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Week 1 - Medical Genetics > Familial Cancer > Flashcards

Familial Cancer Flashcards

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USMLE® Step 1 flashcards Biology 101 flashcards
1
Q

Define Gain of Function mutation.

A

Mutation of a gene that enhances the activity of the product of the mutant gene.

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2
Q

Define Loss of Function mutation.

A

Mutation of a gene that diminishes the activity of the product of the mutant gene or reduce the amount of transcription of the mutant gene.

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3
Q

What is a proto-oncogene?

A

Proto-oncogene is a gene that has the potential to become an active oncogene.

It normally controls the cell cycle.

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4
Q

What is an Oncogene?

A

A gene that is involved in cancer directly or indirectly by altering the cell cycle. A gain of function mutation - one copy of the gene is sufficient enough to over ride the function of the normal copy. Thus, increasing the risk of Cancer.

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5
Q

What is a Tumour Suppressor Gene?

A

A gene that directs the production of a protein that is involved in regulating cell division, for example by promoting apoptosis of defective cells : Tp53, BAX gene

  • A loss of function mutation: cell division becomes disorganised
  • Both copies of Tumour Suppressor Genes must be loss for a neoplasia to form
  • TS gene functions as stability gene
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6
Q

Examples of Tumour Suppressor Gene?

A

Tp53, Rb gene, BAX gene, NF1, MEN1

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7
Q

What is a stability gene?

A

A gene that maintains the structure and integrity of DNA & repair DNA through its product

  • a type of TS gene
  • if inactivated, TS gene and proto oncogenes are prone to mutation
  • account for hereditary cancer predisposition syndromes
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8
Q

What is the Knudson’s Two-Hit Hypothesis?

A

2 events of mutation is required to increase the chance of developing cancer in 2 normal wild type alleles. If there is a predisposed mutation inherited, only 1 event of mutation is sufficient to trigger cancer.

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9
Q

Comparison between sporadic & familial cancers.

A

Sporadic :

  1. Common (90-95%)
  2. later onset
  3. single primary tumour with metastases

Familial

  1. Uncommon (5-10%)
  2. Early onset
  3. Multiple primary tumour
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10
Q

What are the essential information that aid a diagnosis of familial cancer?

A
  1. Family history : More than 1 members in the family are affected by a similar cancer
  2. Age of patient
  3. Multiple foci of primary tumours
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11
Q

What are the common genetic causes of Familial Breast Cancers?

A

BRCA-1 (more common - suspect if relatives have ovarian cancer) , BRCA-2, Tp53, PTEN, RAD51

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12
Q

Male Breast Cancer is associated with the mutation of what gene?

A

BRCA-2

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13
Q

What are BRCA-1 and BRCA-2?

A

BRCA-1 and BRCA-2 are DNA repair genes using homologous recombination.

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14
Q

What are the associated features of Familial Breast Cancers?

A

Ovarian cancer, Peritonial cancer

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15
Q

What is the interaction between BRCA-1 and BRCA-2?

A

DNA damage – phosphorylation of small BRCA-1 gene product – binds to the large BRCA-2 gene product – this complex binds to RAD51 – repair DNA breaks through homologous recombination

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16
Q

What is the factor that is associated with ovarian cancer in BRCA-2 breast cancer?

A

Mutation of Ovarian Cancer Cluster Region in exon 11

17
Q

Where are BRCA-1 and BRCA-2 found?

A

BRCA-1 : chromosome 17

BRCA-2 : chromosome 13 ( also ATP7B in Wilson’s disease)

18
Q

How are BRCA-1 and BRCA-2 tested?

A

Testing the blood for the relevant exons.

  1. WAVE machine for screening each section for mutation
  2. Sanger sequencing
19
Q

What is the scoring system used to identify BRCA-1 and BRCA-2 mutation?

A

Manchester Scoring system

20
Q

Preventive measures for BRCA-1 and BRCA-2 mutation carriers?

A
  • Prophylactic bilateral mastectomies

- Prophylactic oophorectomy + fallopian tube resection

21
Q

Management of breast cancer?

A
  • Masectomy + sampling of regional lymph nodes for prognostic information
  • radiotherapy if lymph nodes are involved and multiple foci of tumours are found
  • If tumour is Oestrogen and Progesterone receptors sensitive : 1. Anti-oestrogen therapy : Tamoxifen 2. Aromatase-inhibitor : Anastrozole
  • Her2/neu +ve (more rapid growth) : trastuzumab
22
Q

What are the genes implicated in Familial Colon Cancer Syndromes?

A

MLH1, MSH2, MSH6, APC, MYH

23
Q

What are the different familial colorectal cancer syndromes?

A
  1. Hereditary Non-Polyposis colon cancer
  2. Familial Adenomatous Polyposis
  3. MYH-associated polyposis
24
Q

Genetic mutation implicated in Hereditary Non-polyposis Colon Cancer

A

MLH1, MSH2. MSH6

25
Q

What are MLH1, MSH2, MSH6?

A

MLH1, MSH2, MSH6 are DNA mismatch repair genes. They are stability genes that excise and rectify errors in the pairing of DNA bases during replication.

26
Q

Pathogenesis of Hereditary Non Polyposis Colon Cancer?

A

Loss of DNA mismatch repair genes – hypermutable state of microsatellite – accumulation of mutations in growth-regulating genes

27
Q

Associated pathology with the mutation of Mismatch Repair genes.

A

Colon cancer, endometrial cancer, ovarian cancer, gastric cancer, urothelial cancer, gliomas

28
Q

Why are certain sites more prone to carcinogenesis when there is a mutation of the Mismatch Repair genes?

A

Different tissues may employ different mechanisms to repair DNA.

29
Q

What are the criteria of diagnosing Hereditary Non Polyposis Colon Cancer?

A

Amsterdam II criteria:

  1. Exclude APC gene mutation
  2. 3 or more relatives with Colon CA
  3. at least one affected person is below 50 years old
  4. Colorectal CA is present in 2 or more generations
30
Q

Features of Hereditary Non Polyposis Colon Cancer?

A
  • Less than 10 polyps
  • Commonest cause of colorectal cancer
  • Occurs at a young age
31
Q

What are the Features of Familial Adenomatous Polyposis?

A
  • more than 100 polyps carpeting the mucosa of large intestine
  • associated with Congenital Hypertrophy or Retinal Pigment Epithelium (CHRPE) in 80% of FAP
32
Q

What is the associated gene of Familial Adenomatous Polyposis?

A

Adenomatous Polyposis Coli (APC) gene in Chromosome 5

33
Q

Pathogenesis of Familial Adenomatous Polyposis?

A

Mutation of APC in Chromosome 5 – loss of both APC genes (TS gene) – Accumulation of Beta catenin – Activates transcription of several genes: MYC, cyclin D1 – promotes cell proliferation – formation of adenomas

34
Q

What is the concerned factor about Familial Adenomatous Polyposis?

A

Each polyp has an opportunity for malignant transformation.

35
Q

What is the attenuated form of Familial Adenomatous Polyposis?

A

MYH-associated polyposis : 15 - 200 polyps

36
Q

What is the gene associated with MYH-associated polyposis?

A

MYH gene - autosomal recessive inheritance

37
Q

What is the normal function of MYH gene?

A

A Tumour Suppressor Gene

  • carries out base excision repair process
  • excises bad fragments of DNA and replaces the correct ones

Week 1 - Medical Genetics (5 decks)

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