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99 Cards in this Set
- Front
- Back
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Carcinoma
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derived from the epithelium
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Sarcoma
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derived from the mesenchyme
(fibroblast, blood vessels, blood cells, muscles, adipocytes, bone, cartilage) |
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Grade
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how bad do cells look
Grade 1: cells look normal and are usually growing Grade 2: cells look abnormal, stick together, and grow faster Grade 3: cells have irregullar shapes, stick together, and grow faster |
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Stage
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where cancer has spread
T=tumor size N=nodal involvement M=metastases |
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Oncogene
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accelerates cell division
gene stuck in "on" |
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Tumor suppressor genes
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1. Caretakers/DNA damage-response genes
Genes: XP (NER), MMR, Bloom/Werner (helicases), Fanconi Anemia (DNA crosslink repair), Ataxia Telangiectasia (double strand break repair), p53 (NER), BRCA (NER, double strand break repair, BER) 2. Gatekeepers: loss increases cell growth or decreases cell death Genes: cell cycle, apoptosis, growth factors |
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Features of cancer genotype
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Genomic instability
Altered DNA damage response Aneupoidy LOH (loss of normal allele) |
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Sporadic v. familial v. hereditary
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Familial= 5-20% show familial clustering, may be due to chance or shared environment and genes
Hereditary=5-10% show recognizable inheritance pattern |
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Features of hereditary cancers
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early age of onset
multiple primaries, multifocal/bilateral physical stigmata distinctive pathological features occasional difference in survival/clinical severity recognizable inheritance pattern with variable age-specific penetrance and expressivity |
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Factors affecting penetrance
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modifier genes
response to DNA damage carcinogens hormonal factors |
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Philadelphia chromosome
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9;22 translocation
BCR/ABL1 fusion which leads to increased tyrosine kinase activity 90% of patients with CML Gleevec=tyrosine kinase inhibitor that provides tailored therapy Major/minor fusion proteins depending on breakpoint |
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Her2/neu and breast cancer
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Overexpressed in 25-50% of breast cancers, usually due to amplifications
correlates with poor prognosis Herceptin targets Her2 gene product |
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Chromosomal breakage syndromes
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Fanconi anemia
Ataxia telangiectasia Bloom syndrome Xeroderma pigmentosum |
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Fanconi Anemia
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at high risk for AML as well as solid tumors
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Ataxia Telangiectasia
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ATM gene
increased spontaneous chromosome rearrangements |
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Bloom syndrome
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increased sister chromatid exchange
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Xeroderma Pigmentosum
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UV hypersensitivity, unscheduled DNA synthesis
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Amsterdam II (1998)
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>=3 cases of HNPCC-associated cancer (colon, endometrial, upper GI, ureter, renal pelvis) PLUS ALL of the following:
-One case should be a first-degree relative of the other 2 -2 or more successive generations -Cancer in one of more relatives dx before 50 FAP excluded verify tumors by path |
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Bethesda (2003)
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Any of the following:
-Dx with CRC <50y -Synchronous or metachronous CRC or other HNPCC-related tumors (upper GI, bladder, urinary, biliary tract, brain-glioblastoma, sebaceous gland adenomas, keratocanthomas) regardless of age -CRC with high MSI dx <60y -CRC with one or more FDR with CRC or other HNPCC-related tumors. One of the cancers must have been dx <50y (including adenoma <40y) -CRC with 2 or more relatives with CRC or other HNPCC-related tumors, regardless of age |
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Screening for Breast Cancer
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self breast exam
clinical breast exam mammogram breast MRI |
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DCIS
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like stage 0 cancer
non-invasive |
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LCIS
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risk factor for invasive disease
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Lobular Carcinoma in Situ
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risk of developing an ipsilateral or contralateral breast cancer is 7-14% over 10 years
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Invasive breast cancers
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Infiltrating/Invasive Ductal (85%)
-Medullary (feature of BRCA tumors) -Others Infiltrating lobular (15%) Sarcoma |
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Uterine screening
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pap smear
transvaginal ultrasound CA-125 |
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Ovarian screening
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CA-125, transvaginal ultrasound
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CA-125
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protein found in most ovarian cancer cells
endometriosis, benign ovarian cysts, first trimester pregnancy, pelvic inflammatory disease can increase levels |
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Uterine Cancer pathologies
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Adenocarcinomas
Sarcomas |
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Uterine adenocarcinomas
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lining of uterus, common in Lynch and Cowden
Types: endometrioid, clear cell, papillary serous, adenosquamous |
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Uterine sarcomas
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muscle or other tissue
Types: carcinosarcomas, leiomyosarcomas, mixed mullerian tumors |
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Ovarian cancers
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Stromal cells (5-10%)
Germ cells (10-15%) Epithelium (80%) |
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Epithelial ovarian cancers
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serous
mucinous endometriod clear cell transitional cell |
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low malignant potential or borderline ovarian tumors
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considered stage 0
not typical of hereditary syndromes |
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Fallopian tube and primary peritoneal cancer
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rare cancers in general population
rare events in hereditary syndromes; high suggestive of BRCA tumors |
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ovarian germ cell tumors
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not a major component of known hereditary cancer syndromes; but has been observed
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Ovarian stromal tumors
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sex cord tumor with annular tubules associated with Peutz-Jehgers
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Polyps
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Epithelial (>95%)
Hamartomatous (<5%) |
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Epithelial polyps
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>95% of polyps
Adenomatous (50%) Hyperplastic (50%); in stomach and fundic gland |
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Hamartomatous polyps
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<5% of polyps
Juvenile Peutz-Jehgers Ganglioneuromas/Neurofibromas Leiomyomas Lipomas Angiomas Lymphangiomas |
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Intestinal gastric cancer
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glandular, solid, or intestinal
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diffuse gastric cancer
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single cells or poorly cohesive cluster of cells that infiltrate gastric wall, leads to widespread thickening and rigidity of gastric wall (linitus plastica)
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Types of Pancreatic Cancer
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Ductal adenocarcinoma (75-80%)
Many other types accounting for <5% each Islet cell (MEN1) |
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Type of Colorectal Cancer
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Epithelial
Carcinoid tumors (rectum) Rare: sarcoma, hematopoietic or lymphoid, melanoma |
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Risk factors for breast cancer
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Age <50
BRCA/high-risk gene Family history, FDR Exposure to ionizing radiation Atypical hyperplasia High breast density on mammogram Relative risk (between 1-2): family hx, SDR, hyperplasia, breast bx, nulliparity, age at first live birth >30, age at menopause >55, age at menarche <12, HRT, alcohol consumption, obesity in post-menopause |
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Population screening for breast cancer includes
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X-ray mammogram yearly starting at 40, digital if <50 and premenopausal with dense tissue
Clinical breast exam every 1-3 years starting at 20 and annually starting at 40 |
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Local breast cancer treatments
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-surgery
-radiation breast/chest wall: follow lumpectomy in all cases, follows mastectomy only if large tumor or positive lymph nodes XRT doesn't appear to increase risk in BRCA carriers |
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Systemic breast cancer treatment
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goal to prevent metastatic recurrence
chemo works in all types of breast cancer endocrine therapy if hormone receptors expressed (80%) -tamoxifen: selective estrogen response modifier -aromatase inhibitors: estrogen synthesis blockers (post-menopause only) - >5 years standard if ER/PR positive Biologic therapy if specific oncogene targets expressed -Herceptin if HER2/neu expressed (20%), 1 year IV therapy |
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Ovarian cancer risk factors
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-family hx strongest risk factor
-parity, protective -OCP use >7y reduces risk by 30-50% -Infertility, risk factor suggesting underlying ovarian pathology? -Possible risk factors: fertility tx, perineal talc exposure, alcohol, smoking |
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Ovarian screening/detection
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NO EFFECTIVE SCREENING
most cases detected at stage III/IV pelvic ultrasound, no proof of efficacy CA-125, no proof of efficacy |
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Breast cancer breakdown
population risk sporadic familial hereditary |
population risk: 12%
sporadic 70-80% familial 15-20% hereditary 5-10% |
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Ovarian cancer breakdown
population risk sporadic familial hereditary |
Population risk 1.5%
85-90% sporadic 10-15% hereditary |
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BRCA1 associated cancer risks
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breast cancer: 46-63% by age 70
second primary breast cancer: 40-60% ovarian cancer: 34-44% smaller risks: prostate cancer, male breast cancer |
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BRCA2 associated cancer risks
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breast cancer: 38-53%
ovarian cancer: 12-20% male breast cancer: 6-10% smaller risks: prostate, laryngeal, bile duct, stomach, melanoma, pancreatic cancer (1.5-3 fold risk) |
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BRCA1 cancer phenotype
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85% Triple negative
11% triple-negatives age <50 have BRCA1 mutation Cluster with "basal-like" cancers on microarray High-grade, p53 mutated, some medullary histology |
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BRCA1 survival
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BRCA1+chemo=risk of death is half that of non-carriers
more responsive to chemo due to DNA damage response effect |
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BRCA2 cancer phenotype
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less striking than BRCA1
ER/PR positive, HER2-negative, grade varies Cluster with "luminal" cancers on microarrays predominantly ductal, mucinous reported |
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BRCA1/2 Ovarian Cancer phenotype
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majority serous, some endometrioid
mucinous and clear cell rare borderline or "low malignant potential" are rare Response to therapy is better than non-carriers |
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Prevalence of BRCA
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BRCA2>BRCA1 mutations carriers
carrier rate 1/200-1/400 AJ 1/40 |
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AJ Founder Mutations BRCA1/2
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BRCA1: 185delAG, 5382insC
BRCA2: 6174delT |
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Other ethnic groups & BRCA1/2
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founder mutations: Netherlands, Belgium, Norway, France, Sweden, Denmark, Scotland, Russia, Iceland, French Canadian
BRCA1: Hispanics>African Americans>Asian Americans |
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BRCA testing guidelines
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Family members with known mutations
Personal hx of breast cancer -onset less than or equal to 40y (8-10% prevalence) -onset of less than or equal to 50y, if 2 primaries, or 1 or greater than than 1 affected relative -onset any age if 2 or more close relatives with br/ov cancer -high risk ethnicity (AJ, 20-25% prevalence) personal hx of ov ca (10-15% prevalence) personal hx of male br cancer (12-16% prevalence) close family member meeting above criteria |
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BRCAPRO
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Bayesian statistical model
best for Caucasians |
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BART
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1-10% positive by BART if sequencing negative
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VUS
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5-10%, higher in ethnic minorities
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Gail
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underestimates br cancer risk because omits SDR
if 5-yr risk >1.7% consider high risk management |
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Claus
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includes FDR and SDR and age of onset
developed before BRCA testing, but still predictive in BRCA negative patients if lifetime risk 20% or greater, consider high risk management |
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Families with breast cancer only-
ovarian cancer risk? |
no increase in ov cancer risk
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Families with ovarian cancer, no mutation-
ovarian cancer risk? |
estimated 2-fold increased risk for FDR (~5%)
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Li-Fraumeni syndrome
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p53 gene
breast cancer (<33, prevalence 1-2% if no other cancers) sarcomas leukemias brain colon childhood cancers |
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Cowden's syndrome
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PTEN gene
uterine cancers thyroid dysfunction lip and mucosal lesions 40-50% lifetime breast cancer risk |
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Hereditary Diffuse Gastric Cancer Syndrome
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CDH1 gene
60-80% risk for gastric cancer 30-40% risk for LOBULAR breast cancer |
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Recommendations for BRCA carriers
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Prophylactic mastectomy
-80-95% relative risk reduction -more frequently opted for if tested at time of br ca dx BSO -80-90% relative risk reduction for ov cancer -recommended between 35-40y, or completion of childbearing -managing early menopause issues high risk breast screening -mammo/MRI q 6 months, starting at 25-30y Cancer chemoprevention -Tamoxifen (less benefit in BRCA1) -OCPs:5yr use associated with 30-50% reduction in ov cancer, but not commonly used bc of concern about br cancer PARP inhibitors -BRCA1/2 deficient cells sensitive to PARP inhibition which leads to failure of DNA repair |
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Colon cancer breakdown
population risk? sporadic? familial? HNPCC? FAP? rare CRC syndromes? |
population lifetime risk: 6%
sporadic: 65-85% familial:10-30% HNPCC: 5% FAP: 1% rare CRC syndromes <0.1% |
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Multistep carcinogenesis of CRCs
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Chromosomal instability (85%)
-aneuploidy and LOH common -point mutations and deletions common -tumor locations is left-sided -older patients -poorer prognosis MSI -15% of CRCs -LOH rare -insertion/deletions in microsatellites -tumor locations right-sided -younger patients -better prognosis |
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Features of
Hereditary Non-Polyposis Colorectal Cancer HNPCC |
-early but variable age of onset (~45y)
-tumor site in proximal colon (right sided) predominates -penetrance = approx 80% -Tumors: Colon 78% Endometrium 43% Ovary 6.7% (greater in MSH2) Stomach 5.8% Urinary tract 8.4% (greater in MSH2) Small bowel 4.3% Bile/pancreatic 4.1% Brain 2.1% Sebaceous skin tumors |
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HNPCC Genes
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MLH1 (30%), MSH2 (30%), MSH6, PMS1, PMS2, EPCAM
30% unknown |
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MSH2
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MSH2>MLH1 lifetime risk for any cancer, included CRC and endometrial
increased risk for cancers of ureter, renal pelvis, stomach, ovary Urinary tract > 10% in MSH2 carriers, expecially men |
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MSH6
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endometrial and ovarian cancer > CRC
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MLH1 silencing
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few extracolonic tumors
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Biallelic MMR mutations
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rare
reported to cause very early onset malignancies in childhood |
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Surveillance for HNPCC
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Colon cancer
-colonoscopy beginning 20-25y (or 2-5y prior to earliest CRC if dx before 25), q 1-2 yrs Endometrial & Ovarian Cancer -prophylactic TAH/BSO is an option to be considered by women who have completed childbearing -annual office endometrial sampling is an option -consider transvaginal ultrasound and CA-125 can be considered Gastric & small bowel cancer -EGD with extended duodenoscopy q 2-3y starting at 30-35 -Consider capsule endoscopy for sm bowel cancer q 2-3y starting at 30-35 Urothelial cancer -consider annual urinalysis starting at 25-30y CNS -annual physical exam starting at 25-30y Pancreatic cancer -no recommendation possible at this time **Gastric Cancer -EGD, annually starting at 25-35 **Renal & Urinary tract -abdominal ultrasound -urinalysis and urine cytology -yearly starting at 25-35 **screen only if cancer runs in family or from area of high prevalence (gastric cancer) |
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MSI and CRC
percentage MSI high? |
15-20% of all CRCs are MSI-H
-due to inherited germline mutations -somatic mutations or LOH of MMR genes -biallelic inactivation of MLH1 due to promoter hypermethylation is common in sporadic MSI-H |
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Familial Adenomatous Polyposis
(FAP) |
APC gene, chr. 5
Autosomal Dominant -30% de novo -most are familial mutations, protein truncating Features -100s-1000s of colonic adenomatous polyps (avg age is 16) -Colon cancer risk 100% (avg age dx 39; 7% by 21, 93% by 50) -Extracolonic tumors: upper GI, desmoid, osteoma, thyroid, brain -CHRPE (congenital hypertrophy of the retinal pigment epithelium) |
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Attenuated FAP
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APC gene, chr 5
Autosomal dominant -onset CRC ~50y -few colonic adenomas -not associated with CHRPE -Upper GI lesions -Associated with mutations at the 5' and 3' ends of APC |
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Management of FAP/AFAP
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Colonic screening
-annual sigmoidoscopy, age 12 -colonoscopy for AFAP Preventative surgery -primary surgery, usually between 15-25y -rectal surveillance Chemoprevention -NSIADS have protective effect against adenomatous polyps or invasive CRC -COX-2 inhibitors significant reduction in polyps |
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Hamartomatous polyp cancer syndromes
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Juvenile polyposis syndrome
Cowden Bannayan-Riley-Ruvalcaba syndrome Peutz-Jehgers syndrome |
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Juvenile Polyposis Syndrome
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SMAD4 (chr 18), BMPR1A (chr 10)
-Autosomal dominant & rare Features -Juvenile hamartomatous polyps mixed with adenomatous histology in the colon and stomach -Symptomatic presentations: <30y, benign complications >30y malignant complications -Cancer risk 20-fold increased risk for CRCs Gastric, small bowel, pancreatic cancer Extracolonic abnormalities (10%): congenital cardiac defects, cleft lip, microcephaly |
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Management for Juvenile Polyposis
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-colonoscopy beginning in late teens or with symptoms, q3y
-Upper GI endoscopy beginning in late teens or with symptoms, q3y |
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Cowden syndrome
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PTEN gene, chr 10
Autosomal dominant Features -few juvenile polyps througout GI tract -Trichilemmomas (hair-follicle hamartoma) -Mucosal papillomatosis -Extra GI cancers: Breast 25-30% Thyroid 3-10% (usually follicular, rarely papillary, but never medullary) Uterine and ovarian increased 80% due to germline mutations in PTEN <5% in BMPR1A |
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Bannayan-Riley-Ruvalcaba syndrome
(BRRS) |
PTEN, chr 10
macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis |
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Peutz-Jehgers syndrome
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STK11 (chr 19)
Autosomal dominant Features -GI hamartomas -Hyperplastic macules of the lips and buccal mucosa in >95% of cases -characteristic pigmentation -10-40% lifetime CRC risk -Other cancers: pancreas, stomach, small bowel, esophagus, ovary, SEX CORD TUMORS, breast, lung, cervix, uterus, testes |
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Management for Peutz-Jehgers
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Colon cancer screening
-colonoscopy w/symptoms or in late teens, q3 years Pancreatic -ultrasound at age 30 q2 years Stomach/esophagus -EGD at age 10, q2 years Small intestine -X-ray at 10, q2 years |
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MYH-associated Polyposis
(MAP) |
MYH (chr: 1)
AUTOSOMAL RECESSIVE!!! -2-3 fold CRC risk in heterozygotes? -carrier freq is 1-2% -10s-100s of adenomas -usually small, mildly dysplastic tubular adenomas -30% of ppl with 15-100 polyps are homozygotes -Testing offered if >15 polyps High penetrance, 80% lifetime risk of CRC Mean age at cancer approx. 50y |
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Multiple Endocrine Neoplasia Type 1
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MEN1 (chr 11)
Autosomal dominant aka Wermer syndrome P-P-P (pituitary, parathyroid, pancreas) Anterior pituitary tumor Parathyroid Pancreatic islets Adrenal cortex |
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Multiple Endocrine Neoplasia Type 2A
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RET (chr 10)
Proto-oncogene, encodes tyrosine kinase receptor Medullary thyroid carcinoma (100%) -MTC accounts for 10% of all thyroid cancers -25% of MTCs are inherit (20% MEN2A) -Signs of hereditary MTC: multifocal, early age of onset, c-cell hyperplasia, family hx, associated endocrinopathies Parathyroid/hyperparathyroidism (15-30%) Pheochromocytoma (adrenal medulla tumor) (50%) Skin lesions in some families |
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Multiple Endocrine Neoplasia Type 2B
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RET (chr 10)
Autosomal dominant Earlier onset & likely more aggressive course of associated tumors -MTC -Pheochromocytoma Developmental abnormalities -Mucosal neuromas -Ganglioneuromatosis -Characteristic marfanoid phenotype -Megacolon |
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Familial Medullary Thyroid Carcinoma
(FMTC) |
RET (chr 10)
-2 or more family members with MTC -No pheochromocytoma or parathyroid disease -Later age at onset with indolent course -Associated with specific RET mutations (50% associated with de novo mutations) |
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RET gene
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chromosome 10
-MEN2A, MEN2B, FMTC -Proto-oncogene -Encodes tyrosine kinase receptor Genotype-phenotype correlations for MEN2A, MEN2B, and FMTC -MEN2B: missense mutation in exon 16 (codon 918) 95%, missense mutation in exon 15 (codon 883) <4% |
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Management for MEN2A & MEN2B
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Testing guidelines
-Any patient with hereditary or sporadic MTC -Better sensitivity & specificity than biochemical screening Biochemical screening -MTC: Mentagastrin & calcium-stimulated calcitonin -Pheochromocytoma: urine catecholamines and metabolites, abdominal US/CT -Hyperparathyroidism: serum calcium and PTH Prophylactic thyroidectomy in childhood+hormone replacement Parathyroid tissue may be conserved or resected and autotransplanted |
