WP4 - Genomic Characterisation (locus mapping)

Work package number 4 Start date or starting event:  Month 1
Work package title Genomic Characterisation (locus mapping)
Activity Type RTD
Participant number 2 13 14 15
Person-months participant 112 48 35 48

Objectives
1. To identify the cancer-associated loci, confirmed by WP2, in which fine-scale mapping will be carried out, with the aim of defining the causative variants in each.

2. To catalogue the full set of common genetic variants identified at each locus to be mapped (Task 1).

3. To identify the minimal set of candidate causative variants, from the full set for each locus, by comparing the strength of association of each andidate variant against the others in relevant cancer cases and controls from the BCAC, OCAC, PRACTICAL and/or CIMBA consortia (Task 2).

Description of work.
WP4 will be responsible for defining and mapping the smallest possible set of candidates for being the disease-causing mutation at each of the loci confirmed in WP2. Funds and time for this work are limited, and it may be necessary to prioritise the loci, which will be mapped in detail, from the total number of confirmed cancer-associated loci identified.

Task 1 will catalogue all the common genetic variants in each of the confirmed loci from WP2.
The aim is to list the full set of known common variants (ie. SNPs, insertions, deletions and CNVs) within each cancer-associated locus. (Previous experience, with BCAC, yielded 241 common SNPs from 163Kb re-sequenced DNA). We propose to mine bio-informatic databases of common variants, such as the 1000 Genomes Project to generate the catalogues. Only a proportion of the common variants within a given locus (previously 10 – 40%) will be correlated with the initial SNP marker, identified by WP2, and only these will be followed-up as candidates for being the cancer-causing mutation.

Task 2 will define the sub-set of variants, from the full list at each locus, which are highly correlated with the most strongly associated locus marker. A mixture of SNP correlation data and genotyping in relevant cases and controls (from BCAC, OCAC and PRACTICAL) will be used to identify the set of genetic markers within each locus that are most significantly associated with the relevant cancer. (Samples from the CIMBA consortium may be used to aid the mapping of cancer susceptibility loci that have additionally been shown, by WP3, to be modifiers of cancer risk in BRCA1/2 carriers.)

These will comprise the candidates for being the causative mutation. It may be possible to further reduce the number of candidates by using cases and controls from non-European populations that have greater genetic diversity. The mapping leaders for BCAC, OCAC, PRACTICAL and CIMBA will make their own best arrangements for undertaking Task 2 and will each concentrate on mapping the loci relevant to their cancer site.

Deliverables
D 4.1 Manuscript describing the fine-scale mapping process and results in one breast cancer locus (month 6)
D 4.2 Report describing initial loci submitted for fine-scale mapping (month 12).
D 4.3 Website cataloguing the candidate causative variants at each locus, identified by WP4 Task 1 (month 24)
D 4.4 Report describing any additional loci identified as suitable for fine-scale mapping if costs permit, from the confirmed loci listed in D2.7 (month 30)
D 4.5 Update of D4.3 (month 36)
D 4.6 Report presenting the list of candidate cancer-causing mutations defined by WP4 Task 2 and listing planned papers (month 48)

Additional information