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Cancer Genetics > Inherited Cancer Part One > Flashcards

Inherited Cancer Part One Flashcards

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1
Q

Risk of Genetic Predisposition to Cancer in Common Tumours

A
  • 5-10% of breast cancer cases (BRCA) due to highly penetrant germline mutations in cancer predisposition genes.
  • Up to half of these families will have mutations in BRCA1 or BRCA2.
  • 1% of colorectal cancer (CRC) cases - due to mutations in APC.
  • 5% of CRC cases - due to mutations in one of the HNPCC genes.
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2
Q

What % of breast cancer cases are due to highly penetrant germline mutations in cancer predisposition genes?

A
  • 5-10% of breast cancer cases (BRCA) due to highly penetrant germline mutations in cancer predisposition genes.
  • Up to half of these families will have mutations in BRCA1 or BRCA2.
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3
Q

What % of colorectal cancer (CRC) cases are due to mutations in APC?

A
  • 1% of colorectal cancer (CRC) cases - due to mutations in APC.
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4
Q

What % of CRC cases are due to mutations in one of the HNPCC genes?

A
  • 5% of CRC cases - due to mutations in one of the HNPCC genes.
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5
Q

Outline the principles of inherited predisposition to cancer.

A
  • A mutation in a single cancer gene can predispose to different tumours in the same individual = Variable expression.
  • It takes time for an individual to accumulate the other hits necessary to cause a tumour = Age-related penetrance.
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6
Q

Outline the 3 divisions of inherited cancer predisposition.

A

1) . Proto-oncogenes - genes whose action positively promotes cell proliferation.
2) . Tumour Suppressor Genes - Inhibit cell proliferation.
3) . Mutator genes - maintain the integrity of the genome.

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7
Q

Outline some syndromes caused by mutations in proto-oncogenes.

A

1) . Multiple Endocrine Neoplasia type 2A (MEN2A), activating germline mutations
- AD
- Condition where you are predisposed to getting tumours in endocrine glands - particularly Medullary thyroid cancer (90%), Parathyroid cancer (20-30%), and Phaechromocytoma (50%).
- Most present first with medullary thyroid cancer <30yrs (as young as 4 in some cases).
- Penetrance is 70% by 70yrs.
2) . Hereditary Papillary Renal Carcinoma - MET mutations
- AD
- Bilateral renal tumours
- Incomplete penetrance

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8
Q

Outline some syndromes caused by mutations in TSGs.

A

1) . Li-Fraumeni Syndrome (LFS):
- TP53 mutations
- Young onset cancers, particularly sarcoma and breast

2) . BRCA1/2:
- Breast and Ovarian Cancer

3) . PTEN:
- Breast cancer
- Particular skin tumours
- Thyroid cancer
- Cowden Syndrome

4) . APC:
- Familial Adenomatous Polyposis Coli (FAP).

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9
Q

Inherited Predisposition to Breast Cancer - BRCA1

A
  • BRCA1 protein is involved in many important pathways including DNA repair and regulation of transcription.
  • Female carriers have around an 80% lifetime risk of breast cancer and a 40% chance of ovarian cancer.
  • The chance of developing a second breast cancer in a female gene carrier is around 50%.
  • There is also an increased risk of prostate, endometrial and pancreatic cancer.
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10
Q

How does BRCA2 risk differ from BRCA1 risk?

A
  • Risk profile different - cancers tend to come on at a slightly later age.
  • Slightly higher risk of prostate cancer in men compared to BRCA1.
  • Will see male breast cancer with BRCA2 families.
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11
Q

What is the average age of colon cancer in untreated FAP individuals?

A

39 years.

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12
Q

What % of untreated FAP individuals develop CRC by 21?

A

7%.

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13
Q

What is the lifetime risk of developing cancer with FAP without surgery?

A

Approximately 99%.

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14
Q

What extra-colonic cancers are associated with FAP?

A
  • 2% risk of thyroid cancer
  • 1.6% risk of bowel cancer
  • 4-12% risk of cancer in duodenum
  • 2% risk of pancreatic cancer
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15
Q

Outline some syndromes caused by mutations in mutator genes.

A
  • Mutator genes are important in maintaining the integrity of the genome.
  • e.g. Mismatch Repair genes that we see mutated in Lynch syndrome (HNPCC).
  • In HNPCC have about a 70% lifetime risk of getting bowel cancer.
  • Mainly see mutations in hMLH1 and hMSH2.
  • MMR protein mutations can increase risk of CRC, endometrial cancer, ovarian cancer, ureteric cancer, renal, pelvis cancer, and brain cancer.
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16
Q

What tumours may you seen in HNPCC other than CRC?

A
  • 60-85% risk of CRC
  • 3-12%Ovarian
  • 25-60% Endometrial
  • 2% Pancreatic
  • 1-4% Brain
  • 2-13% Stomach
  • 1-12% Urinary tract
  • Get wide ranges because you get huge differences when looking at different studies - selection bias.
17
Q

DNA repair defects.

A
  • Mutations in caretaker genes that protect against DNA damage from UV radiation, free radicals and exogenous chemicals.
  • DNA repair proteins alse have a role in joining the double stranded breaks between the variable, diversity and joining gene segments of the lymphocyte immunoglobulin and antigen receptor genes to generate immunological diversity so these conditions often include immunodeficiency as well as neoplasia.
18
Q

What are the different types of DNA repair defects?

A

1) . Nucleotide Excision Repair (NER): a DNA repair pathway that removes DNA damage by excising the region of DNA that contains the damaged base. e.g. Xeroderma Pigmentosa and Trichothiodystrophy.
2) . Transcription-coupled repair: specialised pathway that facilitates repair of DNA during transcription - e.g. Cockayne Syndrome and Cerebro-oculo-facial-skeletal-syndrome
3) . Cross-linking agent repair: agents like mitomycin C and diepoxybutane and many chemotherapy drugs from covalent cross links in double stranded DNA which obstruct DNA replication. Specific pathways are needed to detect DNA replications. Specific pathways are needed to detect the DNA damage and repair it e.g. Fanconi anaemia.

19
Q

Give 2 examples of cancer syndromes caused by deficiencies in Nucleotide Excision Repair (NER).

A

1) . Nucleotide Excision Repair (NER): a DNA repair pathway that removes DNA damage by excising the region of DNA that contains the damaged base.
- Xeroderma Pigmentosa (XP)
- Trichothiodystrophy

20
Q

Give 2 examples of cancer syndromes caused by deficiencies in Transcription-coupled repair.

A

2) . Transcription-coupled repair: specialised pathway that facilitates repair of DNA during transcription
- Cockayne Syndrome
- Cerebro-oculo-facial-skeletal-syndrome

21
Q

Give an example of a cancer syndromes caused by deficiencies in Cross-linking agent repair.

A

3) . Cross-linking agent repair: agents like mitomycin C and diepoxybutane and many chemotherapy drugs from covalent cross links in double stranded DNA which obstruct DNA replication. Specific pathways are needed to detect DNA replications. Specific pathways are needed to detect the DNA damage and repair it.
- Fanconi anaemia.

22
Q

What is Bloom syndrome?

A
  • DNA repair defect related cancer syndrome.
  • Absence of the BLM protein destabilises the enzymes important in DNA replication and repair (helicase is defective).
  • Bloom syndrome = short stature, small head, marked sun sensitivity leading to sun damage, lymphoreticular tumours.

Cancer Genetics (21 decks)

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