LCL Expression StudiesLCL Expression Studies Familial aggregation of expression profiles in LCL Common mutation signatures in blood cells of cases with retinoblastoma, SLE,

autism and bladder cancer Used to triage families for linkage studies in breast cancer Evidence of extra-colonic cancers in families with serrated neoplasia Methylation widespread in normal colon of HPP Creates a common expression state

Limited to lymphocytes Controls for blood collection and transport Controls for in-vivo conditions at blood-draw

Examined 12 cases with serrated neoplasia and 10 age- and sex- matched non-cancer controls with Illumina 47K

Is there a difference between the two groups? Are there expression differences common to

All affected individuals in a family plus more than one family Clue-validation model for confirmation

LCL Expression ArraysLCL Expression Arrays

Of 84 genes at p<0.005, 67 (80%) were up-regulated (up to 2.4 fold)

Family-based AnalysisFamily-based Analysis

Significant Findings (p<0.005)Significant Findings (p<0.005)Family A B C D E

Individuals N=3 N=2 N=3 N=2 N=2

Phenotype Mother and 2 sons with HPS

2 sisters with HPS

Father with HPS and 2 sons with sparse polyps

Brother with HPS, sister with advanced serrated polyps

Mother with CRC and son with HPS

CDC14B

EVC

EVC p=0.00003 CDC14B p=0.0019

Genes of InterestGenes of Interest EVC Ellis van Creveld gene (EVC)

up-regulated in 4/5 families associated with dominant and recessive dysplastic

dwarfism function unknown, may inhibit apoptosis EVC is not normally expressed in lymphocytes

CDC14B and Profilin (PFL) associated with mitotic exit and the cytoskeleton multi-nucleated giant cells are observed in family tumours

Other genes up-regulated SNX7 also up-regulated in bladder cancer twisted gastrulation homolog1 involved in BMP signaling HSRTSBETA, a naturally occurring thymidylate synthase inhibitor.