Term
| What are the Polyposis syndromes that predispose one to colorectal cancer? |
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Definition
1) Adenomatus polyposis coli (APC)
2) Attenuated adenomatous polyposis coli
3) Gardner's syndrome
4) Turcot's syndrome |
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Term
| What are the Non-polyposis syndromes that predispose one to colorectal cancer? |
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Definition
| 1) Hereditary non-polyposis colon cancer (HNPCC) |
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Term
| What are the Hamaratomatous syndromes that predispose one to colorectal cancer? |
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Definition
1) Cowden's syndrome
2) Familial juvenile polyposis syndrome
3) Peutz-Jaegher syndrome |
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Term
| What percentage of colon cancers come from inherited mutations? |
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Definition
| roughly 10%, the rest are from spontaneous mutations |
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Term
| What are the major inherited colon cancers? |
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Definition
1) FAP (Familial adenomatous polyposis coli (APC)- 1% of all colon cancers
2) HNPCC (Hereditary non-polyposis colorectal cancer syndrome (4-10% of all colon cancers) |
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Term
FAP
1) What type of disorder?
2) Affects how many individuals?
3) Average age of onset/life expectancy
4) Avg number of adenomatous polyps
5) This leads to what other disorders? |
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Definition
1) Autosomal dominant disorder with complete penetrance (tumor supressor)
2) Affects 1 in 10,000 individuals
3) Onset is 39 and life expectancy is 42
4) avg number of adenomatous polyps is 1000
5) Also have stomach and duodenum polyps, bone tumors, and teeth abnormalities |
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Term
| Where is APC located and what is the most typical problem that leads to its mis expression? |
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Definition
| Location 5q, mostly have truncated proteins |
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Term
| What is the clinical description of HNPCC? |
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Definition
-Right-sided or proximal colon adenocarcinoma
- Three affected first-degree relatives in two generations
-Age of onset below 50
-Other tumors including urothelium or endometrium |
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Term
| In colorectal tumorigenesis, mutations in APC seem to be the initiating mutation followed by? |
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Definition
1) hypomethylation (increased transcription)
2) mutations in ras
3) mutations in dcc
4) mutations in p53 |
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Term
| What are the biological functions of APC? |
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Definition
1) Binds cytoplasmic ß-catenin, which is a transcription activator, and promotes ß-catenin degradation. This complex also contains axin (required for axis formation) and glycogen synthase 3ß kinase.
2) Binds to microtubules and aids in the assembly of kinetochores (allows connection of microtubules to centromeres of chromosomes, to pull sister chromatids apart as cells divide)
3) involved in regulation of Wnt signaling pathway |
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Term
| What does the Wnt pathway do? |
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Definition
1) Wnt pathway controls cell fate during embryonic development
2) Wnt pathway is a key regulator of homeostasis in adult self-renewing tissues(such as the colonic epithelium) |
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Term
| How do mutations in APC affect the Wnt pathway? |
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Definition
1) Most mutations produce truncated/non-functional APC
2) The axin complex never forms and ß-catenin cannot be phosphorylated and degraded
3) This leads to activation of TCF, and with APC defective, TCF is not removed from the nucleus
4) Constant stimulation of the Wnt pathway results
sidenote- APC is also involved in kinetochore function; its absence leads to genomic instability, as during mitosis aberrant chromosome segregation may occur |
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Term
| TCF is inactivated by binding of? |
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Definition
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Term
| ß-catenin is recognized by tagged for destruction by? |
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Definition
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Term
| What is part of the destruction complex when there is no Wnt signaling? |
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Definition
| ß-CAT, Axin, APC, GSK3ß, CKI |
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Term
| How many women will develop breast cancer is a year? men? |
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Definition
women 200,000- of which 43,000 die
men-1,600 |
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Term
| What percentage of breast cancers are familial? |
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Definition
| 10% of which 45% are related to BRCA1 |
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Term
| What is clinical description of BRCA1 breast cancer? |
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Definition
1) early age of onset
2) multiple family members with the same type of cancer
3) Bilateral or multiple tumors (breast and ovarian tumors in women, maybe prostate in men still controversial)
4) Absence of male breast cancer |
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Term
| BRCA1 is what % penetrant? |
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Definition
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Term
| BRCA1 is what type of gene? |
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Definition
A tumor supressor gene, in familial cases a loss of heterozygosity occurs.
Over 200 germline mutations making it difficult to screen and most mutations lead to truncations. |
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Term
| DNA activates these kinases, which lead to phosphorylation of BRCA1? |
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Definition
1) ATM-IR damage
2) ATR- UV/HU damage
3) CHK2- ? |
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Term
| What does phosphorylated BRCA1 do? |
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Definition
| It can inhibit cell cycle progression, and error=prone repair of double-strand breaks in DNA |
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Term
| BRCA1 also is known to associate with which other proteins? |
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Definition
1) BARD1- ubiquitin ligase activity-TF's are degraded so BRCA1 can assemble repair complex on DNA
2) ZBRK!- corepressor to maintain low levels of proteins necessary for DNA repair |
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Term
| 55% of familial breast cancer cases occur from? |
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Definition
| BRCA2 mutations-men and women with breast cancer, women with ovaria cancer, multiple family members with cancer |
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Term
| Tell me more about BRCA2? |
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Definition
-found by linkage analysis
-Chromosome 13, region q12-13
-Tumor supressor (as is BRCA1)
-Unlike colon cancer, non-familial breast cancer does not contain BRCA1 or BRCA2 mutations |
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Term
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Definition
-Involved in DNA ds breaks (as caused by ionizing radiation)
-Involved in transcriptional regulation w/ BRCA1 (very complex, involved with p53 in regulating genes involved in arresting the cell cycle until the DNA damage is repaired)
-BRCA2 is in all cells – it is still unclear as to why the breast and ovary are primarily targeted with BRCA1 and BRCA2 mutations, except for the estrogen responsiveness |
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Term
| When BRCA1 is phosphorylated by ATM, what is recruited to help with repair? |
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Definition
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Term
What interferes with estrogen binding to the estrogen receptor?
-It is classified as a SERM (selective estrogen receptor modulator)
-SERMs inhibit estrogen action in breast cells, but act as agonists for other tissues, such as the bone and liver (no osteoporosis, cholesterol levels stay low) |
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Definition
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Term
| What stimulates the growth of breast epithelial cells? |
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Definition
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Term
| When is Tamoxifen used for? |
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Definition
1) To prevent breast cancer in younger women with an increased risk of the disease (49% reduction in tumors reported in one study, as compared to control) (5 years on the drug)
2) As an adjuvant to surgery, to prevent recurrence of the tumor
3) As treatment for advanced breast cancer |
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Term
| What are the side effects of Tamoxifen? |
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Definition
1) Increased risk for blood clots
2) If pre-menopausal, brings on menopausal symptoms
3) Increases risk of endometrial cancer and uterine sarcomas |
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Term
| What is a monoclonal antibody to HER2 receptor (the EGF receptor)? |
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Definition
Herceptin
1) HER2 is often over-expressed in metastatic breast cancer (20% of breast cancers)
2) The antibody blocks EGF binding to the receptor, thereby decreasing the rate of growth of the cells. Once bound, the antibody also recruits immune cells to the site of the tumor for destruction of the tumor cells |
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Term
| What are some of the side effects of Herceptin? |
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Definition
1) Cardiomyopathy (left ventricular heart failure)
2) Hypersensitivity reactions |
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Term
What has poor prognosis – negative for estrogen receptor, HER-2 (human epidermal growth factor receptor-2) and progesterone receptor?
-Tamoxifen, Herceptin will not work on these cells due to lack of appropriate receptors
-Treatment has been surgery, chemotherapy, radiation – but not very successful
-New treatments have been devised – PARP inhibitors |
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Definition
| Triple negative breast cancer cells |
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Term
| What are the two forms of repair in ds breaks in DNA? |
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Definition
1) Homologous recombination(HR-occurs in S and G2 as a pair of sister chromatids is required.)
2) Non-homologous end-joining (NHEJ- occurs in the other phases of cell cycle) |
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Term
| Of the two ds breaks in DNA, what one is better? |
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Definition
HR-not ewrror prone
NHEJ- is error prone |
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Term
| What produces large chains of ADP at the ends of single chain breaks in DNA – used as a recognition signal by the repair enzymes (substrate is NAD+)? |
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Definition
| PARP-1 (poly (ADP) ribose polymerase) |
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Term
| What is responsible for 9% of cancer deaths in men? |
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Definition
| prostate cancer-second most common cancer in men-first is lung cancer |
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Term
| Who are more likely to get prostate cancer? |
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Definition
| African-american men 61% more likely than caucasians and 2.5 times more likely to die |
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Term
What are your risks for getting prostate cancer, depending on your age range?
1-less than 40
2-40-59
3-60-79
4- chance in lifetime |
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Definition
1- 1 in 10,000
2- 1 in 45
3- 1 in 7
4- 1 in 6 |
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Term
| Microarray experiments have identified two "candidate" genes for prostate cancer, they come from which two pathways? |
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Definition
1) PTEN pathway
2) Sonic Hedgehog pathway |
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Term
| What antagonizes the PI3K/AKT pathway by converting PIP3 to PIP2, thereby losing the ability to activate AKT(tumor suppressor)? |
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Definition
| PTEN(phosphatase and tensin homolog) |
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Term
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Definition
| Constitutive action of AKT kinase(PKB)- which leads to a resistance to apoptosis via BAD phosphorylation |
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Term
| What happens in the absence of hedgehog signal? |
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Definition
| the patched receptor inhibits smoothened from activating the transcription factor GL 1. |
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Term
| What does GL 1 do when activated? |
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Definition
| it does gene transcription leading to cell growth |
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Term
| Smoothened can be phosphorylated by _____ and also interacts with? |
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Definition
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