genetic predisposition to cancer Flashcards
what is the result of disease-associated mutations
non-functional or missing proteins - truncating mutation, causes disease through haploinsufficiency
proteins with reduced function
how much breast and ovarian cancer is hereditary
breast - 5-10% hereditary (single gene influence), 15-20% family clusters (polygenetic inheritance or accumulation of genetic susceptibility factors accumulating in a family)
ovarian - 5-10%
what are the causes of hereditary susceptibility to colorectal cancer
sporadic - 65-85%
familial - 10-30% - polygenic inheritance
Lynch syndrome (HNPCC - hereditary non polyposis colorectal cancer) - 5%
FAP (familial adenomatous polyposis) - 1%
rare CRC syndromes - <0.1%
how do HNPCC and FAP lead to colorectal cancer
HNPCC - single gene (alterations in mismatch repair genes)
FAP - single mutation in APC, carpet of polyps in colon, very high risk of cancer
what are tumours
clonal expansions of cells and accumulation of genetic faults
cell contains mutation within its DNA
genetic alteration is replicated
with each replication additional mutations can occur
high rate of growth
what are germline mutations
inherited from single alteration in egg or sperm
heritable
cause cancer family syndromes
generally dominant
mutation in egg/sperm of parent –> all cells affected in offspring regardless of area affected by cancer
what are somatic mutations
occur in non-germline tissues
non-heritable
cause the vast majority of cancers
what genes control the first part of cell growth
what genes control the synthesis phase
oncogenes
tumour suppressor genes
DNA repair genes
alterations in which part of the cell cycle generally predispose to familial and sporadic cancer
familial - tumour suppressor and DNA repair
sporadic - oncogenes (one mutation is enough to cause cancer)
give an example of an oncogene mutation which leads to cancer
oncogene ABL
fuses sporadically w/ BCR (similar genetic sequence)
BCR-ABL fusion protein
on switch in BCR switches on activity of ABL
drives formation of leukaemia
what is this called
leukocoria
sign of retinoblastoma
how can tumour suppressor gene mutations lead to cancer
normal genes (prevent cancer) 1st mutation - susceptible carrier - generally germline single base pair variant 2nd mutation/loss - leads to cancer
describe multi-step carcinogenesis e.g. colon cancer
prinicple used in familial colon cancers in terms of prevention
what is the main mechanism for familial cancer
faulty DNA mismatch repair
what causes Lynch syndrome/HNPCC
what cancers does it result in
opportunities for intervention
mutation in mismatch repair genes - germline predisposition to mismatch repair
XS of colorectal, endometrial, urinary tract, ovarian and gastric cancers
adenoma –> carcinoma sequence for polyp formation
opportunities for prevention
clinical features of HNPCC
early but variable age at CRC diagnosis - ~45y/o
tumour site in proximal colon predominantly
cancer risks in Lynch syndrome
WOMEN: CNS 4% stomach 19% endometrial 60% ovarian 11%
MEN: biliary tract 18% urinary tract 10% - esp kidneys and upper renal pelvis colon 78% sebaceous glands 9%
BRCA1 and BRCA2 associated cancer lifetime risks
WOMEN:
breast - 60-80%, often early age at onset
2nd 1y breast cancer - 40-60%
ovarian 20-50% (1>2)
MEN:
increased risk of prostate cancer and breast cancer (BRCA2)
describe autosomal dominant inheritance
each child has 50% chance of inheriting the mutation
no skipped generations
equally transmitted by men and women
describe mendelian risk
dominant high penetrance syndrome
when to suspect hereditary cancer syndrome
cancer in ≥2 close relatives (on same side of family)
early age at diagnosis
multiple 1y tumours
bilateral/multiple rare cancers
characteristic pattern of tumours (e.g. breast and ovary)
evidence of autosomal dominant transmission
who is at highest risk for hereditary cancer
account for only a small proportion of all cancer
cancer FHx is key to:
- accurate risk assessment
- effective genetic counselling
- appropriate medical follow up
guidelines for risk estimation for individuals based on FHx
- all scottish genetic centres
- similar to UK national guidelines
- recommended use by all doctors
- classify as gene carrier, high, medium or low risk
- low risk is low genetic risk - similar to population average risk
cancer genetics process
- obtain detailed FHx
- confirm diagnosis of cancer
- risk estimation
- counselling
