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Retinoblastoma > Genetics > Flashcards

Genetics Flashcards

1
Q

The inheritance of retinoblastoma is…

A

…autosomal dominant.

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2
Q

The penetrance is…

A

…90%.

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3
Q

The percentage of Rb children with hereditary disease is…

A

30-40%.

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4
Q

The clinical features suggesting hereditary Rb are…

A

…positive family history, bilateral disease, multifocal tumors, pre-malignant retinomas, and younger age at diagnosis.

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5
Q

Patients with hereditary Rb are at risk of…

A

…pinealoblastoma, radiation-induced bone and soft-tissue sarcomas, non-radiation-induced second tumors.

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6
Q

The RB1 gene was identified by…

A

…Friend et al in 1986.

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7
Q

The percentage of Rb patients with a positive family history is…

A

10%.

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8
Q

A patient with a positive family history of Rb is said to have the…

A

…‘familial Rb’.

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9
Q

Patients with hereditary Rb can have the ‘sporadic’ form of the disease, which means…

A

…both parents are genetically normal, the mutation occurring in a parent’s gamete, which is usually the father’s sperm.

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10
Q

The percentage of patients with hereditary Rb who have the sporadic form of the disease is…

A

…30%.

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11
Q

Sporadic heritable Rb can arise as a result of …

A

…parental ‘gonadal mosaicism’, with only some of one parent’s gametes carrying the mutant gene.

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12
Q

The percentage of Rb patients with the ‘sporadic nonheritable’ form of the disease is..

A

…60%.

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13
Q

The percentage of patients with heritable Rb having bilateral disease is…

A

…90-95%.

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14
Q

The RB1 gene is located at…

A

…13q14.

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15
Q

The number of exons in the Rb1 gene is…

A

…27.

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16
Q

The span of the Rb1 gene is…kb.

A

…183kb.

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17
Q

The gene codes for…

A

…pRB, which is a nuclear phosphoprotein that regulates cell cycle progression from G1 to S phase.

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18
Q

The number of amino acids in pRB is…

A

928.

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19
Q

The function of pRB is to…

A

…inhibit E2F and DP.

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20
Q

Normally, the Rb protein dissociates from E2F/DP complexes after…

A

…phosphorylation by cyclin-dependent kinases.

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21
Q

Inactivation of pRB occurs by…

A

mutations or epigenetic mechanisms affecting the ‘pocket’ domain.

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22
Q

Another pathway that is inactivated in Rb is…

A

…the p53 tumor suppressor pathway.

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23
Q

The function of the p53 pathway is to…

A

…regulate cell responses to DNA damage and promote cell death.

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24
Q

The p53 pathway is suppressed by…

A

…MDMX amplification.

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25
Q

The interaction between MDMX and p53 is inhibited by…

A

…nutlin-3, so that the p53 pathway is activated.

26
Q

RB tumorigenesis can also be induced by…

A

…the oncogenic microRNA cluster miR-17-92.

27
Q

The RB1 mutations consist of…

A

…single base substitutions in its coding exons in 50% cases; small deletions in 33%; and rearrangements, such as intragenic or intergenic deletions or duplications involving chromosome 13q, which may flank the RB1 locus.

28
Q

RB1 inactivation can also occur as a result of…

A

…mutations that cause aberrant mRNA splicing.

29
Q

The number of introns in the RB1 gene is…

A

…26.

30
Q

The size of the RB1 introns ranges…

A

…from 15-80 base pairs to 17-71,500 base pairs.

31
Q

Mutations deep within introns can be detected by…

A

…reverse transciption and PCR-based amplification of RNA from RB or peripheral blood lymphocytes, followed by evaluation for abnormalities in size and sequence of RB1 transcripts.

32
Q

RB can occur as a result of….

A

…hypermethylation of CpG dinucleotides in the promoter region of RB1, which leads to gene silencing.

33
Q

Hypermethylation of the RB1 promoter occurs only in which RB?…

A

…only in sporadic unilateral RB tumor tissue.

34
Q

Hypermethylation is evaluated by…

A

…isolating tumor DNA, digesting DNA with two restriction endoucleases whose activities depend on presence or absence of methylated cytosines in CpG dinucleotides; and quantifying the products of these digestions.

35
Q

In heritable RB, the mutation is detected by…

A

…sequencing the RB1 coding exons, flanking introns and the promoter region - in DNA isolated from peripheral blood lymphocytes or a saliva sample.

36
Q

In patients with heritable Rb, direct DNA sequencing detects in mutation in what percent of cases?

A

…75%.

37
Q

If direct DNA sequencing fails to detect the mutation in a patient with heritable Rb…

A

…whole or partial gene deletions or duplications are detected in individual exons using quantitative PCR.

38
Q

In probands with heritable RB, the sensitivity of multistep mutation detection is…

A

…90-95%.

39
Q

The percentage of patients with solitary RB and no history having a germline mutation is…

A

…10-15%.

40
Q

In patients with unilateral RB and no family history, mutation screening involves…

A

…evaluation of tumor tissue to detect both inactivating mutations, which one of which is then sought in lymphocyte DNA. If the mutation is found in the lymphocyte DNA, the disease is heritable. If not, the disease is probably non-heritable, but the patient may be a mosaic or the mutation has escaped detection.

41
Q

Germline RB mutations usually…

A

…span the gene consisting of truncating or nonsense mutations.

42
Q

Mild germline RB can occur as a result of…

A

….a frameshift mutation in exon 27 or truncating mutations in the last exon.

43
Q

A low-penetrance phenotype with reduced expressivity mimicking sporadic unilateral RB can be caused by…

A

..small in-frame deletions or point mutations in RB1, which have subtle effects on pRB protein function or expression.

44
Q

A mild RB phenotype can also occur as a result of…

A

….splice site mutations resulting in reduced expression of full length RB1 transcripts or unstable transcripts (eg, single base substitution at codon 654, which gives rise to 3 separate amino acid changes.

45
Q

The percentage of RB patients having the RB1 deletion syndrome is…

A

10%.

46
Q

The size of the deletion varies from..

A

…4000 bases to 34 million bases.

47
Q

Clinical features of the RB1 gene deletion syndrome include:

A

…deafness; bilateral inguinal hernias; submucous cleft palate; dysmorphic features; and neuro-developmental defects.

48
Q

Deletions confined to 13q14 are associated with…

A

…macrocephaly, tall stature, obesity, motor and/or speech delays.

49
Q

Large RB1 gene deletions are associated with…

A

…craniofacial abnormalities; microcephaly; psychomotor delays; constipation; and feeding disorders.

50
Q

In patients with RB1 gene deletion syndrome, a milder phenotype occurs with…

A

…deletions larger than 1 Mb and encompassing MED4.

51
Q

MED4 is…

A

…a gene encoding a mediator of RNA polymerase type II and located centromeric to the RB1 gene. This may lead to cell death, explaining reduced severity of disease.

52
Q

Mosaicism for a germline RB1 mutation occurs in…

A

10% of families with newly-diagnosed RB.

53
Q

The percentage of patients having germline mosaicism in bilateral and unilateral RB patients is…

A

…5.5% and 3.8% respectively.

54
Q

Mosaic mutations are detected by…

A

…allele-specific PCR for 11 recurrent mutations at CpG sites, which change CGA to TGA nonsense mutations within the RB1 gene.

55
Q

Genetic testing for RB1 mutations should be performed when…

A

…the chance of finding a mutation is at least 5-10% and when this will influence management.

56
Q

Is genetic testing indicated in patients with a solitary tumor and no family history?

A

Yes, because a germline mutation enhances screening for second malignancies, screening of relatives and screening of children.

57
Q

The screening protocol includes:

A

…isolation of DNA from peripheral blood lymphocytes or frozen/formalin-fixed paraffin embedded tumor sections; PCR amplification; DNA sequencing of 27 RB1 coding exons, flanking intronic sequences, and 1000 base pairs of the RB1 promoter. If no mutations are identified, deletions encompassing 1 or more of the RB1 exons are identified by quantitative doseage-sensitive PCR. Large deletions or duplications are identified using whole-genome SNP arrays. If no abnormalities are found, DNA samples are then analyzed for methylation of the RB1 promoter or for alterations in the size and /or expression of the RB1 transcript and pRB protein.

58
Q

The sensitivity of mutation detection is…

A

…almost 90%.

59
Q

In patients with heritable RB, the abnormality consists of…

A

…a coding sequence mutation in 75% and a gene deletion or mutation of the RB1 locus in 16%.

60
Q

In unilateral RB without a positive family history, the percentage of patients with detected germline mutations is …

A

…13% This consists of silent, missense, nonsense or frameshift changes in 10% and intragenic RB1 deletions or duplications in 3%.

61
Q

Prenatal genetic testing for RB susceptibility can include…

A

…chorionic villus sampling; amniocentesis; pre-implantation genetic diagnosis (performed in combination with in vitro fertilization). Because there are so many RB1 mutations, an approach is to detect the inheritance of SNPs tightly associated with wild-type or mutant RB. This can however give the wrong result if there is gonadal mosaicism.

Retinoblastoma (1 decks)

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