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86 Cards in this Set
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MEN1
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MEN1 (tumor suppressor "menin") sequence variants
Autosomal dominant 10% de novo (only 1-4% large deletions) "PPP" Pituitary (prolactin) Parathyroid (hypercalcemia and parathyroid hormone; enlargement all glands) Pancreas (insulin or glucagon) Stomach/duodenum, intestinal tract Cafe au lait spots, angiofibromas ALL have hypercalcemia by age 50 Onset in 90% between 20-25 years Carcinoid tumors (in thymus in men, bronchial in women) Adrenocortical tumors (some secrete cortisol) Nonendocrine: angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas |
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Symptoms of hypercalcemia
(and which syndromes?) |
MEN1 and MEN2A
kidney stones, increased bone resorption and increased fracture risk, lethargy, depression, confusion, anorexia, constipation, nausea, vomiting, diuresis, dehydration, hypercalciuria, hypertension, and shortened QT interval |
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Symptoms of high prolactin
(and which syndrome?) |
MEN1
oligomenorrhea/amenorrhea impotence in men (or gynecomastia) |
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What is Zollinger-Ellison syndrome (and which syndrome?)
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MEN1 gastrinoma
PEPTIC ULCER with or without watery diarrhea Gastrin-secreting duodenal mucosal tumor Upper abdominal pain esophageal relux Gastinomas are frequently multiple and usually MALIGNANT |
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Which syndromes have angiofibromas?
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Tuberous Sclerosis Complex (TSC)
MEN1 |
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Detection rate for MEN1
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MEN1 gene mutations
80%-90% of familial MEN1 65% of simplex cases (some are somatic mosaicism so lower rate) 10% are de novo |
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Cushing Syndrome
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TKTKTK (excess of steroids from adrenal cortex)
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Prevention/Screening in MEN1?
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From age 5:
Prolactin Head MRI (every 3-5 years) From age 8: Serum concentrations of calcium From age 20: Gastrin Abdominal CT or MRI (every 3-5 years) Consider fasting serum PTH concentration and yearly chest CT. Prevention is limited: Thymectomy may prevent thymic carcinoid in males, particularly in smokers. Women more likely to get bronchial cardinoids. Pancreas, pituitary can't be ablated. |
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Syndromes with Pheochromocytoma
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Paraganglioma-Pheochromocytoma Syndrome
MEN2A MEN1 (very rarely) VHL |
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Gastrointestinal symptoms associated with MEN1 tumors
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peptic ulcer, watery diarhea (gastrinoma)
hypoglycemia (insulinoma in pancreas); hyperglycemia, anorexia, glossitis, anemia, diarrhea, venous thrombosis, and skin rash (glucagonoma); and watery diarrhea, hypokalemia, and achlorhydria syndrome (vasoactive intestinal peptide [VIP]-secreting tumor) |
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Most frequent tumors in MEN1
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Non-functioning pancreatic endocrine tumors
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Non-endocrine tumors and cutaneous findings associated with MEN1
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Facial angiofibromas (88%)
Collagenomas (72%) Cafe au lait macules (38%) Lipomas (34%; benign fatty tissue tumors, subcutaneous or visceral) Meningiomas Ependymoma Leiomyomas (benign, from smooth muscle) |
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Cafe au lait macules can be seen in what syndromes?
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NF1
MEN1 (38%) TKTK |
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Least dramatic MEN1 gene-related syndrome
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Familial isolated hyperparathyroidism
Parathyroid adenoma or hyperplasia No endocrinopathies 20-57% have an MEN1 mutation Some increased risk for parathyroid carcinoma |
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Sporadic parathyroid adenomas. Do they have mutations in MEN1 also?
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15-20% do
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Least dramatic MEN1 gene-related syndrome
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Familial isolated hyperparathyroidism
Parathyroid adenoma or hyperplasia No endocrinopathies 20-57% have an MEN1 mutation Some increased risk for parathyroid carcinoma |
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Sporadic parathyroid adenomas. Do they have mutations in MEN1 also?
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15-20% do
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Anterior pituitary tumors (up to 60%) in MEN1
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Prolactin-secreting (most common)
Also: Growth-hormone Thyroid-stimulating-hormone ACTH |
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Subtypes of MEN2
RET is a PROTO-ONCOGENE |
Mutations in RET (protooncogene)
100% risk of medullary thyroid cancer Prophylactic removal of thyroid MEN 2A Medullary thyroid carcinoma (early adulthood; M for MEDULLARY) Pheochromocytoma Primary hyperparathyroidism (20-30%, milder than in MEN1; adenoma or enlargement) MEN 2B 50% de novo Medullary thyroid carcinoma (childhood) Pheochromocytoma MARFANOID appearance- ABE LINCOLN Distinct facies, large lips Mucosal neuromas on lips and tongue Ganglioneuromatosis of gastrointestinal tract Familial Medullary Thyroid Carcinoma (FMTC; middle age) |
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Cowden syndrome risks
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1/200,000
Autosomal dominant PTEN Hamartomatous Tumor Syndrome Macrocephaly (>97%) MR or autism spectrum disorder Benign and malignant tumors: Thyroid (follicular and papillary) 10% lifetime Breast 25-50% Endometrium 5%-10% Intellectual disability Majority simplex (no known family history) Mammograms/MRI begin at age 30-35 Annual suction biopsy for endometrial cancer Fibrocystic breasts/uterine fibroids Trichilemmomas Papillomatous papules |
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Bannayan-Riley-Ruvalcaba Syndrome
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Rare type of Cowden syndrome
PTEN gene mutations Macrocephaly Intestinal hamartomatous polyposis Lipomas Pigmented macules of the glans penis Same cancer risks as Cowden 60% of mutations detected through sequencing 10% are deletions |
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Thyroid Cancer
Locations: Cowden syndrome and MEN2? |
Cowden has papules
Follicular and Papillary MEN2 begins with M Medullary |
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Hereditary diffuse gastic cancer
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Autosomal dominant
30-40% due to CDH1 mutations (cadherin 1 cell adhesion protein) Loss of contact inhibition through E-cadherin Accounts for 1-3% gastric adenocarcinoma Lethal if diagnosed late (<20% 5-year survival) Curable if resect before invasion through gastic wall (>90% 5-year survival) Stomach removal recommended Diffuse enough to be missed on biopsy |
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Hereditary diffuse gastic cancer
Risks? |
80% risk of gastic cancer
20-40% risk of LOBULAR breast cancer |
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RB1 gene mutations have what phenotype?
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Retinal tumors
Sarcoma |
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VHL gene mutations have what phenotype?
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Renal Cancer (most common) Pheochromocytomas
Hemangioblastomas |
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PTCH mutations have what phenotype?
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Gorlin syndrome
Skin cancer (basal cell) Jaw cysts Ovarian fibromas |
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PTEN mutations have what phenotype?
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GI hamartomas
Breast cancer Follicular/Papillary thyroid cancer |
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STK11 mutations have what phenotype?
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GI harmartomas
Pigmented spots Ovarian tumors |
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P53 gene mutations have what phenotype?
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Sarcoma
Leukemia Brain tumors |
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CDKN2 gene mutations have what phenotype?
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Pancreatic cancer
Skin cancer |
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RET gene mutations have what phenotype?
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Medullary thyroid cancer
Parathyroid hyperplasia |
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CDH1 gene mutations have what phenotype?
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Hereditary diffuse gastric cancer
Majority before age 40 80% by age 80 40-50% risk for lobular breast cancer |
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(Gorlin syndrome)
Nevoid Basal Cell Carcinoma Syndrome |
PTCH1 gene
(Gore you with a pitchfork) 1/40,000 TUMOR SUPPRESSOR Autosomal dominant 1/3 de novo Nevoid basal cell carcinoma syndrome Avoid sun exposure and X-irradiation Multiple jaw keratocysts Basal cell carcinomas (in 20s) Macrocephaly, bossing of the forehead Coarse facial features Facial milia (small white cysts) Skeletal anomalies (bifid ribs, wedge-shaped vertebrae) Cardiac fibromas 2% Ovarian fibromas 20% 5% of children medulloblastoma (primitive neuroectodermal tumor) ~age 2 years |
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Tumor suppressor genes
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BRCA1/2
TP53 RB1 (retinoblastoma gene) |
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Homozygous mutations in what cause Fanconi anemia?
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BRCA2
Double-stranded break repair |
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Juvenile Polyposis Syndrome
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BMPR1A (20%)
SMAD4 (20%) Autosomal dominant 1/4 no family history >5 colorectal polyps for diagnosis Hamartomatous polyps of GI tract (stomach, small intestine, colon, rectum, pancreas) Most benign "Juvenile" refers to type of polyp not age at onset of polyps Start colonoscopy and upper GI endoscopy In late teens |
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Peutz-Jeghers Syndrome
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1/200,000
Autosomal dominant STK11 gene mutations Gastrointestinal polyposis (Hamartomatous polyps, childhood onset) Mucocutaneous pigmentation Polyps most common in small intestine Also: Stomach, large bowel, nasal passages Dark blue to dark brown macules: Around mouth, eyes, nostrils Perianal, buccal mucosa Epithelial malignancies: Breast (55%) Ovary (20%) Colorectal (10-40%) Pancreatic (35%) Gastric (25%) Small intestine (10%) Rare aggressive cervical cancer (10%) Males may develop Sertoli cell tumors of testes Secrete estrogen: gynecomastia |
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Lynch syndrome tumors
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Proximal, right-sided, ascending colon (2/3)
Colon cancer up to 80% Endometrial up to 60% Stomach 10-20% Ovary 9-12% Small intestine Hepatobiliary tract Urinary tract (ureter, renal pelvis) Brain Skin cancer (mean age at diagnosis 42.5 years; approximately 30% are diagnosed before age 40 years). |
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Responsible gene mutation frequencies in Lynch syndrome
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MLH1 50%
MSH2 40% MSH6 7-10% PMS2 <5% EPCAM ~1%-3% |
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First step in Lynch syndrome testing
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MSI/IHC
IHC helps identify gene responsible (10-15% sporadic colon tumors are MSI high; 80% in Lynch) |
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If MLH1/PMS2 implicated by IHC, what do first?
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Test colon tumor for MHL1 promotor methylation (common cause of MSI in sporadic tumors; rare as a second-hit in Lynch)
Test for BRAF mutations (in 15% sporadic colon tumors; ~none in Lynch) Either one: Sign of sporadic tumor (MLH1 alone missing, suspect germline mutation instead) BRAF NOT RELEVANT FOR ENDOMETRIAL TUMORS |
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Prophylactic surgeries in Lynch?
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No colectomy until cancerous polyp (colonoscopy plus removal of polyps, start age 20-25)
Consider removal of uterus and ovaries When done with childbearing |
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General population colorectal cancer risk
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Prostate 15% (Whites)
Colon 4-6% Endometrial 3% Ovarian 2% Stomach and other <1% |
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Amsterdam II Criteria
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•Three or more relatives with a Lynch-associated cancer, one of whom is a first degree relative of the other two
•Cancer involving at least two sucessive generations •One or more cases of a Lynch-associated cancer diagnosed before age 50 FAP has been excluded (Colorectal, endometrial, small bowel, ureter, renal pelvis) |
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NCCN Surveillance guidelines for Lynch syndrome
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Colon Cancer
**Colonoscopy starting at age 20-25, or 2-5 years prior to the youngest colon cancer diagnosis in the family. Repeat every 1-2 years. Endometrial and Ovarian Cancer **For women with Lynch syndrome, consider endometrial and ovarian cancer screening with transvaginal ultrasounds, CA-125 and/or annual endometrial biopsy. **Reasonable to consider TAH/BSO if postmenopausal or when childbearing is completed. Gastric and Small Bowel Cancer **Consider upper endoscopies that extend into the distal duodenum or jejeunum every 2-3 years for surveillance and polypectomy, beginning at age 30-35. **Consider baseline gastric biopsies **Consider capsule endoscopy for small bowel cancer at 2-3 year intervals beginning at age 30-35. Urinary Tract Cancer **Consider annual urinalysis CNS Cancer **Annual physical exam Pancreatic Cancer **No recommendation possible at this time |
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Revised Bethesda criteria for MSI testing
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CRC <50 years of age
Synchronous or metachronous Lynch tumors at any age CRC with MSI-H histology at <60 years of age CRC in a person with a first-degree relative diagnosed with a Lynch tumor at <50 years of age CRC in a person with two first- or second-degree relatives with a Lynch tumor |
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Pairings of the Lynch syndrome mismatch repair proteins
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MLH1-PMS2
MSH2-MSH6 |
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Why MSI unstable?
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Mismatch repair proteins detect insertion or deletion loops in microsatellite sequences during DNA synthesis
MSI-high: More than two markers (>30%) show instability |
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Role of MSH2 promoter methylation
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Somatic methylation of MSH2
the second hit for 24% of MSH2-related cancers Not a cause of sporadic CRC |
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Role of germline EPCAM mutation
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Deletions in 3' region of this gene silence MSH2 by hypermethylation
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Muir-Torre syndrome
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Most often MSH2
Lynch with: Sebaceous adenomas Sebaceous epitheliomas Sebaceous carcinomas Keratoacanthomas |
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Turcot syndrome
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Colorectal adenomas/carcinomas
Plus CNS tumors Can be due to APC (2/3) gene OR Lynch genes (1/3) APC mutation: More polyps Medulloblastoma MMR genes: Glioblastoma. Brain tumors associated with MMR genes are MSI-high |
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Homozygous mutations in mismatch repair proteins
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Rare
Onset of colon or small bowel cancer in childhood Children can have more than ten polyps |
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Which Lynch gene associated with the most extra-colonic tumors?
(Other than endometrial, which others share) |
MSH2
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Higher risks for endometrial cancer with which gene?
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MSH6
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Lowest overall cancer risk (25%-32%) with mutations in which Lynch syndrome gene?
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PMS2
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Prevalence of Lynch syndrome
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1/440
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Lynch syndrome accounts for what percentage of colon cancers?
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1-3%
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Characteristics of EPCAM deletions?
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Epigenetic silencing of MSH2
Greatly increased risk for colon cancer |
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MYH gene mutations
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Autosomal recessive
MYH gene 80% risk of colon cancer Multiple adenomatous polyps Found in: (1) approximately 30% of individuals with 15-100 polyps (2) a small portion of individuals with a classic FAP phenotype who have no identifiable APC mutation |
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Attenuated FAP
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Mutations in APC
Autosomal dominant Fewer polyps (<100) Later age of onset ALSO: APC p.Ile1307Lys mutation ~2x increased risk for colon cancer Mutation in 6% of individuals of Ashkenazi Jewish ancestry |
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Extra-colonic features of classic FAP
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Epidermal cysts
Dental abnormalities Congenital hypertrophy of retinal pigmented epithelium Desmoid tumors |
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Which has a higher rate of large deletions: MLH1 or MSH2?
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MSH2
20% of mutations are large deletions in MLH1 it's 5-10% (Rare in MSH6) |
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Does FAP require upper endoscopy like Lynch?
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Yes
Upper GI tract cancers |
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BRCA pharmaceutical therapies
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5 years of tamoxifen:
Reduces risk of 2nd breast cancer 50% (if ER+, BRCA2) Removal of ovaries <50 years ALSO reduces risk of breast cancer by half Oral contraceptives: Reduces ovarian cancer risk |
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Retinoblastoma
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RB1
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Retinoblastoma
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1/20,000
RB1 gene TUMOR SUPPRESSOR 40% heritable, rest sporadic Onset by age 2 if bilateral (80%) Risk of second cancers: Osteosarcoma, soft tissue sarcoma Malignant melanoma Brain tumors Risk increased by radiation therapy |
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Retinoblastoma
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1/20,000
RB1 gene TUMOR SUPPRESSOR 40% heritable, rest sporadic Onset by age 2 if bilateral (80%) Risk of second cancers: Osteosarcoma, soft tissue sarcoma Malignant melanoma Brain tumors Risk increased by radiation therapy |
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Xeroderma pigmentosa
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AUTOSOMAL RECESSIVE
Nucleotide excision repair genes (>8) Removes thymine dimers from UV damage 1/1,000,000 in US (higher in Japan) Acute sun sensitivity Severe sunburn on minimal exposure Skin Eyes: Photophobia, keratitis of eyelids CNS: Sensorineural hearing loss, Progressive cognitive impairment Acquired microcephaly Cancer: 1000x risk with sun exposure Childhood onset some cancers 10x risk for: Gliomas, solid tumors of lung, uterus, breast, pancreas, stomach, kidney |
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Hereditary Paraganglioma-Pheochromocytoma Syndrome
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Autosomal dominant
SDHB, SDHC, SDHD Succinate dehydrogenase enzyme components In 25% of affected people find these mutated SCREENING AT AGE 10 Pheochromocytoma: Tumors of the adrenal medulla Secrete catecholamines Paraganglioma: Secreting tumors of the sympathetic nervous system Extra-adrenal pheos |
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Familial Malignant Melanoma
(FAMMM) |
CDKN2A (P16) mutations
In 20-40% of families Multiple primary melanomas Multiple dysplastic nevi Earlier age of diangosis Pancreatic cancer increased risk Non-hereditary Risk factors: Red hair/blue eyes Freckling of skin Atypical moles History of sunburn |
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Which syndromes have hamartomatous colon polyps
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Juvenile polyposis
Peutz-Jeghers Syndrome PTEN disorders (Cowden, BRR) |
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Distribution of hereditary colon cancers
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Normal pop: 4-6% prevalance
Sporadic 65-85% Familial 10-30% HNPCC 5% FAP 1% Other |
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Bethesda vs Amsterdam
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Bethesda more sensitive, less specific
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HNPCC
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Has both endometrial and ovarian
(not breast) |
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FAP
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1/10,000
Autosomal dominant APC gene (Wnt-Frizzled) TUMOR SUPPRESSOR 1/3 de novo mutations 100nds to 1000nds of polyps Average age 16 years Nearly 100% lifetime risk Start annual colonoscopy at age 10-12 Total colectomy NSAIDS chemoprotective |
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Li-Fraumeni
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Autosomal dominant
P53 mutations Controls cell-cycle arrest after DNA damage Breast cancer (25%) Bone and soft tissue sarcomas (24%) Brain cancer (12%) Leukemia Adrenocortical carcinoma Multiple primaries |
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Von Hippel-Lindau
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VHL tumor suppressor
Autosomal dominant 1/3 due to gene deletions, rest sequencing Kidney cancer (40%) Pheochromocytoma (hypertension) Hemangioblastoma (cerebellum, retina, spinal cord) Screening starts at age 5 for eye exam Age 15 for abdominal US Renal cancer less if complete gene deletion |
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BRCA1
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Tends to be triple-negative
(But more common in African-Americans) ER, PR, HER2/Neu negative 11% of these under age 50 have a BRCA1 mutation BRCA2 tends to be ER/PR positive |
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AJ carrier rate for BRCA mutation
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1/40
2 mutations on BRCA1, 1 on BRCA2 General population 1/400 |
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When should be tested for BRCA mutation
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Personal breast cancer with:
-Onset age <45 (8-10% have a mutation) -Onset <50 if 2 primaries or 1 close relative with breast at <50 or 1 close relative with ovarian or limited family history -Onset <60 if triple negative -Onset any age if 2 close relatives with breast or ovarian -High risk ethnicity (20-25% AJ) Personal history of ovarian cancer (10-15% have mutation) Personal history of male breast cancer (12-16% have mutation) Close family member with male breast cancer |
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What percentage of BRCA testing yields a VUS?
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5-10%
Higher in ethnic minorities |
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Claus model cutoff for lifetime risk,
High-risk screening? |
20%
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TAH BSO decreases breast cancer by how much?
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50% breast cancer risk reduction if premenopausal
90% reduced risk for ovarian |
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Tamoxifen less benefit for which BRCA?
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BRCA1 (ER negative)
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