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B353 > L5, Genes + Environment > Flashcards

L5, Genes + Environment Flashcards

1
Q

From where do mutations arise?

A

Sporadic (90%)

  • Replicative mutations
  • Environmental factors
  • Intrinsic sources such as ROS/RNS

Inherited

  • Inherited susceptibility via germline (sperm/egg) mutation
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2
Q

Sporadic mutations: Features

A
  • Occurs during individual’s lifetime
  • Affects somatic cells
  • Results from DNA damage
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3
Q

Contrast sporadic and inherited cancers:

A
  • In sporadic cancers, many mutations build up in cells over time, eventually leading to cancer
  • In hereditary cancers, the first mutation is already present from birth in every cell - additional mutations build up over time
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4
Q

Cancer predisposition syndromes:
Penetrance, identification, modes of inheritance, characteristics

A
  • Highly penetrant (sometimes up to 100%)
  • Genes usually identified by linkage analysis and positional cloning
  • Typically AD inheritance and involves mutation of a tumour suppressor
  • Often bilateral; in paired organism both develop tumours (e.g. p53)
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5
Q

AD hereditary cancer syndromes (3 examples with gene and pathologies)

A
  • Familial adenomatous polyposis (APC gene): High risk of colorectal cancer
  • Hereditary Breast and Ovarian Cancer (BRCA1/2 gene): High risk of Breast, Ovarian, Pancreas cancers
  • Li Fraumeni Syndrome (TP53 gene): High risk of Sarcoma, Breast, Brain cancer, leukaemia
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6
Q

AR hereditary cancer syndromes: 3 examples with genes and pathologies

A
  • Ataxia Telangiectasia (ATM gene): Intermediate risk of lymphoma and leukaemia
  • Fanconi Anemia (FANCA-H): High risk of hematological cancers
  • Xeroderma pigmentosum (XPA-G or -V): High risk of skin cancers
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7
Q

What are familial cancers?

A
  • Common within families but don’t have a single gene linked to the condition; may be affected by lifestyle choices
  • Distinct from hereditary cancers
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8
Q

Give the 2 types of skin cancer: Include characteristics and prevalence

A
  • Non-melanoma skin cancers (rarely life-threatening) - Basal cell carcinoma and squamous cell carcinoma; 1.2M cases/year worldwide
  • Melanoma (less common, often fatal) - 325,000 cases/year worldwide
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9
Q

Why are melanomas difficult to treat compared to non-melanoma skin cancers?

A
  • They are typically more difficult to treat than non-melanoma skin cancers
  • Exist in a slightly lower level in skin; closer to blood flow so better access to vascular system
  • Ease of metastasis
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10
Q

FAMMM: Prevalence/penetrance, genes of interest, gene products, tumour sites

A
  • 7-15% of MM cases occur in patients with a family history of the disease
  • FAMMM is the most highly penetrant of these (90%)
  • Inherited missense or nonsense mutations in CDKN2A or CDK4 genes
  • CDKN2A produce p16 and p14 (2 alternative splice variants)
    -> Those with FAMMM have mutations in both p16 and p14
  • Tumours occur anywhere that melanocytes can be found (including skin, eye, CNS)
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11
Q

Loss of p16 and p14 in melanoma:

A
  • p16 normally acts as a tumour suppressor, binding CDK4 to inhibit formation of cyclin D/CDK4 complex and ultimately preventing G1/S transition in damaged cells
  • Without functional p16, this complex forms -> phosph. Rb to release E2F -> E2F initiates transition
  • p14 normally binds HDM2 to inhibit formation of HDM2/p53 complex -> p53 retained in cell -> cell cycle arrest/apoptosis in damaged cells
  • Without p14, HDM2 targets p53 for proteasomal degradation and the damaged cells evades regulatory machinery
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12
Q

Gene-environment interaction in CDKN2A penetrance: (include 4 risk factors)

A
  • Penetrance of CDKN2A varies according to geographic location
  • Australia (91%) > USA (76%) > Europe (53%)
  • Risk factors co-interact to increase risk
  • Women lower than men -> lifestyle choices
  • Australia: ozone layer hole -> higher UV exposure
  • Population demographics: Caucasian proponents?
  • Increasing over years - Ageing populations
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13
Q

What is the main cause of skin cancers?

Typical protective response?

A
  • Exposure to solar UV (UVA and UVB)
  • ~1hr of exposure = 100,000 - 200,000 DNA lesions
  • Protective response: epidermal melanin unit, tanning
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14
Q

Tanning response to UV:

A
  1. UV exposure
  2. DNA damage (upregulates melanocyte hormone, aMSH)
  3. cAMP/CREB signalling pathway (aMSH activates via MC1R in membrane)
  4. Melanosome formation
  5. UV protection (melanin produced)
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15
Q

How does UV radiation cause mutations? Sequence of events leading to melanoma:

A
  • 95% of exposure is UVA (penetrates skin further) -> UVA typically generates ROS
  • UVB typically introduces lesions
  1. DNA damage to susceptible melanocytes after UV exposure
  2. Mutated melanocyte (driver mutations: BRAF, NRAS, RAC1, STK19, PPPEC)
  3. DNA repair failure (hyperactivation of RAS-RAF-MEK-ERK)
  4. Melanoma progression (hyperactivation of PI3K-AKT-mTOR)
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16
Q

What is the Fitzpatrick scale? Issue?

A
  • Pigmentary phototype in individuals from low to high epidermal melanin
  • Shows UV phenotype from more sensitive to more resistant in correspondence with lowered melanoma risk
  • Issue: False sense of security -> Still at risk, should still take precautions under UV exposure
17
Q

Risk associated MC1R polymorphisms and melanoma risk:

A
  • 5 SNPs associated with red hair, fair skin and freckling (RHC variants); hypomorphic
  • Lower signalling, lower eumelanin, higher DNA damage
  • 2.2 to 3.9x risk of melanoma for a single allele (additive!)
18
Q

Eumelanin vs pheomelanin

A
  • Upon aMSH binding, MC1R initiates pathway that produces pheomelanin or eumelanin
  • Functional MC1R variants produce more eumelanin -> skin tanning
  • Impaired MC1R variants produce more pheomelanin -> increased free radicals thus increased BRAF mutations
19
Q

Application of GWAS

A
  • Genome wide association studies
  • ‘Genetic epidemiology’ -> Use SNP arrays to analyse populations
  • Identify low penetrance SNPs (small effects, typically 1.2-1.4x increase)
  • Identifying variants not mutations
20
Q

Low penetrance genes (SNPs): (5 gene groups relevant to melanomas with examples)

A
  • Pigmentation genes (ASIP, TYR, TYRP1)
  • DNA repair/damage response genes (XPD, XPF, MGMT, MDM2)
  • Immune genes (IL10, TNF-a)
  • Biotransformation genes (GSTM1, GSTT1, GSTP1, CYP2D6)
  • Vitamin D receptor polymorphisms
21
Q

+ Other polymorphisms in cancers (bladder and colon example):

A
  • NAT2: Slow acetylator phenotype -> increased risk of bladder cancers
  • I1307K SNP in APC gene -> ~2x colon cancer risk (1 in 20 ashkenazi jews carry)
22
Q

+ Further gene-environment interactions (lung and breast cancer examples):

A
  • Large lung cancer risk due to passive smoking in GSTM1-deficient women
  • Increased breast cancer risk from smoking in postmenopausal women with NAT2 slow acetylator phenotype
23
Q

+ Ethics issue in cancer research and epidemiology:

A
  • Some ethically-based laws around patient consent and data protection actively hinder epidemiological research
  • e.g. Under the Data Protection Act, may be illegal to use historical personnel records to study the mortality of factory workers (impractical to obtain informed consent)
  • Issue arises in that the research has ‘no effect on individual concerned’ - rights of individual vs importance of this data for bona fide medical research
24
Q

Carcinogen found in some foods which acts as an alkylating agent:

A
  • Nitrosamines (degradation products of nitrosamines can also oxidise and damage adenine and cytosine)
25
Q

+ Theoretically, how much improvement could be made in cancer deaths if no-one had a BMI over 25 kg/m2?

A
  • About a 5% reduction in all incident cancers in the EU
  • Data suggests that about 10% of all cancer deaths among American non-smokers are caused by overweight
26
Q

+ Cancer incidence and oral contraceptives: Effect on incidence of different types

A
  • Use of oral contraceptives transiently increases breast cancer incidence
  • Endometrial and ovarian cancer are less common in oral contraceptive users
27
Q

+ Predicted effect of asbestos exposure on mesothelioma and lung cancer levels in Western Europe:

A
  • Long latency period for disease -> rates began to climb after asbestos had already begun to be eradicated from construction
  • Asbestos exposure prior to 1980 may eventually cause 250,000 mesotheliomas and 250,000 lung cancers in Western Europe

B353 (15 decks)

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