Hereditary tumors

8 important questions on Hereditary tumors

What is genetic susceptibility?

The increased likelihood of developing a particular disease based on a person's genetic makeup.

Knudson Two-Hit Hypothesis

The Knudson two-hit hypothesis explains hereditary cancer syndromes by suggesting that two mutations are necessary for cancer to develop—one inherited and one acquired.

What are the criteria for a cancer to be hereditary?

  1. Development of tumor at relatively young age
  2. Several primary tumors
  3. Several siblings with the same phenotype
  4. Specific combination of tumors in patients/family
  5. Presence of precursor lesions
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How can PARP inhibitors be good drugs to treat cancer?

PARP is a protein important for repairing single-stranded breaks in the DNA. If such breaks stay unrepaired until DNA is replicated, then the replication itself can cause double stranded breaks to form. Drugs that inhibit PARP1 causes multiple double stranded breaks to form in this way. In normal cells these DSBs will be repaired leading to normal cell survival and cell proliferation. In tumors with BRCA1 or BRCA1 mutations these double stranded breaks cannot be efficiently repaired, leading to the death of cells (synthetic lethality).

What are the two most well-known hereditary colon cancers syndromes?

  • Lynch syndrome: autosomal dominant inactivating mutations in MMR genes, no increased incidence of polyps.
  • Familial adenomatous polyposis (FAP): autosomal dominant inactivating mutations in the APC gene, causing 100 to 1000 polyps in the colon

What is MUTYH-associated polyposis (MAP)?

An autosomal recessive polyposis syndrome caused by mutations in both alleles of the DNA repair gene MUTYH. Bi-allelic MUTYH mutations lead to G-to-T transversions, resulting in an accumulation of point mutations e.g in APC.

What are the Amsterdam criteria?

Three or more first close relatives with lynch syndrome
  • One is a first degree relative of the other two
  • two successive generations are affected. 
  • One patient is <50 years

How can the lynch syndrome (HNPCC) be recognized (onderzoek)?

  • MSI analysis (microsatellite instability analysis): checks repeat length using PCR
  • Immunohistochemistry: antibodies against mismatch repair genes (MSH6, MSH2, MLH1, PMS2)

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