hereditary cancer

heritability

proportion of variability of a train in a population accounted for by hereditary factors

penetrance

probability that having a genetic condition leads to cancer

factors that contribute to number of CPGs

level of evidence
clinical use
risk conferred
is neoplasia the predominant phenotype

overlap of hereditary genes with somatic genes

30% cancer genes are somatically and hereditary mutated - in all cells
70% mutated only in tumours - not hereditary due to incompatibility with life

inheritance of MMR defects

monoallelic - lynch
biallelic - MMR deficiency

hereditary TSG mutations

PTEN - BC, EC and thyroid cancer
MMR genes - lynch

hereditary OG mutations

RET gene - MEN2

PTEN

normally inhibits PI3K/Akt/mTOR pathway by converting PIP3 to PIP2 = limits cell proliferation
LOF mutation leads to uncontrolled proliferation

MMR - Lynch

results in MSI
can stain for presence of MMR proteins to diagnose
if somatic and not lynch = BRAF mutation and MLH1 promoter mutation

RET - MEN2

RET is a pro proliferative RTK
dimerisation - MEN2A
autophosphorylation - MEN2B
few conserved mutated areas

RET LOF

HSCR disease
absence of ganglion in long intestine leads to megacolon

SH2D1A - XLP

X linked proliferative disorder
risk of EBV driven cancer and B cell NHL
defects in SAP which regulates T and NK cell signalling

TSPY1 - gonadoblastoma

overexpression associated with cancer in males
Y linked

SWI-SNF

chromatin remodelling pathway associated with meningiomas and rhabdoid tumours
repositions or removes nucleosomes
acts as TSG - opposes PRC
SMARCB1 most frequently mutated as a TSG loss

VHL

normoxia = HIF1a binds VHL which tags for degradation
hypoxia = HIF1a doesn’t bind VHL and activates HRE genes
VHL mutation means hypoxic response is upregulated
target - inhibit VEGF or HIF