Genetics of cancer

Question 1

What are the proportions of the human genome components

Answer 1

Gene (1.5%)
Proteins, non-coding RNA
Related sequences (40%)
Introns, transcriptional regulatory regions, pseudogens and segmental duplication
repetitive DNA (45%)
Interspersed repeats, mini and microsatellites, telomeres, centromeres

Question 2

What are cancer risk factors

Answer 2

age, environment, exercise, obesity, infection, genetics/family history

Question 3

What could somatic mutations do

Answer 3

May cause cell death (limited consequence), may damage DNA that is non coding or inactive (limited consequence), may damage gene controlling cell growth (potential consequence), could inactivate a ‘tumour suppressor gene’ (allows cells to divide faster), could activate oncogene (drives cell to divide faster), create new fusion gene (chromosome rearrangements)

Question 4

Give examples of targeted therapies for cancer

Answer 4

bevacizumab-binds to VEGF (VEGF stimulates blood vessel growth. Tumours are vascular)
Imatinib-Blocks tyrosine kinase activity

Question 5

Genes associated with canacer predisposition

Answer 5

tumour suppressor genes-important for controlling rate of cell growth. Cancer occurs with bi-allelic loss/mmutation. Heterozygous constitutional mutations=increase risk
oncogenes-accelerate cell division. Cancer arises when stuck in ‘on’ mode
DNA damage-response/repair genes
constantly repairing DNA. Cancer arises due to accumulation of mutations accross genome

Question 6

DNA repair mechanism

Answer 6

mismatch repair (lynch syndromee, colon,  ovarian cancer)
Double strand break repari (BRCA1, BRCA2))
Nucleotide excision repair (XP)

Question 7

What errors do these damaging agents cause and how is it repaired: 1) Xray, oxygen radical, alkylating agent, spontaneous mutations 2) UV light, polycyclic aromatic hydrocarbonss 3) X rays, anti tumour agents 4) replication errors

Answer 7

1) Xray, oxygen radical, alkylating agent, spontaneous mutations
=single strand break->baase excision repair
2) UV light, polycyclic aromatic hydrocarbons
=bulky adduct, CPD->nucleotide excision repair
3) X rays, anti tumour agents
=interstrand cross link, double strand break->recombinational repair 4) replication errors
=A-G mismatch, T-C mismatch, insertion, deletion->mismatch repair

Question 8

How to spot person with genetic susceptibility genes

Answer 8

Most cancer susceptibility genes are dominant with incomplete penetrance (may appear to skip generations). Individuals inherit susceptibility genes, not cancer

Question 9

HIgh penetrance cancer susceptibility syndromes

Answer 9

BRCA1/2
Lynch syndrome (mismatch repair deficiency)
Li-Fraumeni syndrome
Multiple endocrine neoplasia
hereditary leiomyomatosis and renal cancer

Question 10

Cancer risk assessment

Answer 10

Young age onset, multiple primary cancer in same person, same type of cancer in several relatives, recognizable pattern of cancer in families, patterns, ethnicity, close relatives

Question 11

Which type of cancer does lynch syndrome increase the likelihood of

Answer 11

colorectal cancer, endometrial cancer, ovarian cancer, urothelial cancer, brain tumours, gastric cancer, biliary tract cancer, skin tumours

Question 12

What is lynch syndrome caused by

Answer 12

mismatch repair deficiency

Question 13

Process of mismatch repair

Answer 13

DNA replication->mismatch arises->recognition of mismatch–>stabilisation of complex->cleavage of error strand->unwinding by helicase and stabilisation of single-stranded DNA by single stranded DNA binding protein->removal of error strand by REcJ protein->resysnthesis by PolIII and Lig I

Question 14

Lynch syndrome management

Answer 14

colonoscopy from 25 years of age, discussion of risk reducing hysterectomy and bilateral salpingo-oophorectomy from 45. Daily low dose aspirin, symptom awareness

Question 15

Familial adenomatous polyposis

Answer 15

Autosomal dominant

extracolonic tumours: Upper GI, desmoids, ostema, thyroid, liver, brain

Question 16

What is the implication of having BRCA mutation

Answer 16

high risk of breast and ovarian cancer

Question 17

Management of BRCA mutation woman

Answer 17

high risk breast screening, consider bilateral risk reducing mastectomy, consider bilateral salpingo-oophoredctomy from 40 because no effective ovarian screening available. Take prophylactic tamoxifen, be offered pre-implantation genetic diagnosis for family plannning

Question 18

Management of BRCA mutation man

Answer 18

INcreased risk of breast and prostate cancer
no screening currently available
children and siblings at 50% risk of having mutation

Question 19

Cowden syndrome what mutation, symptom and therapy

Answer 19

Mutaiton: germline PTEN
SYmptom: endoometrail cancer, tumours of breast and thyroid, hamartomatous bowel polyps, skin and mucosal lesions, macrocephaly, developmental delay
Target therapies: PARP inhibitors, mTOR inhibitors

Question 20

Peutz-Jeghers syndrome mutation, symptom, management

Answer 20

Mutation:STK11
Symptom: gastrointestinal polyposis disorder, characteristic pigmented lesions on lips and buccal mucosa, increased rissk of breast, gastro and gynae tumours
Management: annual pap smear from 18, TVUSS and CA125 from 25

Question 21

Li-Fraumeni syndrome

Answer 21

Mutation: germline TP53
symptoms: sarcomas, breast cancer, adrenocortical tumours, leukaemia, brain and spinal cord tumours, general increase in cancer risk

Question 22

What are the 2 types of genetic mutations

Answer 22

somatic, germline. Most cancer carry somatic mutations not present in the germline (so not inherited susceptibiliity for developing cancer )

Question 23

What are the 2 types of genetic tests

Answer 23

diagnostic-full screen of gene, normally undetaken in affected individual
predictive-targeted test for specific mutation identified in another family member, normally undertake in individual unaffected with condition

Question 24

Cancer predisposition gene discovery

Answer 24

rare but high penetrance=family studies

common but low penetrance=GWAS in large population cohorts

Question 25

How do somatic cancer genetics and constitutional cancer genetics differ

Answer 25

Somatic=mutations within clones of cells that drive ccancer develoopment and spread. Used for prognossis, therapy choice and research
Constitutional cancer genetics=mutations in cancer predispositon genes, often inherited and therefore present in every cell, typically younger onset cancer, risk of multiple primaries, frequent asssociation with family history of same cancer or recognised pattern of cancer