The flashcards below were created by user
on FreezingBlue Flashcards.
HNPCC (Lynch Syndrome)
- Autosomal dominant - due to germline mutations in on of the DNA mismatch repair genes (MLH1, MSH2, MSH6) leading to defective DNA mis-match repair, microsatellite expansion and instability.
- Lynch syndrome I - colon cancer, predominantly cecal and asc colon
- Lynch syndrome II- colon cancer as well ass endometrial and ovarian cancer
- Related syndromes- Muir Torre (sebaceous neoplasm and colon ca) and Turcot (brain tumors and colon ca)
MSI seen in 15% of sporatic colon ca- associated with serrated adenoma, are poorly diff, trabecular, mucinous, signet ring component, well circumscribed, lymphoid infiltrate (medullary-like) appearance.
PCR in paraffin neoplastic and non-neoplastic tissue from same pt to assess microsatellite differences. Also an IHC stain can be performed as well.
Familial adenomatous polyposis (FAP)
Autosomal dominant- mutations in the APC gene 5q21 (WNT signaling pathway). Normal APC binds and causes degredation of beta-catenin. APC mutation leads to excess B-cat, which translates to nucleus and activates TCF trsc factor- inv c-myc, cyclin d1.
Develop thousands of colon adenomas early in age, eventually develop adenocarcinoma.
Autosomal dominant variant of FAP involving APC mutation on 5q21
Develop many adenomatous polyps of colon in addition to osteomas of the skull (jaw most common), thyroid carcinoma, desmoid tumors (fibromatosis), fibromas, sebaceous cysts and epidermoid cysts. Also associated with a number of other cancers.
i.e. periampullary carcinoma, osteosarcoma, chondrosarcoma, liposarcoma, hepatoblastoma, etc.
Autosomal dominant- associated withmutation in STK11 gene, Chr 19.
Development of benign hamartomatous polyps (branching muscle bundles in an arborizing pattern) of the GI tract and hyperpigmented macules of the lips and oral mucosa
Females at risk for sex cord tumor with annular tubules (SCTAT) of the ovaries as well as adenoma malignum of the cervix.
Males at risk for calcifying Setoli cell tumors of testes.
von Hippel-Lindau disease
Autosomal dominant- germline mutation in VHL gene, a tumor suppressor on 3p. Sporatic deletion of this gene common in clear cell RCC.
Patients high risk for numerous tumor types: hemangioblastomas (cerebellar, cerebral, or retinal), pheochromocytoma, renal cell carcinoma (clear cell type), pancreatic cysts, islet cell tumors, cystadenomas (epididymal and ovarian) and tumors of endolymphatic sac of ear.
RCC in patients with vHL syndrome present early, are often multifocal and bilateral
Autosomal dominant- germline mutations in either the TSC1 gene on 9q34 (hamartin protein) or TSC2 gene on 16p13.3 (tuberin protein).
Clinical triad of seizures, mental retardation, facial angiofibromas (fibrous papule)
Numerous tumors: angiofibromas (adenoma sebaceum) of skin, periungual fibromas, shagreen patches (thickened skin), hypopigmented macules (ash-leaf spots), cardiac rhabdomyomas, pulmonary lymphangioleiomyomatosis LAM, subependymal giant cell astrocytomas (SEGA), and renal angiomyolipomas. Also increased risk for RCC and renal oncocytomas.
BRCA1 and BRCA2
Both are tumor suppressor genes that mediate DNA repair processes (over 2000 mutations identified). High frequency in Askenazi Jewish descent. Found in approx 5% of breast cancer cases (25% of ashk jewish).
Lifetime risk of breast ca is 75%, high rate of medullary breast ca, high grade histology, tend to be ER/PR negative.
Also increased risk of epithelial ovarian ca, pancreas, uterus and prostate ca.
Multiple endocrine neoplasia 1 (MEN1, Wermer syndrome)
Autosomal dominant- germline mutation in menin gene (MEN1) on 11q13
Manifests as parathyroid adenomas, pituitary adenomas, and pancreatic islet cell tumors (the 3 P's). Non-endocrine lesions include facial angiofibromas, collagenomas, lipomas and meningiomas.
Multiple endocrine neoplasia 2A (MEN2A, Sipple syndrome)
Autosomal dominant- mutations in exons 10-11 of RET gene on 10q
Manifests by medullary thyroid carcinoma (also background of C-cell hyperplasia, multifocal), pheochromocytoma and parathyroid adenoma
Multiple endocrine neoplasia 2B (MEN2B, Sipple syndrome)
Autosomal dominant- germline mutations affecting exon 16 (encoding tyrosine kinase domain) of RET gene on 10q.
Manifests as medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, ganglioneuromatous intestinal polyps and Marfanoid body habitus.
Familial medullary thyroid carcinoma (FMTC)
Mutations (usually point mutations in Cysteine residues) of the RET gene on 10q.
Manifests as medullary thyroid carcinoma only.
Carney complex (LAMB syndrome, NAME syndrome)
Half of cases due to mutations in PRKAR1A gene on 17q which encodes a regulatory subunit of cAMP-dependant protein kinase.
Manifests in the formation of mostly benign tumors: simple lentigos (on oral and conjuctival mucosa, vagina and penis), Cellular blue nevi, cardiac myxomas, endocrine tumors (follicular adenomas of thyroid, pituitary adenomas, primary pigmented nodular adrenocortical disease PPNAD). Large cell sertoli tumors in males.
Different syndrome than Carney complex.
Triad of GISTs, pulmonary chondroma and extra-adrenal paraganglioma.
Autosomal dominant- germline mutation in PTEN gene (tumor suppressor) on 10q.
Manifests as hamartomatous GI polyps, lipomas, fibromas, GU malformations, and multiple cutaneous lesions (facial tricholemmomas, papillomas, palmoplantar keratosis, palmoplantar hyperkeratotic pits). Microcephaly and mental retardation are common.
Increased risk of malignancy of the breast, thyroid (follicular ca), colon and endometrium
Proteus syndrome also associated with PTEN mutations- variable manifestations, mosaic distribution- connective tissue nevi, assymmetric limb growth, skull hyperostosis, megaspondylodysplasia of vertebrae, visceral overgrowth (spleen and thymus particularly)
Juvenile polyposis syndrome
Autosomal dominant- germline mutation in either BMPR1A gene on 10q or SMAD4 on 18q.
Tendency to develop juvenile polyps (hamartomatous polyps, similar to hyperplastic polyp) in stomach, small and large intestine, and increased risk of GI malignancy.
Autosomal dominant- due to mutations in the BHD gene on 17p11.2 encoding folliculin.
Three cardinal features: fibrofolliculomas, pneumothorax and renal tumors (features of combined oncocytoma and chromophobe ca, multifocal, bilat)
Neurofibromatosis Type 1 (NF1, von Recklinghausen disease)
Autosomal dominant- germline mutation in NF1 gene on 17q (neurofibromin protein). Neurofibromin regulates signal transduction by RAS protein, facilitates "turning off" RAS by GTPase activity. Mutated NF allows RAS to be active, signaling state.
Manifests by multie cafe au lait spots, neurofibromas (plexiform neurofibroma is pathognomic), lisch nodules of iris. Increased risk for malignant peripheral nerve shealth tumors.
Neurofibromatosis Type 2 (NF2, bilateral acoustic neuromas)
Autosomal dominant- germline mutations in NF2 gene (merlin) on 22q, tumor suppressor and cell cytoskeletal/adhesion function.
Also known as MISME syndrome, or multiple inherited schwannomas, meningiomas and ependymomas
Manifested by bilateral vestibular nerve schwannomas. Also at increased risk of schwannomas of other nerves, meningiomas, ependymomas and astrocytomas.