Familial cancer Flashcards
What is the typical genetic basis of familial cancers?
Autosomal dominant with incomplete penetrance.
What is the normal function of retinoblastoma?
Prevents progression through the cell cycle by inhibiting the transcription factor E2F.
If mutated, E2F allows transcription of proteins which promote cell cycle progression.
What is the two hit hypothesis?
Inheriting one copy of a mutated allele means that only one mutation in the corresponding allele is needed for cancer to occur.
The first mutation is normally a germline mutation and the second a chromosomal deletion.
What is Li Fraumeni syndrome?
Inheritance of p53 mutations, resulting in sarcomas of bone/soft tissue, leukaemia, and other tumours.
What do MEN1 mutations result in?
Multiple endocrine neoplasia type 1.
Follows 2 hit hypothesis.
What are DNA stability genes?
A subset of TSGs which have a role in DNA repair mechanisms (repair due to mutagens/replication errors
Give examples of disease with errors in DNA stability genes?
Xeroderma pigmentosum
BRCA1/2 breast/ovarian cancer
MLH1
What oncogene mutations are seen in inherited cancers, and what do they cause?
RET (multiple endocrine neoplasia)
MET (papillary renal cell carcinoma)
What is the function of BRCA1 and 2 and what do mutations result in?
Roles in DNA repair, cell cycle regulation, and maintaining genomic integrity.
BRCA1 high risk breast and ovarian cancer.
BRCA2 not as high risk, but risk of inheriting other cancerous mutations.
High penetrance.
What is cancer predisposition syndrome?
A genetic disorder where inherited mutations in >1 gene predispose to development of cancers, which may be early onset.
High lifetime risk of cancer and of >1 primary tumour.
Give examples of conditions associated with cancer predisposition syndrome?
HNPCC
Breast-ovarian cancer syndrome.
What pedigree features suggest cancer predisposition syndrome?
Young age of onset
Deceased
Males affected
>1 affected in a sibship
What testing and screening is available for BRCA mutations?
Testing: next generation sequencing
Screening: mammography or MRI
What mutations are associated with ovarian cancer?
BRCA1/2, HNPCC, MLH1, MSH2
What screening and treatment is available for ovarian cancer?
Screening: difficult. If found, can give prophylactic oophorectomy.
Treatment: poly ADP ribose polymerase (PARP) inhibitor Olaparib.
