hereditary prostate cancer (HPC) is challenging due to locus and disease heterogeneity. One approach to reduce disease heterogeneity is to stratify families based on the occurrence of multiple cancer types. This method may increase power for detecting susceptibility loci, including those with pleiotropic effects. We have completed a genome-wide SNP linkage analysis of 96 HPC families, each of which has one or more first-degree relatives with colon cancer (CCa), and further analyzed the subset of families with two or more CCa cases (n=27). When only a prostate cancer (PCa) phenotype was considered affected, we observed suggestive evidence for linkage (LOD≥1.86) at 15q14, 18q21 and 19q13 in all families, and at 1p32 and 15q11-q14 in families with two or more CCa cases. When both the PCa and CCa phenotypes were considered affected, suggestive evidence for linkage was observed at 11q25, 15q14 and 18q21 in all families, and at 1q31, 11q14, and 15q11-14 in families with two or more CCa cases. The strongest linkage signal was identified at 15q14 when both the PCa and CCa phenotypes were considered affected in families with two or more CCa cases (recessive HLOD=3.88). These results provide further support for the presence of HPC susceptibility loci on chromosomes 11q14, 15q11-q14 and 19q13 and highlight loci at 1q31, 11q, 15q14 and 18q21 as having possible pleiotropic effects. This study demonstrates the benefit of utilizing a comprehensive family cancer history to create more genetically homogenous subsets of HPC families for linkage analyses.

Unsupervised Analysis of Array Comparative Genomic Hybridization Data from Early-Onset Colorectal Cancer Reveals Equivalence with Molecular Classification and Phenotypes

“…In this respect, it is important to mention that losses of large parts of chromosome 4 (where some genes important for carcinogenesis appear to be located) are repeatedly reported in several cancers [21], [22], [23], [24], [25], [26], [27], [28]. Also supporting our results, there are many studies that identify different loci in chromosomes 11 and 15 as candidates for CRC susceptibility [29], [30], [31], [32], [33], [34]. Finally, it is worth mentioning chromosome 13 since all tumors of B3 showed alterations in 13q12.…”

Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

“…The EPCAM gene in addition to MMR genes has already been associated HNPCC phenotype [33] as well as MYH in addition to APC gene has been associated FAP phenotype [34]. Recently, association studies have identified a number of loci that appear confer more increases in colon cancer risk [35, 36]. Further studies are needed to better identify the underlying genetic risk factors associated with disease in these families.…”

Screening for familial and hereditary prostate cancer

“…A study of 764 carriers of the mismatch repair gene mutations causing the Lynch syndrome with its high familial predisposition to colon cancer found it to be associated with a two‐fold increase in PC incidence . A study of 96 hereditary PC families found 422 individuals with PC and 97 with colon cancer . Twenty‐seven of the PC pedigrees harbored at least two individuals with colon cancer.…”