Lecture 39: Familial cancer predisposition Flashcards by Niamh Millar

True or false: All cancers are genetic but only a small proportion is caused by a high-risk hereditary cause.

True

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Describe multi- stage carcinogenesis.

A series of genetic changes occur within cells leading to increasingly abnormal behaviour and histology

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True or false: germ line mutations are more likely to enable cancer than somatic mutations

True

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Is it more likely for cancer to develop after a primary somatic mutation or a secondary somatic mutation?

Secondary somatic mutation

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What is Penetrance?

The percentage of individuals with a specific genotype who also express the expected phenotype

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Name two ways Penetrance may be modified?

May be modified by other genetic variations
May be modified by environmental factors

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What is the role of gatekeeper genes?

they directly regulate tumour growth by monitoring and controlling cell division and death while preventing the accumulation of mutations

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What is the role of caretaker genes?

improving genomic stability (repairing mutations)

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What is the role of landscaper genes?

they control the stromal surrounding environment

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What does the likelihood of developing cancer depend on?

The importance of the gene function

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A defect in which type of gene is associated with familial adenomatous polyposis?

Gatekeeper

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A defect in which type of gene is associated with Lynch syndrome?

caretaker

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What is another name for Lynch syndrome?

Hereditary nonpolyposis colorectal cancer (HNPCC)

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A defect in which type of gene is associated with juvenile polyposis syndrome:

landscaper

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What is the function of the tumour suppressor genes

Protects cells from becoming cancerous
Inhibit cell division, preventing the formation of tumours

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What affect does loss of function of the tumour suppressor genes have?

Increases the risk of cancer.

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What is the function of oncogenes?

Regulate cell growth and differentiation
Gain of function/activating mutations increase the risk of cancer

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Give 5 examples of tumour suppressor genes:

1) APC

2) BRCA 1

3) BRCA 2

4) TP53

5) Rb

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Give 2 examples of oncogenes:

1) growth and signal transduction factor genes

2) RET gene

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What is the name of the theory that states that a cell requires both genes to be mutated for cancer to arise?

Knudson’s two hit hypothesis

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What does Knudson’s two-hit hypothesis state?

for a cell to become cancerous, two hits are required on a specific gene in a single cell

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Describe Knudson’s two hit hypothesis in inherited cancers:

one gene will already be affected due to inheritance meaning just one is required for cancer

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What mode of inheritance do most familial cancers follow?

autosomal dominance

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Give three examples of autosomal recessive familial cancers:

1) MUTYH associated polyposis

2) Fanconi anaemia

3) ataxia telangiectasia

Each parent is a carrier of one mutated copy, usually without the disease (but may have a different phenotype e.g. BRCA2)
¼ of children inherit both mutated copies and the cancer risk

Give 6 mutation types associated with carninogenesis:

1) missense 2) nonsense 3) frame shift 4) splice site mutations 5) large deletions and duplications 6) translocations

Do sporadic cancer mutations arise at young or old ages?

Old

Do familial cancer mutations appear at young or old ages?

Young

Name 6 ways of finding familial cancer genes

Disease-causing translocations may give locations Studying sporadic cancer Family studies – linkage analysis Candidate gene analysis Newer technologies e.g. whole exome sequencing Focus now on ‘moderate risk’ genes and genetic modifiers

Name the stages of a taking a family history

Include maternal and paternal sides Consanguinity? Diagnoses in apparently unrelated people may be linked At least 3 generations Children, siblings, parents, uncles, aunts, nephews, nieces, grandparents, cousins Types of cancer, age of diagnosis Confirm if possible – medical records, cancer registries, death certificate

Do sporadic cancer mutations commonly have one primary cancer or many?

One

Do familial cancer mutations commonly have one primary cancer or many?

Many

What gene is retinoblastoma associated with?

Rbl

What are the purposes of genetic assessment?

Diagnosis/explanation of family history Counselling of advantages and disadvantages of testing Risk of further cancers for affected cases Risk of cancer for unaffected relatives Screening Prevention Treatment Research

What are the disadvantages of genetic assessment?

‘Can of worms’ Anxiety/unhappiness – self, children, other relatives Genetic discrimination - ?? Not so much in UK Results may not lead to any change in management Financial costs to NHS (though has to be viewed as a whole)

When is diagnostic testing used?

Initial diagnostic testing (mutational analysis) usually performed on DNA from a relative affected with cancer to try to identify the familial mutation

When is predictive testing used?

If a mutation is identified in the family, predictive testing for the specific mutation may then be offered to other relatives to determine whether or not they are at risk

What causes bilateral retinoblastoma?

germline mutations

How many children are diagnosed with retinoblastoma a year in the UK?

30-50

What is familial adenomatous polyposis?

the presence of hundreds of bowel polyps that appear from the teens onwards, giving a very high risk of bowel cancer

Describe the presentation of retinoblastoma

Childhood ocular cancer Very rare: 1 in 15,000-30000 live births ~30-50 children/year in UK Classic example following Knudson 2-hit hypothesis Retinoblastoma (Rb1) gene

What 3 other cancers is famliial adenomatous polyposis associated with?

1) CHRPE (retinal disease) 2) desmoid tumour 3) osteomas

What gene is familial adenomatous polyposis associated with?

APC (tumour suppressor gene)

Describe the features of FAP

Hundreds of bowel polyps (adenomas) from teens onwards Accounts for ~1% of bowel cancers High risk (up to 100%) of bowel cancer if untreated (note attenuated form) Other features – CHRPE, desmoid tumours, osteomas APC tumour suppressor gene Autosomal dominant inheritance Colonoscopies, total colectomy late teens/early 20s

What is Lynch syndrome?

Hereditary non-polyposis colorectal cancer

What 5 mismatch repair genes is Lynch syndrome associated with?

1) MLH1 2) MSH2 3) MSH6 4) PMS2 5) EPCAM

What other 4 cancers is Lynch syndrome associated with?

1) endometrial 2) ovarian 3) stomach 4) urinary tract

What criteria is often used to diagnose familial Lynch syndrome in the family?

Modified Amsterdam Criteria

How is Lynch sydnrome managed? (3)

1) colonoscopy every 2 months 2) removal of any polyps 3) aspirin

What cancers are BRCA 1 and 2 mutations associated with? (5)

1) breast 2) ovarian 3) male breast cancer 4) pancreas 5) prostate

What is the name of the surgery used to remove both ovaries and fallopian tubes?

bilateral salpingo-oopherectomy

What gene mutation causes Li Fraumeni syndrome?

P53

What is Li-Fraumeni syndrome?

Germline mutation of one copy of p53 causing a 100% lifetime risk of cancer

What cancers is Li-Fraumeni syndrome associated with? (4)

1) breast 2) sarcomas 3) brain 4) leukaemia

What is CHEK2 syndrome?

a mutation of the CHEK2 syndrome, giving a 22% lifetime risk of breast cancer

How often should patients with Lynch syndrome have a colonoscopy?

every 24 months from age ~25 or 35 (gene dependent (Removal of polyps/early detection of cancer improves survival Role of aspirin in preventing polyps)

How often should women get a breast screening?

annual MRI 30-50, annual mammography from 40 onwards (some eligible for screening from 25)

What is the benefit of breast screenings?

Risk-reducing mastectomies +/- reconstruction Risk-reducing BSO (ovarian screening probably no use) Lifestyle changes Pharmacological prevention BRCA2 (limited evidence)

What are your risk of cancers with BRCA1 and BRCA 2 genes?

Risk of breast cancer 70%; ovarian BRCA1 – 44%; BRCA2 – 10-20% Some increased risk of other cancers – e.g. prostate, male breast cancer, pancreas

What are the function of BRCA1 and BRCA2 genes?

BRCA1&2 are involved in DNA repair