Oncologic disorders Flashcards
**BRCA1 and BRCA2
Hereditary Breast/Ovarian Cancer
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Treatment/Prognosis: d
Responsible genes: BRCA1and BRCA2
Proteins: Breast cancer type 1 and 2 susceptibility protein
Cytogenetic loci: 17q21, 13q12.3
Inheritance: AD
Clinical Features and Diagnostic Criteria: BRCA 1 and 2: Br, ovarian, prostate cancer; ?colon. BRCA2:larynx, esophagus, colon, stomach, gallbladder, bile duct, hematopoietic system, and melanomas.
Clinical Tests: mammography, MRI, BRCA1-related breast tumors show an excess of medullary histopathology, are of higher histological grade, and are more likely to be estrogen receptor-negative and progesterone receptor-negative. BRCA1-related ovarian cancer: excess of serous adenocarcinomas
Molecular Tests:Common mutation analysis or full gene sequencing(about one-third of mutations identified in BRCA1 and BRCA2 sequencing are of uncertain clinical significance).185delAG(BRCA1) and 6174delT (BRCA2) mutation s are found in 20-30% of Jewish women with early breast cancer and in 45-60% of Jewish women diagnosed with ovarian cancer. Dutch women with early bror ovarian ca: often one of 3 large BRCA1 deletions. BRCA2999del5occurs in 7.7% of women and 40% of men with breast cancer from Iceland. BRCA2mutation 6174delTfound in 1% of women of AshkenaziJewish descent.
Disease Mechanism: BRCA1and 2 are tumor suppressor genes
Treatment/Prognosis: discussion of cancer screening protocols, chemoprevention trials, and options for prophylactic surgery. 85% will develop Br ca by age 70 yrs.
FAMILIAL ADENOMATOUS POLYPOSIS
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Disease Mechanism: f
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Responsible gene: APC
Protein: Adenomatous polyposis coli protein
Cytogenetic locus: 5q21-22
Inheritance: AD (15-30% new mutation)
Clinical Features and Diagnostic Criteria: adenomatous colonic polyps (100-1000) in childhood to adolesence, abdominal desmoidtumors, jaw osteoma, absent/supernumerary/malformed teeth, hepatoblastoma, thyroid cancer, epidermoid cysts. Attenuated FAP: fewer polyps, more proximal in the colon. Gardner syndrome: colonic adenomatous polyposis, osteomas, and soft tissue tumors. Turcotsyndrome: colon cancer and CNS tumors (medulloblastoma)
Clinical Tests: Clinical findings on colonoscopy
Molecular Tests:APCsequence analysis (up to 90%), protein truncation testing (up to 80%)
Disease Mechanism: When abnormal protein is present, high levels of free cytosolic b-catenin result which migrates to the nucleus, binds to a transcriptionfactor Tcf-4 or Lef-1 (T cell factor-lymphoid enhancer factor), and may activate the oncogenes c-Mycand cyclin D1
Treatment/Prognosis: Without colectomy, colon cancer is inevitable, and colectomy is recommended when adenomas emerge. The mean age of cancer in untreated individuals is 39 years.
HEREDITARY NONPOLYPOSIS
COLON CANCER (LYNCH SYNDROME)
Responsible gene (protein and cytogenetic locus):
Inheritance:AD
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Responsible gene (protein and cytogenetic locus):MLH1(3p21.3, DNA mismatch repair protein MLH1), MSH2(2p22-p21, DNA mismatch repair protein Msh2), MSH6(2p16, DNA mismatch repair protein MSH6), and PMS2(7p22, PMS1 protein homolog 2) Inheritance:AD
Clinical Features and Diagnostic Criteria:Amsterdam II Criteria: 3 or more family members (at least one 1st degree of the other 2) with HNPCC related cancers; 2 successive affected generations; 1 or more of the HNPCC-related cancers diagnosed before age 50; exclusion of FAP. Bethesda 2004: CRC diagnosed under age 50yrs, 2 HNPCC related tumors at once, CRC with high MSI in someone <age 60yrs, CRC in one or more 1stdegree relatives with and HNPCC related tumor with 1 cancer diagnosed before age 50yrs, or CRC diagnosed in 2 or more 1stor 2nddegree relatives (any age). HNPCC-related tumors: colon, endometrium, stomach, ovary, hepatobiliary tract, urinary tract, small bowel, brain/CNS.
Clinical Tests:Microsatellite instability (MSI) of tumor tissue, immuno-histochemistryof tumor tissue for the presence or absence of DNA mismatch repair proteins MLH1, Msh2, and MSH6.
Molecular Tests:Mutation scanning MLH1 (60-69%), MSH2(50-69%). Full sequencing MLH1(90-95%), MSH2(50-80%). Deletion analysis MLH1 (5-10%), MSH2(17-50%), MSH6 (rare)
Disease Mechanism:These proteins work in a recessive manner at the cellular level-LOH leads to absence of any functional protein and dysfunctional mismatch repair.
Treatment/Prognosis:80% lifetime risk of CRC. If CRC present, full colectomy with ileorectal anastomosis indicated. Colonoscopy every 1-2yrs by age 20-25. Consider annual pap smear, transvaginal US, endometrial bxand CA-125 level.
LI-FRAUMENI SYNDROME
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Responsible genes: TP53
Proteins: Cellular tumor antigen P53Cytogenetic locus: 17p13
Inheritance: AD
Clinical Features and Diagnostic Criteria: Probandwith sarcoma <age 45 yrs, 1stdegrelative with cancer <45 yrs, and 1stor 2nddegrelative with any cancer <45yrs or a sarcoma at any age. Inc risk of multiple primary tumors: bone, cartilage, and soft tissue sarcoma; early onset breast cancer; spine or brain tumor, childhood adrenocortical tumors, Wilms’ tumor, and malignant phyllodes tumors
Clinical Tests: Pathology
Molecular Tests:TP53 sequencing
Disease Mechanism: Abnormal DNA repair: P53 protein plays a role in determining whether cells undergo arrest for DNA repair or apoptosis
Treatment/Prognosis: No cancer surveillance protocol has been shown to reduce mortality except annual exam and mammography for women over 40 yrs. Avoid or minimize exposure to radiation.
LI-FRAUMENI SYNDROME
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ONCOLOGIC
MULTIPLE ENDOCRINE NEOPLASIA TYPE 1
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Responsible gene: MEN1
Protein: Menin
Cytogenetic locus: 11q13
Inheritance: AD
Clinical Features and Diagnostic Criteria: MEN1= tumor in 2 of: parathyroid, enteropancreaticendocrine tissue, or anterior pituitary OR Tumor in one and 1stdegree relative with MEN1. Facial angiofibroma, collagenoma, café au lait, lipoma
Clinical Tests: Parathyroid function studies, anterior pituitary hormone abnormalities, Brain MRI
Molecular Tests:MEN1 sequencing (70-90% familial, 65% sporadic), Dup/del testing (1-3%)
Disease Mechanism: MEN1 is a tumor suppressor gene by regulating transcription of proteins involved in the regulation of cell proliferation and development
Treatment/Prognosis: biochemical testing of serum concentrations of calcium (from age 8 yrs), gastrin (from age 20 yrs), pancreatic polypeptide (from age 10 yrs), prolactin (from age 5 yrs), abdominal CT or MRI (from age 20 yrs) and head MRI (from age 5 yrs).
MULTIPLE ENDOCRINE NEOPLASIA Type 2
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Responsible gene: RET
Protein: proto-oncogene tyrosine-protein kinase receptor ret
Cytogenetic locus: 10q11.2
Inheritance: AD
Clinical Features and Diagnostic Criteria: MEN2Atwo or more of medullary thyroid carcinoma, pheochromocytoma, or parathyroid adenoma/hyperplasia in a single person or close relatives. MEN2Bmucosal neuromas of the lips and tongue, medullated corneal nerve fibers, Marfanoid habitus, and medullary thyroid carcinoma
Clinical Tests: Calcitonin, catecholamines, catecholamine metabolites, Ca, PTH
Molecular Tests:RET sequencing: Exon 10 and 11 (95% MEN2A), Exon 16 (95% MEN2B)
Disease Mechanism: Gain of function mutations in RETlead to consitutiveactivation of tyrosine kinase
Treatment/Prognosis: Prophylactic thyroidectomy, screen for pheochromocytoma annually and prior to any surgery, annual calcitonin stim test, annual PTH screening
NEUROFIBROMATOSIS Type 2
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Responsible gene: NF2
Protein: Neurofibromin-2 (Merlin)
Cytogenetic locus: 22q12.2
Inheritance: AD
Clinical Features and Diagnostic Criteria: Benign nerve tumors (schwannomas, meningiomas, ependymonas, astrocytoma). Hallmark is bilateral acoustic schwannoma, onset age 18-24 yrs, hearing loss, tinnitus, balance problems. Also cataracts, mononeuropathy, café-au-lait(fewer than in NF1).
Clinical Tests: MRI/CT, BAER, audiology evaluation, eye exam
Molecular Tests:NF2sequencing (75%), dupl/del testing (10-15%)
Disease Mechanism: NF2 is a tumor suppressor, 2ndhit leads to complete loss of function when one germline mutation present
Treatment/Prognosis: Symptomatic tumors removed surgically (XRT may induce tumor formation). Bevacizumab may shrink vestibular tumors and stabilize hearing in some patients.
PTEN HAMARTOMA TUMOR SYNDROME
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Responsible gene: PTEN
Protein: Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase
Cytogenetic locus: 10q23
Inheritance: AD
Clinical Features and Diagnostic Criteria: Cowden: Presents 2nd/3rddecade: mucocutaneousfacial and oral papules, gingival cobblestoning, acralkeratosis; dystrophic and adenomatous multinodular goiter, GI polyps, adenosisand fibrocystic breast lesions, macrocephaly, dolichocephaly, lipomas, GU anom. High risk for breast, thyroid, and endometrial cancer. **Bannayan-Riley-Ruvalcaba(BRR) **macroceph, polyposis, lipomas, pigmented macules of the glans penis. Proteus: CT nevi, disprop. overgrowth, dysregulated adipose tissue, vascular malformation, risk of ovarian or parotid tumor in 2nddecade
Clinical Tests: Lesion pathology, MRA/MRI, CT
Molecular Tests:PTEN seq(80%), promoter region mutations (10%)
Disease Mechanism: Wild-type protein is a major lipid phosphatase that downregulates the PI3K/Aktpathway to cause G1 arrest and apoptosis
Treatment/Prognosis: Annual dermexam, annual breast exam, annual breast MRI and mammography starting age 30, annual thyroid US starting age 18, annual endometrial bxstarting age 35 until menopause then annual transvaginal US with bxof suspicious lesions
TUBEROUS SCLEROSIS COMPLEX
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malignant transformation Heart:
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Responsible genes: TSC1 and TSC2 Proteins: Hamartin and Tuberin
Cytogenetic loci: 9q34, 16p13 Inheritance: AD (2/3 de novo)
Clinical Features and Diagnostic Criteria: Skin: hypomelanotic macules, facial
angiofibroma, shagreen patch, ungual fibromata. CNS: subependymal glial nodules, cortical
tubers, giant cell astrocytoma, seizures. Renal: angiomyolipomas, epithelial cysts, <1%
malignant transformation Heart: cardiac rhabdomyoma, tend to regress in infancy without
intervention. Lung: lymphangiomatosis (TSC2, women aged 20-40 yrs) Eye: hamartomas or
achromic patches. There is a TSC2/PCKD contiguous gene deletion syndrome with features
of TS and PKD.
Clinical Tests: brain MRI, echo, renal ultrasound, Wood’s lamp exam, eye exam, EEG
Molecular Tests: TSC1 sequencing (30% familial, 15% sporadic) and TSC2 sequencing
(50% familial and 60-70% sporadic)
Disease Mechanism: Abnormal tumor suppressor activity
Treatment/Prognosis: Renal US q1-3 yrs, renal CT/MRI if numerous lesions on US,
semiannual renal US if angiomyolipomas <3.5-4.0 cm, chest CT if pulmonary symptoms;
everolimus for renal angiomyolipoma or subependymal giant cell astrocytoma
VON HIPPEL-LINDAU SYNDROME
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Responsible gene: VHL
Protein: Von Hippel –Lindau disease tumor suppressor
Cytogenetic locus: 3p25 Inheritance: AD
Clinical Features and Diagnostic Criteria: Hemangioblastoma (cerebellum, retina, spinal
cord), pheochromocytoma (hypertension), renal cell carcinoma (40%). Acquired VHL
mutations can give rise to sporadic VHL associated tumors.
Clinical Tests: CT or MRI, urine catecholamine metabolites, renal US
Molecular Tests: VHL sequencing (72%), southern blot for partial or complete gene deletion
(28%)
Disease Mechanism: Abnormal tumor suppressor function. Truncating or missense
mutations that grossly disrupt protein folding lead to VHL Type I: low risk for pheo. Other
missense mutations lead to VHL Type II: high risk of pheo.
Treatment/Prognosis: Reduced risk of renal cancer in those with complete gene deletion.
Starting at age 5: annual eye exam, fractionated metanephrines, BP. Starting age 15 every
other year abdominal US, every 2-3 years brain and spine MRI. Temporal bone MRI if
documented hearing loss.
XERODERMA PIGMENTOSUM
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Responsible genes: Most common: XPA, XPC, ERCC2, POLH
Proteins: DNA-repair protein complementing XP-A cells, DNA-repair protein complementing XP-C cells,
TFIIH basal transcription factor complex helicase subunit, DNA polymerase theta
Cytogenetic loci: 9q22.3, 3p25, 19q13.2-q13.3, 6p21.1-p12
Inheritance: AR
Clinical Features and Diagnostic Criteria: severe sun sensitivity, UV exposure to conjunctiva, cornea,
and lids-> severe keratitis, progressive neurologic deterioration: acquired microcephaly, dec/absent
DTR’s, prog. SNHL, cognitive impairment. > 1000x inc. risk of skin and eye neoplasms
Clinical Tests: Cellular UV hypersensitivity (a post UV exposure cellular survival plot reflecting capacity
for DNA repair.
Molecular Tests: Research only direct DNA testing of XPA (25%), XPC (25%), ERCC2 (15%), POLH
(21%)
Disease Mechanism: Impaired ability to sense, excise, and repair UV-induced DNA damage
Treatment/Prognosis: Regular detailed skin and eye exam, regular audiometry, protection of all body
surfaces from UV light, UV meter to detect unexpected sources of high levels of UV light (eg halogen
lamps).
