Transcript Serrated Neoplasia and Genetic Predisposition

LCL Expression Studies
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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 noncancer controls with Illumina 47K
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Is there a difference between the two groups?
Are there expression differences common to
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All affected individuals in a family plus more than one family
Clue-validation model for confirmation
LCL Expression Arrays
Of 84 genes at p<0.005, 67 (80%) were up-regulated (up to 2.4 fold)
Family-based Analysis
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 Interest
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EVC Ellis van Creveld gene (EVC)
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CDC14B and Profilin (PFL)
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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
associated with mitotic exit and the cytoskeleton
multi-nucleated giant cells are observed in family tumours
Other genes
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up-regulated SNX7 also up-regulated in bladder cancer
twisted gastrulation homolog1 involved in BMP signaling
HSRTSBETA, a naturally occurring thymidylate synthase
inhibitor.