Genetics of Breast Cancer Flashcards
What is breast cancer often responsive to?
Oestrogen.
Why is tumourigenesis so complex?
It is a multi-step process.
What is required for a tumour to form?
Acquisition of six specific capabilities.
What are the six specific capabilities?
- Become independent of external growth stimuli.
- Become insensitive to external anti-growth signals.
- Become capable of tissue invasion and metastasis.
- Become capable of indefinite replication.
- Become capable of sustained blood supply-angiogenesis.
- Become able to avoid cell death-apoptosis
What is the incidence of breast cancer?
Common but good survival
What are the risk factors for breast cancer?
Age is major
Environmental
Diet
Weight
Lifestyle
Genetics
What are lobular units?
Where milk in mammals is formed.
What is the Normal histology of the breast?
Epithelial cells
Myoepithelial cells
Stromal cells
What kinds of lesions occur during breast cancer?
In situ malignant
Invasive malignant
What is a lesion?
A region in an organ or tissue which has suffered damage through injury or disease
What is malignant?
Virulent or infectious.
What is involution?
The shrinkage of an organ in old age.
What is the normal function?
Mammary gland
Differentiation and expansion
Involution
What is the function of the mammary gland?
Puberty
Cyclical changes
Pregnancy
Lactation
What kinds of hormones promote breast cancer?
Natural variations
Contraception
Hormone replacement
Phyto-oestrogen
Zeno-oestrogen
What kinds of natural variation can increase the risk of breast cancer?
Early menarche
Late menopause
Nulliparity
Absence of lactation
What are Phyto-oestrogen?
Soya products
Peas
Beans
What are zeno-oestrogen?
Oils
Detergents
Pesticides
What is oophorectomy?
Removal of ovaries
What was proved by Beatson in 1896?
Oophorectomy resulted in regression of the breast tumour in a young woman
What are the systematic treatments of breast cancer?
Antagonise oestrogen
Competitive inhibitor of aromatase
What are some of the proofs that cancer is a genetic disease?
Some gross alterations
Small nucleotide changes
Epigenetic disease
What are some gross alterations that could cause DNA genetically?
Loss of DNA
Gain of DNA
Altered DNA
What are some small nucleotide changes that could cause DNA genetically?
Point mutations
Small insertions
Small deletions
Small inversions
What are some epigenetic effects that could cause DNA genetically?
Hyper-methylation
Hypo-methylation
Histone modification
What aspects of cancer are genetic?
It is enabled by genome instability
Can lead to gain or loss of function
Inherited predisposition
Is cancer hereditary?
All cancer is caused by genetic alterations but those aren’t always inherited.
What percentage of breast cancer is sporadic?
80%
What percentage of breast cancer is familial?
15%
What percentage of breast cancer is hereditary?
5%
What does it mean when cancer is sporadic?
Arises in a family for the first start.
What does it mean when cancer is familial?
Some arise in families for a second or third time but do not show a clear pattern of Mendelian inheritance
What does it mean when cancer is hereditary?
Several cases in the family
Autosomal dominant inheritance
High but variable penetrance
Early onset and bilateral
What is The BRCAs evidence for genetic cause of breast cancer?
Map loss of gene region in BRCA1 family to chromosome 17q.
Then BRCA2 to 13q chromosome arm
What is the BRCA1?
Tumour suppressor gene on
chromosome 17
How is BRCA1 transmitted?
Autosomal dominant transmission
What is the function of BRCA1?
Nuclear phosphoprotein
Forms a large multi-subunit protein complex
Important in DNA repair
What is BRCA2?
Tumour suppressor gene on chromosome 13
How is BRCA2 transmitted?
Autosomal dominant transmission
What is the function of BRCA2?
BRC repeated motifs bind to the RAD51 recombinase is important in DNA repair.
Binds PALB2 which binds single-
stranded DNA
What is the role of BRCA proteins?
Genomic stability
DNA damage response and repair
Cell cycle checkpoints
What is the effect of BRCA protein on chromatin?
Remodelling
What is the effect of BRCA protein on oestrogen?
Controls responsiveness
What is the effect of BRCA protein on p53?
Coactivator of p53 responsive genes
What histological grade is a BRCA1-associated breast tumour?
Higher histological grade
70% are Grade 3
What is the effect of BRCA1-associated breast tumours on TP53?
Increased alterations in tumour suppressor gene TP53.
What kind of phenotype are BRCA1-associated breast tumours?
Triple-negative
What is the proliferative capacity for BRCA1-associated breast tumours?
An increased proliferative capacity, higher S-phase fraction.
What type of tumour are often DNA-aneuploid?
BRCA1-associated breast tumours
What kind of disorder is Li Faumeni Syndrome?
An autosomal dominant hereditary disorder.
What mutation causes Li Fraumeni Syndrome?
Germline mutations in TP53 tumour suppressor
How does Li Fraumeni Syndrome cause cancer
Responds to DNA damage to halt cell proliferation
When does Li Fraumeni Syndrome present?
At a young age
What kind of disorder is Cowden syndrome?
Autosomal dominant hereditary disorder
What kind of mutation causes Cowden Syndrome?
Germline mutations in PTEN tumour suppressor
How does Cowden syndrome cause cancer?
Restrains cell division
When does Cowden syndrome present?
Develop benign hamartomas in late twenties on skin and mucous membranes
What kind of syndrome is Peutz Jeghers Syndrome?
Autosomal dominant heriditary disorder
What kind of mutation causes Peutz Jeghers Syndrome?
Germline mutations in STK11 tumour suppressor
How does Peutz Jeghers Syndrome cause cancer?
Serine threonine kinase, regulates cell polarity
When does Peutz Jeghers Syndrome present?
Develop benign hamartomatous polyps in childhood in gastrointestinal tract
What kind of syndrome is Gorlin syndrome?
Autosomal dominant heriditary disorder
What kinds of mutations cause Gorlin syndrome?
Germline mutations in PTCH1 tumour suppressor
How does Gorlin syndrome cause cancer?
Receptor for sonic hedgehog and restrains cell division
What kind of syndrome is Ataxia Telangasia Syndrome?
Autosomal recessive heriditary disorder
What kind of mutation causes Ataxia Telangasia Syndrome?
Germline mutations in ATM tumour suppressor
How does Ataxia Telangasia Syndrome cause cancer?
Recognises double-stranded DNA damage
Affects nervous and immune systems → affects movement coordination.
What mutation causes Ataxia Telangasia Syndrome?
Germline mutations in ATM tumour suppressor
What other genes were found to have a connection to breast cancer?
CHEK2
BALB2
What is the high risk allele SNP of breast cancer?
rs2981582 in intron 2 of FGFR2
What was COGS?
Collaborative Oncological Gene-environment Study
