Hereditary Cancer Syndromes

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  • Created by: amh4
  • Created on: 15-02-17 14:24

Familial Adenomatous Polyposis

Autosomal dominant inheritance, affects 1 in 10,000 individuals average diagnosis is 39 years

100-1000s of adenomatous polyps through the colon and rectum, initally benign but will lead to malignancy

Germline mutation in the APC gene, over 500 are known. Mutations at 5' or 3' end cause attenuated FAP (less severe)

APC is a tumour supressor in cell cycle control, differentiation, migration and apoptosis by interacting with B catenin in the Wnt signalling pathway. 

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MUTYH associated polyposis (MAP)

Autosomal recessive, by age 65 100% will have developed cancer

5-100 colorectal polyps

Caused by biallelic mutations in the MUTYH gene. MUTYH encodes the MYH glycosylase enzyme - involved in base excision repair of DNA (G:A) mismatches. 

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PTEN Harmartoma Tumour Syndrome

Includes Cowdens, BBRS, Proteus and Proteus like syndromes. 

PTEN is a tumour supressor gene, 85% of patients will have a mutation. 

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Juvenile Polyposis Syndrome

Rare autosomal dominant harmartoma syndrome. Found in children/teens. 

Juvenile refers to they type of polyps rather than the age of onset. Polyps number 5-200. 

Germline mutations in SMAD4 and BMPR1A.

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Lynch Syndrome

Autosomal dominant with 70-80% penetrance.

Most common form of colorectal cancer, increased risk of developing other cancers as well.

Young age of onset compared to population. Rapid progression from adenoma to carcinoma due to high mutation rate in tumour cells. 

Mutations in MMR genes MLH1 and MSH2. 

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Lynch Syndrome testing

Amsterdam criteria - at least three relatives with colorectal cancer, one should be first degree, two sucessive generations, one CRC before age 50, FAP should be excluded. BUT 50% of families fail to meet this criteria.

Bethesda guidelines developed to increase senstivity but are less specific - patient diagnosed <50, CRC diagnosis <60 with MSI - high tumour histology. CRC or LS tumour diagnosed <50 years in at least 1 FDR, CRC or LS tumour diagnosed at any age in 2 FDR or SDR. 

Testing strategy - Detect MSI (90% show MSI). Immunohistochemisty (IHC) antibodies detect presence or absence of MMR protein. MLH1 hypermethylation studies (MLH1 promoter methylation seen in 15% of sporadic tumours) using MS-MLPA kit. 

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Breast and Ovarian Cancer

Germline mutatuins in BRCA1 or BRAC2 predisposes to breast and ovarian cancers aswell as others.

>750 mutations known in BRCA1, >400 in BRAC2. Majority ae frameshift/nonsense mutations that lead to termination of protein. Genotype-phenotype correlations exist. 

Variable penetrance. 

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Retinoblastoma

Childhood malignant tumour of the developing retina. AD inheritance with 90% penetrance. Risk of secondary cancers. 

Symptoms - cat eye reflex, squint, inflammation.

Sporadic 40% and hereditary forms 60%

Unilateral, bilateral or trilateral (in pineal gland)

RB1 tumour supressor gene mutation controls cell cycle progression, not functional pRB leads to uncontrolled cell growth. 

Treatment - radiotherapy, chemo, cyrotherapy, ennucleation

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Li-Fraumeni Syndrome

Autosomal dominant. high penetrance. 90% develop cancer by 60 years. 

Very rare, only 400 families diagnosed worldwide.

Mutation in p53 gene, leading to a variety of cancers, radiation induced cancers. Some breast cancer only mutations. 

p53 controls DNA damage: delays cell cycle progression for repair or initiates apoptosis. 

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Ataxia Telangiectasia

AR condition

ATM gene - DNA repair pathway signalling

High risk of leukaemias lymphomas brain tumours and radiation sensitive. Females have increased risk of breast cancer. 

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Dr Knudson's two it hypothesis

In 1971, Dr. Alfred Knudson proposed the two-hit hypothesis to explain the early onset at multiple sites in retinoblastoma

 Most loss-of-function mutations that occur in tumor suppressor genes are recessive in nature, thus in order for a particular cell to become cancerous, both of the cell’s tumor suppressor genes must be mutated.

 In the first event in the two-hit model is an inherited mutation, however inheriting one germline copy of a damaged gene present in every cell in the body was not sufficient to enable this cancer to develop.

 A second hit (or loss) to the good copy in the gene pair could occur somatically, though, producing cancer.

 This hypothesis predicted that the chances for a germline mutation carrier to get a second somatic mutation at any of multiple sites in his/her body cells was much greater than the chances for a noncarrier to get two hits in the same cell

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Proto-oncogenes

A proto-oncogene is a normal “good” gene that that can become an oncogene (a gene that has potential to cause cancer) due to mutations or increased expression.

 Proto-oncogenes are genes involved in the four basic regulators of normal cell growth (growth factors, growth factor receptors, signal transduction molecules and nuclear transcription factors).

 Oncogenes are usually dominant at a cellular level, i.e. only a single copy of a mutated oncogene is required to contribute to the multi-step process of tumor progression. 

Example - RAS oncogene - normally functions to sustain proliferative signalling.

Most cancer-causing mutations involving oncogenes are acquired, not inherited.

They generally activate oncogenes by chromosome rearrangements, gene duplication, or mutation.

For example, a chromosome rearrangement can lead to formation of the gene called BCR-ABL  leads to chronic myeloid leukemia (CML). 

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TP53

Tumour supressor gene 'the guardian of the genome' because of its role in conserving stability by preventing genome mutation.

p53 has many mechanisms of anticancer function and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms:

  • It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging.
  • It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle).
  • It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable.
  • It is essential for the senescence response to short telomeres.
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BRCA1 and BRCA2 functions

BRCA1 and BRCA2 are tumour supressor genes, involved in the repair of double stranded DNA breaks.

BRCA1 is phosphorylated by ATM and CHK2 in response to dsDNA breaks.

BRCA1 binds to BRCA2 which interacts with RAD51 to form a complex which is involved in dsDNA repair - homologous recombination.

Mutations in BRCA1 or BRCA2 are not simply associated with increased breast cancer risk. Mutation carriers are also susceptible to cancers of the ovary, prostate, pancreas and male breast.

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DNA damage response

The importance of the DNA damage response network for the development and well being of humans is illustrated by the large variety of diseases and cancer-predisposition syndromes that have been linked to mutations of DDR genes.

The DNA damage response (DDR) signaling pathway orchestrated by the ATM and ATR kinases is the central regulator of this network in response to DNA damage. Both ATM and ATR are activated by DNA damage and DNA replication stress, but their DNA-damage specificities are distinct. Furthermore, ATM and ATR often work together to signal DNA damage and regulate downstream processes.

The phenotypic manifestation of AT is due to the broad range of substrates for the ATM kinase, involving DNA repair, apoptosis, G1/S, intra-S checkpoint and G2/M checkpoints, gene regulation, translation initiation, and telomere maintenance. Mutation in the ATM gene causes Ataxia Telangeictasia. People with A-T have a highly increased incidence (approximately 25% lifetime risk) of cancers, particularly lymphomas and leukemia, but other cancers can occur. When possible, treatment should avoid the use of radiation therapy and chemotherapy drugs that work in a way that is similar to radiation therapy (radiomimetic drugs), as these are particularly toxic for people with A-T. 

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Xeroderma pigmentosa

Xeroderma pigmentosa is an autosomal recessive disease caused by mutations in global NER genes XPA-XPG or XPV this results in nucleotide excision repair (NER) enzymes being mutated, leading to a reduction in or elimination of NER. If left unrepaired, damage caused by ultraviolet light can cause mutations in individual cell's DNA. The molecular defects in XP cells result in a greatly elevated induction of mutations in sun-exposed skin of affected individuals and therefore symptoms are extreme sensitivity to UV light, skin cancer and neurodegeneration.

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First 3 Hallmarks of Cancer (2000)

Self-sufficiency in growth signals - activates H-ras oncogene. GTPase HRas is involved in regulating cell division in response to growth factor stimulation HRAS acts as a molecular on/off switch. 

Tissue invasion and metastasis - Inactivates e caderhin the cell to cell adhesion regulator, so cells can migrate and enter the blood and lymphatics system. 

Evading apoptosis - cells produce IGF survival factors to evade cell death.

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Next 3 Hallmarks of Cancer 2000

Insensitivity to anti-growth signals - Loss of tumour supressor genes eg RB1

Limitless replicative potentialTelomerase reverse transcriptase lengthens telomere DNA allowing cells to overome the Hayflick limit

Sustained angiogenesis - cells can produce Vascular endothelial growth factor to form new blood vessels. VEGF gene expression is upregulated by hypoxia and by oncogene expression.

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2011 4 New Hallmarks of Cancer

Deregulating cellular energetics - Adjustment of energy metabolism is seen in order to fuel cell growth and division. Cancer cells limit their energy metabolism largely to glycolysis. 

Avoiding immune destruction - immunocomprimised people are prone to certain cancers - downregulate certain antigens, produce immunosupressive proteins

Tumour promoting inflammation - inflammation is a selective advantage, tumours can actively recruit inflammatory cells. 

Genome instability and mutation - hallmarks depend on succession of alterations in the genomes of neoplastic cells.

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Retinoblastoma continued..

Bilateral (40%) - all cases are hereditary, plus increased risk of developing a second cancer

Unilateral (60%) - 15% are hereditary

Trilateral - both eyes and the pineal gland 'the third eye' 

9 out of 10 children with retinoblastoma are cured. 

4 stages: 1-confined to retina 2-confined to orbit 3-spread beyond orbit 4-distant metastasis

Treatment - smaller tumours: laser photocoagulation, cyrotherapy. Larger tumours: chemotherapy or enucleation and prosthesis is then fitted. Sometimes radiotherapy is needed but does have some effect on the surrounding tissue. 

Familial retinoblastoma there is sometimes multiple independant tumours in one eye - multifocal. 

RB1 tumour supressor - pRB regulator of the G1 cell cycle checkpoint. Can repress DNA transcription and prevent cell division. 

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