LIN ANAL FAM AGGR BR · Identification of new cancer susceptibility genes by linkage analyses in Polish families with aggregation of breast or colorectal cancers

Final Activity Report Summary - LIN ANAL FAM AGGR BR (Identification of new cancer susceptibility genes by linkage analyses in Polish families with aggregation of breast or colorectal cancers)

International hereditary cancer centre (IHCC), Szczecin, Poland in years 2004 - 2008 successfully performed scientific project entitled: 'Identification of new cancer susceptibility genes by linkage analyses in Polish families with aggregation of breast or colorectal cancers' financed by the European Commission (MTKD-CT-2004-510114; Marie Curie host fellowship for the transfer of knowledge). Project has been coordinated by IHCC with cooperation with International Agency for Research on Cancer (Lyon, France) and University of Helsinki (Helsinki, Finland). The aim of the study was the identification of new cancer susceptibility genes. The objectives of the study were achieved by realisation of three major steps: - collection of biological samples and detailed pedigree / clinical data on registered and preselected families and on unselected consecutive cases; - linkage analyses and genome-wide association studies, sequencing of preselected genes / loci. Qualitative indicators of success are summarised below. Breast cancer The highest Logarithm of the odds (LOD) score in any single family was found in one family which showed a LOD score of 0.86 on chromosome 10q, corresponding to odds in favour of linkage of 7.8:1. In all 15 families combined, the highest evidence of linkage was found for chromosomes 10q (LOD=1.35) and chromosome 4p (LOD=1.56). At this stage new derived projects arise from the results: to further examine the evidence in favour of a genomic region harbouring a breast cancer susceptibility locus this set of data is pooled with the previous set of 149 families (Smith et al., 2006) and 120 newly families recently collected by the international linkage consortium. Colon cancer 16 markers showing significant distribution differences between colorectal cancers and controls have been identified. Among them, eight polymorphisms were located in chromosome 4 and five polymorphisms were located in chromosome 8. One of them maps directly inside the region of interest highlighted by the linkage analysis of the two analysed families. At this stage, a derived project for a further fine-mapping of the peak at chromosome 4 is actually ongoing. Results of analysis obtained from 922 lung cancer patients were included in multi-centre studies on tobacco-related cancers. The variants in the region 15q25 and an additional variant rs402710 in the region 5p15.33 was detected in the genome-wide data (p = 2x10-7), and was also detected in the replication study (p = 7x10-5) resulting in p=2x10-10 in the combined dataset. A second unlinked SNP from this region, rs2736100, was also identified in the combined dataset (p = 4x10-7). Inheritance of multiple risk alleles from both variants resulted in a statistically significantly increased risk of lung cancer (p = 2x10-13). No statistical significant effects for any of the analysed SNPs were observed among bladder and laryngeal cancer cases. In spite of this, we observed an increased risk associated with a different marker, rs4324798, (OR = 1.206, 95 % CI 0.86-1.68, p = 0.273) for laryngeal cancer cases. Results of analysis were included in a multi-centre studies on tobacco-related cancers. A measurable effect of their activities is the research article 'Identification of gene region 5p15.33 as a novel lung cancer susceptibility locus using 5 800 lung cancer cases and 9 300 controls' accepted for publication by Nature Genetics in September 2008.

Data: CORDIS, © European Union