BSC 422 Final

• DNA Repair and Protein Homeostasis

  -essential metabolic processes

  -addiction to DNA Repair pathways

  -sensitive to inhibition of protein degredation
• DNA repair - ?

  genome integrity
• Protein synthesis and degradation:

  -cell division

  -cell maintenance

  -cell survival
• Synthetic Lethals (4 points):

  -Disabling mutation in either gene A or gene B allows survival but disabling mutations in BOTH genes result in death.

  -Inhibitors of partners - highly targeted anti-cancer drugs.

  -Less toxicity

  -Identification of synthetic lethal interactors
• Disabling mutation in either gene A or gene B allows what? What about disabling mutations in BOTH genes?

  1. survival

  2. death
• cellular homeostasis


  Balance between protein synthesis and degradation
• protein synthesis is determined by what three factors?

  -epigenetic states

  -transcription factors

  -translation regulators (miRNAs)
• Ubiquitin-proteasome pathway


  -conserved

  -E1 = activating

  -E2 = conjugating

  -E3 = ligase

  -polyubiquitination

  -20S core (proteolytic), Two 19S regulatory

  -Trypsin-, chymotrypsin-, caspase-like, 3-25 AA peptides
• UPP roles and targets

  -Degradation

  -Signaling

  -Protein trafficking

  -Protein degradation: cell division, cell survival

  -Hematopoietic cancers
• Aggresome Pathway


  -Auxillary pathway

  -UPP Overload or Inhibition

  -Large aggregates, misfolded and polyUb = aggresome

  -Lysosome

  -HDAC6 assembly, dynein transport

  -Inhibit tubulin or HDAC6

  -Multiple myeloma
• Most common cancer in American women?

  Breast Cancer
• How many breast cancer cases are hereditary?

  5-10%
• How many breast cancer cases are associated with familial predisposition?

  20%
• Which gene mutations are most hereditary cases of breast cancer caused by?

  -most due to mutations in BRCA1, BRCA2, and PALB2

  -few rare cases involve mutations in PTEN, p53, CDH1, and STK11
• What do BRCA1 and BRCA2 do?

  encode tumor suppressor proteins that repair damaged DNA
• BRCA1


  protein & a component of a multisubunit protein complex the BRCA1-associated genome surveillance complex (BASC)
• What does BRCA1 do in BASC?

  repairs double-strand DNA breaks via homologous recombination
• BRCA1 also associated with what function?

  another form of DNA repair termed mismatch repair
• BRCA1 interacts with RNA polymerase II and histone deacetylase (HDAC) complexes which means ...?

  it plays an important role in the control of transcription and DNA double strand break repair
• BRCA2 does what?


  interacts with a single-strand DNA and the recombinase RAD51 and together with BRCA1 and PALB2 (partner and localizer of BRCA2), the BRCA2 completes DNA double strand break repair by recruiting RAD51 for the final step of homologous recombination
• What happens when either of the BRCA1 or BRCA2 genes are mutated or altered?

  the loss of the remaining wild-type allele (loss of heterozygosity) will impair the DNA repair response, allowing the cell to accumulate additional genetic alterations that may lead to malignant transformation
• What are Poly(ADP-Ribose) Polymerases (PARPs)?


  a group of proteins that play a central role in the repair of single-strand DNA breaks (SSBs) by detecting SSBs, binding DNA, and synthesizing a poly(ADP-ribose) chain that signals other critical DNA repair enzymes to travel to the site of DNA damage which is called base-excision repair (BER)
• What percentage of hereditary breast cancers and all breast cancers do mutations in the BRCA1 and BRCA2 genes account for?

  1. 20-25%

  2. 5-10%
• What is the lifetime risk for women of developing breast cancer? How much does this increase with a BRCA1 mutation? BRCA2?

  1. 12%

  2. 55-65%

  3. 45%
• What is the likelyhood of developing ovarian cancer if you have a mutation in either the BRCA1 or BRCA2 genes?

  39%
• Which type of mutation is associated with higher rates of fallopian tube cancer and peritoneal cancer?

  BRCA1 mutations
• Which type of mutation is associated with higher rates of male breast cancer and prostate cancer?

  BRCA2
• In which groups of people are the risks of harboring a BRCA1 or 2 mutation highest?

  Ashkenazi Jewish descent, Norwegian, Dutch, or Icelandic origin
• What are some recommendations for BRCA1/2 asymptomatic carriers?

  -Breast self-exam training and education

  -Regular monthly breast self-exam starting at age 18

  -Semiannual clinical breast exam starting at age 25

  -Annual mammogram and breast MRI screening starting at age 25

  -Discuss options of prophylactic bilateral mastectomy on a case-by-case basis

  -Recommend risk-reducing salpingo-oophorectomy (RRSO) which is the removal of the ovaries and the fallopian tubes

  -Consider chemoprevention options for breast and ovarian cancer (such as taking tamoxifen or exemestane)

  -Consider investigational imaging and screening
• How does neoadjuvant therapy affect those with breast cancer?

  -it may downsize a tumor and allow for breast conservation in cases where a mastectomy would otherwise have been necessary

  -The time taken to deliver neoadjuvant chemotherapy allows for concurrent genetic testing and the availability of results which can influence surgery

  -Approximately 25% of the time after neoadjuvant chemotherapy is administered, no remaining cancer cells are identified in the breast or axilla which is termed a pathologic complete response (pCR)
• What is the first line of treatment for breast cancer typically?

  Chemotherapy is given to some women with breast cancer early in treatment to reduce the risk of recurrence
• How is localized BRCA1/2 related breast cancer managed?

  -treatment does not differ from the treatment of spontaneous breast cancers in non-carriers

  -Participation in clinical trials of novel therapies is encouraged

  -Cisplatin or carboplatin chemotherapy is usually administered in clinical trials

  -Standard-of-care combination chemotherapy regimens include doxorubicin/cyclophosphamide/paclitaxel
• How is metastatic BRCA1/2 related breast cancer managed?


  -The standard treatment of BRCA1/2 related breast cancers does not differ from the metastatic treatment in non carriers

  -The use of PARP inhibitors is in development

  -The oral drug olaparib (trade name Lynparza) is a PARP inhibitor developed for the treatment of solid tumors and is the first drug in this class to be approved by the FDA
• BREAST CANCER CASE STUDY:

  -37 y/o female with past medical history of child birth

  -presents with a breast mass

  -Paternal grandmother had breast cancer at age 50

  
  

  What tests will be run?

  What will her treatment likely be?

  Mutations in which genes are likely responsible for this cancer?


  TESTS RUN:

  -Mammogram revealed bilateral dense tissue

  -Ultrasound and needle biopsy of the abnormal revealed a high-grade invasive ductal carcinoma

  -Triple-negative straining put her tumor in the "basal-like" category

  -No enlarged or abnormal lymph nodes on ultrasound

  -CT scans showed no distant metastasis, stage 3, T4N0

  
  

  TREATMENT:

  -Four cycles of doxorubicin and cyclophosphamide (result: Patient no longer had a large/very detectable breast mass)

  -Elected to undergo right mastectomy along with the modified left mastectomy and lymph node biopsy.

  -Breast reconstruction was also completed afterwards. (result=Biopsy showed no viable cancer cells)

  MUTATIONS:

  -Patient opted for genetic testing -> BRCA1 deletion mutation. Patient's father also had the mutation.
• BREAST CANCER CASE STUDY:

  IF RECURRANCE OF METASTATIC BREAST CANCER... what next?

  Treatment?

  -PARP inhibitor was prescribed (olaparib), which resulted in shrinkage of the masses in her lungs.

  -patient has remained olaparib for three years with no new symptoms
• Multiple Myeloma CASE STUDY:

  -39 y/o male

  -anemia after feeling fatigued (decrease in endurance after running and increased fatigue)

  -no history, healthy, no medical problems

  
  

  What tests will be run?

  What will his treatment likely be?

  Mutations in which genes are likely responsible for this cancer?

  Tests: Blood test w/ complete blood count - Anemia (not vitamin deficient), Chemistry panel - Normal, Thyroid function - Normal, Kidney function - Normal

  
  

  NEXT STEP TESTS:

  -Chemistry panel = Elevated immunoglobulins (indicator for monoclonal gammopathy); Serum protein electrophoresis (SPEP) = M protein at 2.37 g/dl (MGUS-level); Serum beta-2-microglobulin test = 3.8 mg/l

  -Skeletal survey - multiple bone lesions are visible

  -Bone marrow biopsy - 34% clonal plasma cells

  
  

  Treatment:

  -chemo: eight cycles of the three drug regimen Revlimid and dexamethasome (known as RVD) -> resulted in 90% reduction of monoclonal proteins

  THEN: chemo high dose + autologous stem cell transplant

  Mutation: malignant plasma cells
• Plasma cells


  -Immune cells that develop from activated B lymphocytes

  -Produce and secrete antibodies

  -Antibodies respond to specific antigens to fight infections

  -Found in bone marrow, normally in small amounts
• multiple myeloma


  -malignant plasma cells (myeloma cells in bone marrow)

  -Produce abnormal levels of a monoclonal immunoglobulin (paraprotein or M protein)

  -Cause injury to kidneys
• Accumulation of myeloma cells in bone marrow:

  Blocks red cell production and cause anemia
• Activation of osteoclasts:


  -Resorb bone (break down bone)

  -Cause osteolytic metastases and hypercalcemia