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Midterm 504 > Inherited predisposition to cancer > Flashcards

Inherited predisposition to cancer Flashcards

1
Q

True or false: Rb1 is the first hereditary cancer susceptibility gene and first tumor suppressor gene discovered

A

True

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2
Q

What are the characteristics of Retinoblastoma

A

At a young age (before 10)
Risk goes down with age, because eye is fully developed
Pediatric cancer
Tumor is unilateral or bilateral
Tumor is unifocal or multifocal

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3
Q

What are the type of way (context) you can get retinoblastoma

A

Familial (hereditary) or sporadic

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4
Q

In an autosomal dominant mode of inheritance, carriers are homozygous or heterozygous? why?

A

Carriers are heterozygous (one normal allele , one at risk allele) and theres a 50% chance of inheriting the risk allel from carrier

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5
Q

What does autosomal dominant mode mean

A

Multiple cases in a family (transmission of trait)
- Almost a dominant effect, high risk

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6
Q

True or false: Knudson proposed to explain the development of both familial and sporadic cases of retinoblastoma and disease presentation in these context. He came up with the 2-hit theory

A

True

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7
Q

True of false: Knudson made the assumption that Familial and sporadic form of the disease is caused by same gene

A

True

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8
Q

Whats the Familial context in the case of retinoblastoma

A

Familial retinoblastoma ; theres an unfonctional Rb gene, but you carry a normal copy of the gene, so youre heterozygous.
The disease occurs when the normal copy also gets a mutation leading to cancer

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9
Q

Whats the sporadic context in the case of retinoblastoma

A

The same gene mutate itself twice in the same cell causing cancer

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10
Q

The two hit hypothesis states that for both forms (sporadic or familial)…

A

Two mutations in the same genes are necessary for disease to develop

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11
Q

What are the effect of the gene (rb) ..,

A

-

-behave as a tumor suppressor

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12
Q

In familial retinoblastoma, theres a higher or lower chance to get the cancer? Unilateral or bilateral? unifocal or multifocal?

A

Higher
Bilateral
multifocal

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13
Q

What does unilateral or bilateral mean in Rb?

A

Unilateral = one eye is affected
Bilateral = both eyes

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14
Q

What does unifocal or multifocal mean

A

unifocal = one mass
multifocal = multiple focis of tumors

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15
Q

true or false: in tumor cells you have only the mutated form of Rb

A

True

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16
Q

True or false: Tumor arises because of the inaactivation and the loss of function of the Rb gene

A

True

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17
Q

What happens when you have loss of Rb function in tumor cells….it leads to…

A

Loss of cell cycle regulation leading to unprogrammed cell division

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18
Q

How was Rb discovered? explain what it was

A

Positional cloning, they identified where in the human chromosome the gene is and created a map of the region using clone segments

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19
Q

could genetic testing reveal that a seemingle sporadic case be hereditary?

A

Yes, its easu to miss the hereditary aspect of the disease, Genetic testing checks both patients genes and the tumor to understand the full risk, specially when family history is unclear

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20
Q

How high is Rb penetrance in %?

A

95%

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21
Q

How did scientist discover BRCA1 BRCA2

A

By leakage approach - they looked at segregation of these polymorphic gene which were transmitted in Mendelian way

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22
Q

Which chromosome is the location of BRCA1?

A

Chromosome 17

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23
Q

Hwo many cancer predisposing gene are there?

A

Over 100 oderate to high risk cancer predisposition genes have been identified

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24
Q

Associated cancer syndromes? Features?

A
  • Multiple primary tumor
  • Bilateral primary tumors in paired organs
  • Multifocal tumors in single organ
  • Younger than usual age at cancer diagnosis
  • Family history (often autosomal dominant mode of inheritance)
  • Timore with rare histology
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25
Q

Rb is located on which chromosome

A

13

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26
Q

Whats a germline variant ?

A

Hereditary

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27
Q

Whats somatic mutation?

A

mutations not passed on to children, point mutation or complete deletion of function and loss.
Cannot occus in germ cells

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28
Q

True or false: Rb is at very rare frequency, and high risk

A

true

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29
Q

True or False: BRCA1 is a highly penetrant gene

A

True

30
Q

BRCA is like Rb, all somatic cells have a normal copy of BRCA1 and a copy of pathogenic variant and that puts them at rish of developing….

A

Breast cancer

31
Q

RB1 is on chromosome…. BRCA1 is on chromsome….

A

13

17

32
Q

True or false: Cancer predisposing genes more likerly associatied with the genetic transmission of an autosomal dominant trait than recessive trait

A

True

33
Q

in autosomal recessive mode of inheritance, which is true:
1- carriers are biallelic for pathogenic variants
2- Pathogenic variants are inherited from both parents
3- Heterozygous carriers of such pathogenic variants may express other manifestation of the disease

A

All of them are true

34
Q

Are cancer predisposing genes always tumor suppressors?

A

NO. Rb is a tumor suppressor involved in cell cycle regulation and DNA repair… but theres also oncogenes

35
Q

Tumor suppressor genes or loss of function genes that are involved in DNA repair pathways (name 3)

A

Rb
CDK
P53

36
Q

True or false :BRCA1 tumor suppressor gene is involved in maintaining the integrity of DNA by its function in DNA repair pathways

A

True

37
Q

The number of oncogenes are significantly lower than the number of tumor suppressor genes found in cancer predisposing genes… why?

A

Oncogenes are altered versions of proto-oncogenes, promoting cancer development. Since there’s a limites set of proto-oncogenes in cells, the potential oncogenes is relatively lower. Theres more tumor suppressors than oncogenes.

38
Q

P53 is also the cancer predisposing gene involved in

A

Li-Fraumeni Syndrome, rare genetic disorder that increases the risk of developing breast cancer and other types of cancer

38
Q

True or false: PT53 is the most frequently somatically mutated gene in cancer often the designated driver of many cancers….

A

True

39
Q

Is somatic BRCA1 mutations reported in cancers?

A

no, theure associated with hereditary form and less somatic form

40
Q

Genetic heterogeneity or hereditary cancer?

A

A phenomenon in which a single phenotype or genetic disorder may be associated with a germline risk allele in any one of a multiple number of different gene

41
Q

True or false; Both BRCA1 or BRCA2 are involved in maintaining the integrity of DNA by their function in DNA repair pathway

A

True

42
Q

Are you surprised that both BRCA1 and BRCA2 have been associated with hereditary Breast Cancer Syndrome families?

A

Not surprising, because they’re part of the same signalling pathway

43
Q

True or false: Hereditary breast cancer is a genetically heterogenous disease associated with autosomal dominant mode of transmission of loss of function variants in a variety of rare clinically defined cancer syndromes

A

True,

44
Q

True or false: Hereditary breast cancer is heterogeneous disease , its associated with - dominant inheritance or specific genes, LOF in these genes, which contributes to the development of cancer, and occurs with clinically defined cancer syndromes

A

True

45
Q

Colorectal cancers have 2 major genes …

A

MLH1, MLH2

46
Q

Whats variable penetrance

A

Probability of developung cancer in carrirs of pathogenic variants un cancer predisposing genes during their life-times
… whats is your lifetime risk

47
Q

True or false: 98% carriers of RB1 loss of function pathogenic variants (risk alleles) develop retinoblastoma)

A

False, 95%

48
Q

Why do you have less chances to develop retinoblastoma after age 10

A

Risk is much lower because your eyes are fully developed and cells are not replicating, so low chances for second-Hit

49
Q

Which gene has the highest penetrance for breast cancer

A

Brca1 brca2

50
Q

Whats variable expressivity

A

A cancer predisposing genes that also has increased risk to different cancer type…

51
Q

True or false: Carriers of pathogenic variants in BRCA1 and BRCA2 are ALSO at significantly increased risk for ovarian cancer… why

A

True, penetrance for female breast cancer than for ovarian, but its a autosomal dominant mode of inheritance

52
Q

True or false: Mutation in BRCA1 and BRCA2 play a role in hereditary cancers

A

True

53
Q

Bilateral has a higher incidence % during time after retinoblastoma diagnosis and is often…

A

hereditary (Familial)

54
Q

Unilateral has a lower incidence % during time after retinoblastoma diagnosis and is often…

A

Sporadic

55
Q

IS there a genotype and phenotype correlation?

A

Genotype = risk variant and phenotype (cancer)

56
Q

Could a specific mutation, a specific risk variant have an effect phenotype that is different than another variant in the same gene?

A

Yes, retinoblastoma… the vast majority of germline retinal pathogenic variant is Rb are a result in a premature termination codon, that results in knocking out the function of the encoded gene because it affects transcription

57
Q

what is a nonesense media decay?

A

Natural way for the body to clear any mistakes made in transcript that could lead to the synthesis of an abberant protein due to somatic mutation

58
Q

Where are located the low penetrant pathogenic variants and what do they do

A

in the promoter region and what they do is that they affect the efficient transcription of retinoblastoma

59
Q

Are there variants that dont confer increased risk to rb ?

A

Yes

60
Q

Ovarian cancer cluster region (OCCR) of BRCA2 is associated with higher risk of ovarian cancer… how so

A

The penetrance for Breast cancer is lower which allows the expressivity for oarian cancer to be higher

61
Q

True or false: Not all breast is attributed to a hereditary high risk factors

A

True, fewer than 15% of female breast cancer cases carry a pathogenic variant in a known high rick cancer predisposing gene

62
Q

BRCA1 and BRCA2 have high frequency of carriers and high risk for cancer in carriers because…

A

Theyre major breast cancer genes

63
Q

How can Rb alleles be dominant and recessive?

A

The RB alleles demonstrate dominant behavior in the entire organism. If a cell in the eye inherits a mutant allele, there is a high likelihood of developing retinoblastoma. On the other hand, the Rb alleles behave recessively when examining the mutant allele within the same cell. In this scenario, one cell has a normal allele (WT) while the other carries the mutant allele.

64
Q

Why are tumor suppressor genes transmitted to the germline whereas mutant oncogenes usually not?

A

Oncogenes function dominantly within cells, meaning a single altered allele can disrupt normal processes. If such a change occurred in germline cells, it could disturb the development of individuals and tissues.

In contrast, tumor suppressor genes require both copies to be mutated to cause cancer. This means that one mutated allele can be inherited without causing cancer, as the second, unaffected allele provides protection.

65
Q

How can there be breast and ovarian cancer as predominant cancer?

A

BCRA1 and BCRA2 increase the risk for breast and ovarian cancer, theyre also hormonally sensitive, screening etc…

66
Q

How can we be carrying P53 and not be full of cancer?

A

Because P53 prevents cancer, its help cells regulate the cell cycle and act as a tumor suppressor

67
Q

How can we be heterozygous for BRCA1 and BRCA2 if they play such a strong role in DNA repair?

A

Having a heterozygous mutation in BRCA1 or BRCA2 indicates having one healthy and one altered copy of the gene. Despite the mutation, our cells possess strong DNA repair abilities. The presence of at least one functioning gene copy enables cells to effectively repair the majority of DNA damage

68
Q

which of the following is false regarding retinoblastoma?
1-Patients with unilateral tumors are at greater risk for other types of cancer compared to patients with bilateral tumors
2- The sporadic form of this cancer usually occurs later than the familial type
3- Multifocal presentation is more common in the familial type
4- unilateral presentation is more common in the sporadic type

A

1

69
Q

Hereditary breast cancer has been described as “genetically heterogenous disease” because:
A. Of the complex somatic mutational spectrum exhibited in breast tumours.
B. Of autosomal dominant mode of inheritance and loss of wild-type allele in breast tumours
C. Breast cancer risk could be due germline pathogenic variants in more than one gene
(example, BRCA1, BRCA2 or TP53)
D. Both BRCA1 and BRCA2 are involved in maintaining the integrity of DNA
E. Male carriers may have the same pathogenic variants in BRCA1/BRCA2 but their risk of developing breast cancer is lower than that of female carriers

A

C

70
Q

Which of the following statements correctly describes a feature of hereditary cancer predisposing genes?
A. Only tumour suppressor genes associated with complete loss of function at the cellular level have been implicated in conferring increased risk
B. Cancer predisposition genes with gain of function variants are more common than those with loss of function variants
C. Cancer predisposition genes are unique because they are not involved in the onset of the sporadic disease counterpart
D. Oncogenes exhibiting an autosomal dominant mode of transmission have been reported

A

D

71
Q

Penetrance of cancer means:
A. Probability of sporadic cancer in carriers of pathogenic variants
B. Lifetime probability of developing cancer in risk allele carriers
C. A cancer predisposition that also confers increased risk to a second cancer type
D. The chance of inheriting one risk allele from a carrier parent

A

B

Midterm 504 (5 decks)

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