13 Cancer Genetics

  1. How many cancers are hereditary?
    • VERY FEW
    • 90-95% of cancers are due to sporadic mutations in somatic cells
    • 5-10% are due to germline mutations (are hereditary) - parent may have had the cancer & passed it on or it could be a new mutation IN the germline
  2. What causes all cancers?
    • DNA mutations
    • something has to make the cell go from normal to abnormal
    • most mutations are acquired, not inherited
    • predisposition to a cancer can be inherited, & is usually done so as an autosomal dominant (single) trait
    • there’s Incomplete Penetrance with AD traits: someone may or may not get the cancer
    • there’s also Variable Expressivity: when or where
    • (there fore it's autosomal dominant)
  3. How many mutations at the cellular level does cancer require?
  4. What's the difference between sporadic and hereditary cancer?
    • sporadic: two ACQUIRED mutations
    • hereditary: one inherited & ONE acquired mutation
  5. Knudson’s Two-Hit Hypothesis
    • in hereditary cancer, you inherit 1 mutated gene; if at some point during life the 2nd gene is knocked out via a sporadic event → tumor
    • the same thing happens with sporadic cancer, except you start with 2 NORMAL gene copies; both have to be knocked out sporadically over the lifetime
    • a somatic mutation isn’t passed onto children
    • with a germline mutation, every cell in the body is at risk for LOSING the 2nd normal gene copy because of a sporadic event
    • observation based on the occurrence of retinoblastoma
  6. Hereditary Cancers
    • tend to occur at younger age - only 1 rare event needs to happen, so it’s likely to take less time than sporadic somatic cancer where TWO rare events need to occur for a tumor to result
    • more likely to be bilateral
    • eg. Retinoblastoma, Wilm’s tumor
  7. Retinoblastoma
    • hereditary Rb will likely affect both eyes eventually
    • the chances that 2 sporadic events will occur in BOTH eyes is unlikely, therefore sporadic Rb will likely only occur in 1 eye
  8. What kind of genes are usually involved in cancer (tumorigenesis)?
    Loss of Function genes, aka

    1. Tumor suppressor genes (Rb, NF1, p53, APC [colon cancer]) - restrain cell growth

    2. Mismatch repair genes (MLH1, MSH2, MSH6) - maintain correct DNA sequences

    both copies of any of those genes is needed for cancer to result
  9. What kind of genes are very rarely inherited in the realm of cancer?
    • Gain of Function Genes - where a single somatic gene mutation can cause cancer
    • tend to be in growth & transcription factors
    • are called Oncogenes
    • eg. RET (lung, multiple endocrine neoplasia), BCR-ABL (chrom. 9-22 rearrangement seen in chronic myeloid leukemia, acute lymphocytic leukemia), HRAS (Costello syndrome)
  10. What are some red flags for hereditary cancers?
    • early onset cancers (< 50, other than leukemia)
    • multiple or bilateral tumors
    • rare or unusual tumors
    • combinations of certain cancers
    • BRCA1, 2: breast, pancreatic, & ovarian
    • p53: breast, sarcomas, leukemia, & brain
    • autosomal dominant pattern of inheritance
    • lack of known contributing factors
  11. Red Flags for BRCA
    • Early onset breast cancer (< 40/50)
    • Bilateral breast cancer
    • Male breast cancer
    • Ovarian cancer at any age
    • Breast or ovarian cancer in women of Ashkenazi Jewish descent (1/40 carrier rate)
    • Families with combinations of breast, ovarian, & PANCREATIC cancer
    • Families with known BRCA1/2 mutation
  12. Breast Feeding & BRCA
    breast feeding for more than 12 months was shown to decrease a woman with a BRCA1 mutation’s risk of ovarian cancer by 38% & decrease a woman with a BRCA2 mutation’s risk of ovarian cancer by 50%
  13. Children & BRCA
    while having children in general can decrease risk of cancer caused by BRCA mutations, having MORE children increased the risk of developing cancer for BRCA1 carriers but NOT BRCA2 carriers
  14. Removal Surgery & BRCA
    • getting a mastectomy reduces the risk of developing cancer in a BRCA carrier by 95%
    • Oophorectomy by age 40 reduced ovarian cancer risk 56% in BRCA1 carriers & 43% in BRCA2 carriers
  15. Concerns about BRCA testing for the symptomatic individual:
    • Guilt & concern over passing on gene
    • Worry over risk of developing additional cancers
    • Medical insurance discrimination NOT an issue because insurer already knows the patient has cancer + GINA (Federal Genetic Information Nondiscrimination Act)
  16. Concerns about BRCA testing for the asymptomatic individual:
    • Psychological distress (wondering if, when, & where cancer is going to happen)
    • Medical insurance discrimination not an issue
    • Life Insurance discrimination: companies raise rates based on actuarial assessments of risk
  17. DNA Testing Limitations
    • DNA testing could result in discovering VUS (VUS were originally discovered via BRCA testing)
    • a negative BRCA test does NOT completely rule out the possibility of an inherited predisposition to cancer
    • & while a mutation does increase cancer susceptibility, it can’t predict if or when cancer will develop
  18. What’s an example of a cancer that exhibits Variable Penetrance?
    • Colorectal Cancer: Familial Adenomatous Polyposis coli (FAP or APC mutations inherited as an AD disorder)
    • characterized by multiple polyps in the colon from a young age
    • over time the polyps develop into cancer (the number of carcinomas is low, but the potential to develop them is high)
    • the patterns of hereditary FAP & sporadic colorectal cancer are very similar (APC, KRAS, p53 mutations), the difference is the age of onset
  19. Lynch Syndrome
    mutations in mismatch repair genes can often result in lynch syndrome, which is a high risk for HNPCC (hereditary nonpolyposis colorectal cancer) – colon & uterine cancers most common, ovarian & other GI cancers also occur (endometrial, stomach & ovarian cancer)
Card Set
13 Cancer Genetics
Genetics Exam 2