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TIN > WK 7- CANCER GENETICS > Flashcards

WK 7- CANCER GENETICS Flashcards

1
Q

What are the 4 most commonly mutated genes in cancer

A
  1. TP53
  2. RB1
  3. PIK3CA
  4. RAS
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2
Q

What are the 4 major types of mutations that give rise to somatic cancer

A
  1. Single nucleotide variants
  2. Small insertions of deletions
  3. Copy number variants
  4. Methylation variation
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3
Q

What are the 3 types of single nucleotide variant mutations

A
  1. Missense mutation
  2. Nonsense mutation
  3. Read through mutation
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4
Q

How do somatic mutations result in cancer formation

A

Mutations result in a mutated and non-effective gene being produced-> these genes can be tumour suppressor or oncogenes and when mutated they result in either a gain of function or loss of function mutation-> contributes to uncontrolled and abnormal cell growth

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5
Q

What are the 4 features that suggest the cancer being diagnosed may be an inherited cancer

A
  1. Cancer is being diagnosed at an abnormally young age
  2. There are several different types of cancer occurring within the same person
  3. The cancer has developed in both of a paired set of organs (eg. both lungs)
  4. The patient has birth defects known to be attributed to some form of inherited cancer
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6
Q

What are the 4 most common types of inherited cancer

A
  1. Lynch syndrome
  2. Hereditary breast cancer and ovarian cancer
  3. FAP (familial adenomatous polyposis)
  4. Retinoblastoma
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7
Q

What should you consider before testing someone for a genetic cancer

A
  1. Can the test be adequately interpreted
  2. Is there a treatment available for the cancer/will knowledge of the cancer affect management
  3. Will the test reveal issues of parentage
  4. Are there psychological risks associated with knowing the genotype
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8
Q

When grading a tumour, what does each of the following stand for;
GX, G1, G2, G3, G4

A 
GX- grade cannot be determined
G1- well differentiated (low grade)
G2- moderately differentiated (intermediate grade)
G3- poorly differentiated (high grade)
G4- undifferentiated (high grade)
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9
Q

What grading system do prostate, cervical and breast cancer use

A

Breast: Nottingham grading system
Prostate: Gleason scoring system
Cervical: FIGO

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10
Q

What does tumour grading determine

A

Grading refers to the histopathological description of the tumour cells and is used to determine tumour grade between different types

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11
Q

What does tumour staging determine

A

Refers to the extent of cancer- how large the tumour is and if it has spread to surrounding lymph nodes and tissues

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12
Q

What staging system is most commonly used for tumour staging and what does each letter stand for

A

TNM-
T= size and extent of tumour
N=number of nearby lymph nodes that are affected
M= metastasis

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13
Q

How is T (from TNM) graded

A 
Tis= carcinoma in situ
TX= tumour cannot be measured
T0=tumour cannot be found
T1= tumour <20mm
T2= 20> tumour <50mm
T3= tumour >50mm
T4= tumour of any size with direct extension into the chest wall/skin
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14
Q

How is N (from TNM) graded

A

NX= cancer in nearby lymph nodes cannot be measured
N0=no cancer in nearby lymph nodes
N1/2/3= number and location of lymph nodes that contain cancer (higher number=more lymph nodes affected)

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15
Q

How is M (from TNM) graded

A 
MX= metastasis cannot be measured
M0= no metastasis
M1= metastasis- cancer has spread to other portions of body
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16
Q

What is staging - what are the 4 stages

A

TNM combinations can be grouped into staging

  • Stage 0= carcinoma in situ
  • Stage 1/2/3= cancer is present, the higher the stage number the larger the tumour and the more it has spread
  • Stage 4= cancer has metastasised
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17
Q

What are the 2 types of histo/cytology lab detection tests for neoplasia

A
  1. Haematoxylin and eosine (H&E) staining (allows you to see cells and determine degree of differentiation
  2. Immunocytochemistry (IHC) to confirm tumour histogenesis and subtype (shows presence of biomarker)
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18
Q

What are the 2 sorts of molecular diagnostic tests used for determining the type of cancer

A
  1. Molecular histopathology- take a healthy sample and compare it to the diseased tissue- allows you to determine genetic components of the tumour
  2. Gene profiling
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19
Q

What is the difference between biomarkers and tumour markers

A

Biomarker= physiological markers expressed by the body that indicate the presence of a tumour, but are not directly secreted by a tumour
Tumour marker= tumour derived or associated molecules that are detected in blood or other body fluid - not specific to cancers though as there are lots of non-cancerous conditions that can raise levels (eg. PSA in BPH)

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20
Q

What cancers are possible if alpha-fetoprotein is raised

A

Liver, ovary or testis, but also hepatitis

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21
Q

What cancers are possible if HCG is raised

A

testis, ovary, liver, stomach, pancreas, lung

-also high in pregnancy

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22
Q

What cancers are possible if PSA is raised

A

prostate cancer but also BPH

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23
Q

What cancers are possible if carcinoembryonic antigen (CEA) is raised

A

colorectal cancer

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24
Q

What cancers are possible if CA 125 is raised

A

ovarian cancer

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25
Q

What cancers are possible if CA 15-3 is raised

A

used in evaluating treatment of advanced breast cancer

26
Q

What are the 3 main ways in which tumours can produce local effects

A
  1. Impingement on adjacent structures (eg. GI tumour could create a bowel obstruction)
  2. Bleeding and infection (due to increased angiogenesis)
  3. Symptoms from tumour rupture or infarction
27
Q

How can tumours have hormonal effects

A

Tumours can show altered functional activity and can produce hormones/change the production/release of hormones (eg. tumour of pituitary gland)

28
Q

What is cancer cachexia

A

Occurs in advanced patients and contributes to cause of death
-Is the loss of body fat, loss of lean body mass and profound weakness and anemia

29
Q

What causes cancer cachexia

A

Multifactorial but believed to be a result of TNFalpha an other cytokines produced in response to tumours or directly by tumours-> TNF can also cross into brain and decrease appetite

30
Q

What is paraneoplastic syndrome

A

they are tumour associated syndromes where symptoms are not directly related to the tumour or local hormones–> often represent earliest clinical manifestations of neoplasia

31
Q

What are the 4 most common types of paraneoplastic syndromes

A
  1. Endocrinopathies: non-endocrine cancers produce hormones or other factors
  2. Hypercalcemia: cause by bone resoprtion resulting from increased PTH-like peptides
  3. Neuropathc paraneoplastic syndromes: peripheral neuropathies; likely due to autoatnibodies against tumour antigens that cross react with host tissues
  4. Hypercoaguability: due to tumour cells producing thromboplastic material
32
Q

What is the classical approach to curing cancer (main mechanism)- what are the problems and what are the solutions

A

Induce DNA damage and prevent cell replication

  • This isn’t always effective as mutations associated with tumours are shared with cancer stem cells that slowly divide (so some cancer cells can remain dormant)
  • This is fixed by addressing each of the hallmarks of cancer-> counteracting the effects of each hallmark and attacking pathways involved in the hallmarks
33
Q

What are the three main types of breast cancer- which is more prevalent

A

Ductal carcinoma (most prevalent), lobular carcinoma and Histologically indeterminate group

34
Q

What are the 4 molecular subtypes of ductal breast cancer

A
  1. HER-2 enriched
  2. Luminal A- associated with mutations of; GATA3, PIK3CA, MAP3KI
  3. Luminal B
  4. Basal-like- associated with germinline BRCA1 mutations, Lack expression of ER, progesterone receptor (PR) and HER2 “Triple-negative breast cancers”, Shares genetic features with high-grade serous ovarian cancer→Mutation profile suggests susceptibility to Angiogenesis inhibitors
35
Q

What are the 3 molecular subtypes of lobular carcinoma

A
  1. Reactive like- associated with the best outcomes
  2. Immune-related
  3. Proliferative – has the worst outcome
36
Q

What 2 genes convey the most risk in INHERITED breast cancer

A

BRCA 1 and BRCA2

37
Q

What is the function of BRCA1/2

A

Plays a role with RAD51 in DNA repair→ homologous recombinational repair of DNA double strand breaks.

38
Q

What hallmarks are affected when BRCA1/2 is mutated

A

evading programmed cell death

and exhibiting genome instability

39
Q

What genes are most commonly mutated in SOMATIC breast cancer

A

TP53 and PIK3CA,

40
Q

What type of mutation most commonly affects TP53

A

missense mutation

41
Q

What hallmarks are affected when TP53 is mutated

A

evading growth suppression, evading programmed cell death, invasion and metastasis, exhibiting genome instability, promoting Inflammation

42
Q

What is the function of TP53

A

transcription factor/master regulator→ aids to induce cell cycle arrest (at G1), DNA repair (prior to cell committing to DNA replication→ if repair is unsuccessful will causes apoptosis (through stimulation of Bax and Bak), Senescence

43
Q

What is the function of PIK3C

A

Encodes p110α→ is one of the catalytic subunits of Phosphatidyl 3-kinases (PI3K) which is the 2nd signal for several receptor tyrosine kinases→PI3K activates AKT/mTOR pathway→Survival activates MAPK (RAS/RAF/MEK/ERK) → Proliferation of cells

44
Q

What happens when PIK3CA is mutated

A

proto-oncogene→ when mutated will affect hallmarks; Sustaining proliferative signalling and evading programmed cell death

45
Q

What is triple negative breast cancer

A

Estrogen receptor negative, progesterone receptor negative and HER2 receptor negative (growth factor)→ ones that don’t express receptors for these hormones have the potential to grow faster (cant be treated with oestrogen/progesterone blockers- those with receptors can

46
Q

Why do PIK3CA mutations not guarantee a dramatic response to PI3K inhibitors

A

Because PIK3CA is too far down in the pathway and the downstream component is also mutated

47
Q

True or false: colon and rectal cancers are the same type of cancer molecularly

A

True

48
Q

What are the 2 disorders associated with somatically inherited colon cancer

A

FAP (familial adenomatous polyposis) and Lynch syndrome

49
Q

What types of genes are associated with Lynch syndrome (which genes are mutated)

A

Mismatch repair genes/tumour suppressor genes-> involved in correcting DNA errors missed by proof reading→ when these genes become mutated they result in microsatellite instability
Mismatch genes= MSH2, MLH1, MSH6, PMS2

50
Q

What 4 other cancers are pts whos suffer from Lynch syndrome at an increased risk of developing

A

Colorectal cancer, Endometrial carcinoma, digestve adenoma, ovarian serous cystadenocarcinoma

51
Q

What is microsatellite instability

A

Microsatellites are repeated sequences of DNA–> causes the hallmark of exhibiting genome instability

52
Q

What cancers are those who suffer from FAP at an increased risk of developing

A
  • Colorectal cancer
  • Thyroid cancer
  • Benign and cancerous tumours in small intestine, brain, stomach, bone, skin
53
Q

What mutated gene leads to FAP

A

APC; Confers a life time risk of Colorectal cancer of 100%

-Colectomy or proctocolectomy indicated as preventative treatment

54
Q

What genes are most commonly somatically mutated in colorectal cancer

A

APC, TP53, DCC, KRAS PIK3CA, TGFBR2, MLH1, BRAF

55
Q

What is APC- function

A

Adenomatous polyposis coli
-tumour suppressor genes- negatively regulates the Wnt/β-catenin pathway (acts an anti-proliferative) → WNT can induce cellular proliferation by binding to its receptor and sending signals to prevent the degradation of β-catenin (β-catenin is able to move to the nucleus and activate cell proliferation)→ APC encourages degradation of β-catenin→ if APC is mutated then cell proliferation results

56
Q

What is DCC- function

A
  • Deleted in colorectal carcinoma (DCC)
  • conditional tumour suppressor→ only blocks cellular proliferation in absence of ligand Netrin-1→ When not bound to netrin-1, an intracellular domain of DCC is cleaved by a caspase, and induces apoptosis in a caspase-9-dependent pathway.
  • When DCC is mutated/lost it will result in loss of this apoptotic pathway→ causes proliferation and affects hallmarks; evading growth suppression and evading programmed cell death
57
Q

What is KRAS- functino

A
  • KRAS transduces signal from EGFR (epidermal growth factor)→ KRAS activates several downstream pathways → RAS/RAF/MAPK → these pathways control cell proliferation and differentiation, apoptosis and senescence
  • When KRAS is mutated it impairs the intrinsic GTPase activity of the Kras protein so that it is constitutively active→ increases cell proliferation and carcinogenesis- making KRAS a proto-oncogene
58
Q

What is TGFBR2- function

A

TGFBR2 is a proto-oncogene that aids to suppress immune response, induce epithelial to mesenchymal transformation, induces tumour invasion and metastasis and feeds into the PI3K/AKT/mTOR pathway
-When mutated it affects hallmarks; sustaining proliferative signalling, evading programmed cell death, enabling replicative immortality, invasion and metastasis and immune evasion

59
Q

What is MLH1- function

A

MLH1 is a mismatch repair gene and a tumour suppressor→ when mutated it will affect hallmark: exhibiting genome instability

60
Q

What is BRAF- function

A

-Proto-oncogene
BRAF is a member of RAF family of serine/threonine kinases→ transmits growth signals via RAS-RAF-MAPK pathway and drives cellular proliferation and survival → causes resistance to growth factor deprivation and stress-induced apoptosis -BRAF is downstream of KRAS so will have the same issue with mAb targeting EGFR

61
Q

Does the growth factor TGF-β function as a tumour suppressor, an oncogene, or both ? Explain.

A

One arm of TGFB inhibits growth and proliferation by affecting cell cycle progression (through CDK), other arm of the pathway is involved in immune evasion and angiogenesis→ depending on where the mutation is in the signalling cascade determines whether you get growth inhibition or growth proliferation→ if you get a mutation early in the pathway, it is usually only loss of function mutation that will cause a problem (tumour suppressor gene if hit early on will cause a problem, if the pathway is mutated later in the pathway (second hit-late stage) then it will effect oncogenes)

TIN (14 decks)

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