Breadt Cancer Genetics Flashcards
Why is angiogenesis a requirement for tumorigenesis (1/6 requirements)
Tumour needs oxygen aupply
What epigentic fsctor causes metastatic breast cancers
HDAC increased reduces exp of ecadherins
Explain what makes up the breast
Lobular units where milk is made then ducts take it down
Epithelial cells make the milk
Myoepithelium surround them as a barrier
Stromal cells also present
In situ malignancy is what
Where cells are malignant but stay surrounded by myopeithelial cells
What is the difference between invasive malignancies and metastatic breast cancer
Invasive means they peoentraye the Myoepithelium barrier and spread to breast connective tissues
Metastatic is where they invade other tissues via lymphatic drainage,neural network or vasculature
What 3 breast event changes occur eg during mestrual cycle, pregnancy, puberty and lactation
Cells will expand, differentiate and then involution occurs to counteract changes
What is this controlled by
Hormones
When is breast cancer risk increased
During early and late menopause
Contraceptive pill
Hormone rt for menopause
Phytoestrogens
Zenoestrogens (mimic hormones)
Why does oestrogen and progesterone promote mutagenesis
Increased cell proliferation
Why is pregnancy seen as protective
Allows differentiation in mammary gland which is protective
What else helps reduce risk
Lactation/breastfeeding
How can this explain demographic incidence
Reduced risk in areas like africa with more pregnancy and breastfeeding
What are the sources of oestrogen for pre, post menopausal women and men
Pre- ovarian androgens converted
Post- adrenal androgens converted
Men- testicular androgens converted
Converted to estrogens by aromataae
Why may obese people have more aromatise and so bigger risk
Present in adipose tissue
Give examples of anti-oestrogen treatment which could reduce risk
Aromatase inhibitors
Serms- antagonist of er binding
What do serms like tamoxifen stop
Cell proliferation / block cell cycle
Explain how the er can affect genes for cell proliferation,apoptosis and differentiation
It has tf activity and can interact with other tf in nucleus like ap-1
Which genes are usually gained or lost in breast cancers via mutations or epi genetics
Loss of tumour suppressors via gene exp or mutation
Gain of oncogenes via mutation in Proto-oncogenes
What are proto-oncogenes
Genes which when mutated can cause cancer
They usually regulate cell growth
What % of breast cancer is hereditary (I.e dominant pattern of inheritance and high penentrance)
5%
What % does sporadic bc make (ie de novo variants/ mutations)
80%
What does familial breast cancer mean
Runs in family but not Mendelian inheritance- either shared environment, by chance or low risk alleles
What are the major hereditary cancer genes (autosomal dominant)
Brca 1/2 and they are tumour suppressirs
Which brca gets commonly methylated
Brca1
What are some of their roles
Dna damage response
Hr
Cell cycle checkpoint role
Chromatin remodelling
What dna repair which is error prone occurs if brca mutated
Nhej
Why does brca1 allow for hr
It interacts with chromatin remodellers like hats and swi/snf to allow for better access for Hr
How does brca2 allow for hr
It’s brc motifs bind rad51 enzyme for hr and also regulate rad51 activity and availability
Which part of brca2 is commonly mutated
Brc motifs
What happens in late g1 and s and g2/m phases to brca1 for cell cycle regulation
Phosphorylated by cdk , atm and atr when dna damage is sensed
= activated dna repair response
Which inherited syndrome with tp53 germ line mutation causes frequent breast cancer
Li fraumeni syndrome (ad)
Which tumour suppressor gene is ad mutated and inherited to cause cowden syndrome and thus high breast cancer risk
Pten
Which gene is mutated germ line that recognises dna ds breaks in ataxia telangasia
Atm gene (phos of brca1)
What does chek2 do which is found to have medium penetrance hereditary variants in bc predisposition
It is a kinase whcih autophosphorylates and dimerises and activates downstream targets like p53 and brca1 in cell cycle checkpoints
Why is brca not so important in sporadic cancer
Rare to be somatic mutations
What types of studies are used to study breast sporadic cancers
Gwas to find snps with associations with risk of breast cancer
What was the biggest OR high risk allele but low penetrance
Fgfr2
are sporadic associations low penetrance
Yes except brca
How many susceptibility loci found
Over 80
Which 3 somatic mutations were only ones found in many subtypes of bc eg her2 , luminal a and b
Tp53, pik3ca and gata3
Why would basal like bc found to be able to be treated by parp inhibitors
20% have a variant in brca genes somatic or germline
What % of sporadic bc was actually found to be due to germline variants
10%
Which gene usually screened for germline predisposition
Brxa, sometimes p53 is li fraumeni suggested
How do parp inhibitors work
In healthy cells, both parp and brca used to repair dna eg during radiation
If you block parp from working in cancer cells with mutant brca they can’t repair dna and apoptosis occurs
