Pathology (neoplasm 7)
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What is cachexia?
Individuals with cancer commonly suffer progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia, and anemia, referred to as cachexia
What is the difference between cachexia and starvation?
- Unlike starvation, the weight loss seen in cachexia results equally from loss of fat and lean muscle
- In persons with cancer, the basal metabolic rate is increased, despite reduced food intake. This is in contrast to the lower metabolic rate that occurs as an adaptational response in starvation.
True or False: cachexia is caused by the nutritional demands of the tumor
True or False: There is some correlation between the tumor burden and the severity of the cachexia
What is the mechanism of cancer cachexia?
- Although patients with cancer are often anorexic, cachexia probably results from the action of soluble factors such as cytokines produced by the tumor and the host rather than reduced food intake.
- TNF produced by macrophages in response to tumor cells or by the tumor cells themselves mediates cachexia. TNF at high concentrations may mobilize fats from tissue stores and suppress appetite; both activities would contribute to cachexia.
- Other cytokines, such as IL-1, interferon-γ, and leukemia inhibitory factor, synergize with TNF.
- Additionally, other soluble factors produced by tumors, such as proteolysis-inducing factor and a lipid-mobilizing factor, increase the catabolism of muscle and adipose tissue.
- These factors reduce protein synthesis by decreasing m-RNA translation and by stimulating protein catabolism through the activation of the ATP-dependent ubiquitin-proteasome pathway.
- It is now thought that there is a balance between factors that regulate muscle hypertrophy, such as IGF, and factors that regulate muscle catabolism. In cachexia these homeostatic mechanisms are disrupted, tilting the scales toward cachectic factors
How does factor in cachexia reduce protein synthesis?
These factors reduce protein synthesis by decreasing m-RNA translation and by stimulating protein catabolism through the activation of the ATP-dependent ubiquitin-proteasome pathway.
How can cancer cachexia be cured?
removal of the underlying cause
What are paraneoplastic syndromes?
Symptom complexes in cancer-bearing individuals that cannot readily be explained, either by the local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor arose, are known as paraneoplastic syndromes
What are the endocrine paraneoplastic syndromes?
- Cushing-->Small-cell carcinoma of lung, Pancreatic carcinoma, Neural tumors
- SIADH --> Small-cell carcinoma of lung; intracranial neoplasms (either ADH or ANF)
- Hypercalcemia-->Squamous cell carcinoma of lung, Breast, RCC, adult T cell leukemia (PTHRP, TGF-α, TNF, IL-1)
- Hypoglycemia--> Ovarian carcinoma, Fibrosarcoma, Sarcoma (Insulin or insulin-like substance)
- Carcinoid syndrome--> HCC, Bronchial adenoma (carcinoid), Pancreatic carcinoma (Serotonin, bradykinin)
- Polycythemia--> Gastric carcinoma, RCC, Cerebellar hemangioma, HCC
Paraneoplastic myasthenia is associated with.............................
What are the mechanisms of of AN and dermatomyositis seen as paraneoplastic syndrome?
- AN-->gastric, lung,uterine(Immunological; secretion of epidermal growth factor)
- DM--> breast, bronchogenic (immune)
Hypertrophic osteoarthropathy and clubbing of the fingers is seen in..............
What is the mechanism of Venous thrombosis (Trousseau phenomenon)?
Tumor products (mucins that activate clotting)
Venous thrombosis (Trousseau phenomenon) is seen in ................
- Pancreatic carcinoma
What is the mechanism of Nonbacterial thrombotic endocarditis?
- Advanced cancers
Red cell aplasia is seen in ..............
...................... is the most common endocrinopathy seen in cancer
Approximately 50% of individuals with Cushing endocrinopathy have ....................
carcinoma of the lung, chiefly the small-cell type
What is the mechanism of Cushing syndrome in lung cancer?
excessive production of corticotropin or corticotropin-like peptides
What is the difference between ectopic Cushing syndrome and Cushing disease?
- The precursor of corticotropin is a large molecule known as pro-opiomelanocortin. Lung cancer patients with Cushing syndrome have elevated serum levels of pro-opiomelanocortin and of corticotropin.
- The former is not found in serum of patients with excess corticotropin produced by the pituitary.
..............................is probably the most common paraneoplastic syndrome
overtly symptomatic hypercalcemia is most often related to.............................
What are two general processes are involved in cancer-associated hypercalcemia?
- (1) osteolysis induced by cancer, whether primary in bone, such as multiple myeloma, or metastatic to bone from any primary lesion
- (2) the production of calcemic humoral substances by extraosseous neoplasms. Hypercalcemia due to skeletal metastases is not a paraneoplastic syndrome.
What are the factors associated with paraneoplastic hypercalcemia?
- IL-1, TGF-α, TNF, and dihydroxyvitamin D,
What is the function of PTHrP?
- PTHRP resembles the native hormone only in its N terminus.
- It has some biologic actions similar to those of PTH, and both hormones share a G protein–coupled receptor, known as PTH/PTHRP receptor (often referred to as PTH-R or PTHRP-R).
- In contrast to PTH, PTHRP is produced in small amounts by many normal tissues, including keratinocytes, muscles, bone, and ovary.
- It regulates calcium transport in the lactating breast and across the placenta, and seems to regulate development and remodeling in the lung.
- Tumors most often associated with paraneoplastic hypercalcemia are carcinomas of the breast, lung, kidney, and ovary.
- In breast cancers, PTHRP production is associated with osteolytic bone disease, bone metastasis, and humoral hypercalcemia.
- The most common lung neoplasm associated with hypercalcemia is squamous cell bronchogenic carcinoma.
Which of the tumors are associated with humoral hypercalcemia of malignancy?
What are the neurologic paraneoplastic syndrome?
peripheral neuropathies, cortical cerebellar degeneration, a polymyopathy resembling polymyositis, and a myasthenic syndrome
What are the morphological features of OA?
- (1) periosteal new bone formation, primarily at the distal ends of long bones, metatarsals, metacarpals, and proximal phalanges
- (2) arthritis of the adjacent joints
- (3) clubbing of the digits
True or False: HOA is commonly seen in noncancer cases
- Only clubbing component is seen
Clubbing seen in..............
liver diseases, diffuse lung disease, congenital cyanotic heart disease, ulcerative colitis
Acute disseminated intravascular coagulation is most commonly associated with
- Acute promyelocytic leukemia
- Prostatic adenocarcinoma
What are the features of NBTE?
Bland, small, nonbacterial fibrinous vegetations sometimes form on the cardiac valve leaflets (more often on left-sided valves), particularly in individuals with advanced mucin-secreting adenocarcinomas
What is grading?
Grading of a cancer is based on the degree of differentiation of the tumor cells and, in some cancers, the number of mitoses or architectural features
The staging of cancers is based on the ..........................
size of the primary lesion, its extent of spread to regional lymph nodes, and the presence or absence of blood-borne metastases
FNA is used most commonly for the assessment of ............................
readily palpable lesions in sites such as the breast, thyroid, and lymph nodes
Cytologic (Pap) smears permits ..................................
differentiation among normal, dysplastic, and malignant cells and, in addition, permits the recognition of cellular changes characteristic of carcinoma in situ.
A normal cervicovaginal smear shows large, flattened squamous cells and groups of metaplastic cells; interspersed are some neutrophils. There are no malignant cells
An abnormal cervicovaginal smear shows numerous malignant cells that have pleomorphic, hyperchromatic nuclei; interspersed are some normal polymorphonuclear leukocytes
What are the uses of IHC in cancer?
- Categorization of undifferentiated malignant tumors
- Determination of site of origin of metastatic tumors
- Detection of molecules that have prognostic or therapeutic significance
How can IHC be used for Categorization of undifferentiated malignant tumors?
- In many cases malignant tumors of diverse origin resemble each other because of limited differentiation.
- These tumors are often quite difficult to distinguish on the basis of routine hematoxylin and eosin (H&E)–stained tissue sections.
- For example, certain anaplastic carcinomas, lymphomas, melanomas, and sarcomas may look quite similar, but they must be accurately identified because their treatment and prognosis are different.
- Antibodies specific to intermediate filaments have proved to be of particular value in such cases, because solid tumor cells often contain intermediate filaments characteristic of their cell of origin. For example, the presence of cytokeratins, detected by immunohistochemistry, points to an epithelial origin (carcinoma), whereas desmin is specific for neoplasms of muscle cell origin.
How can IHC be used for Determination of site of origin of metastatic tumors?
Many cancer patients present with metastases. In some the primary site is obvious or readily detected on the basis of clinical or radiologic features. In cases in which the origin of the tumor is obscure, immunohistochemical detection of tissue-specific or organ-specific antigens in a biopsy specimen of the metastatic deposit can lead to the identification of the tumor source. For example, prostate-specific antigen (PSA) and thyroglobulin are markers of carcinomas of the prostate and thyroid, respectively.
How can IHC be used for Detection of molecules that have prognostic or therapeutic significance?
- Immunohistochemical detection of hormone (estrogen/progesterone) receptors in breast cancer cells is of prognostic and therapeutic value because these cancers are susceptible to anti-estrogen therapy.
- In general, receptor-positive breast cancers have a better prognosis. Protein products of oncogenes such as ERBB2 in breast cancers can also be detected by immunostaining. Breast cancers with overexpression of ERBB2 protein generally have a poor prognosis.
- In general practice, the overexpression of ERBB2 is confirmed by fluorescent in situ hybridization (FISH) to confirm amplification of the genomic region containing the ERBB2 gene
In general practice, the overexpression of ERBB2 is confirmed by ............................
fluorescent in situ hybridization (FISH) to confirm amplification of the genomic region containing the ERBB2 gene
What are the uses of Flow Cytometry in tumor diagnosis?
- Flow cytometry can rapidly and quantitatively measure several individual cell characteristics, such as membrane antigens and the DNA content of tumor cells.
- Flow cytometry has also proved useful in the identification and classification of tumors arising from T and B lymphocytes and from mononuclear-phagocytic cells
What are the cytological markers of immune cells?
- PRIMARILY T-CELL ASSOCIATED CD1: Thymocytes and Langerhans cells/ CD3: Thymocytes, mature T cells/ CD4: Helper T cells, subset of thymocytes/ CD5: T cells and a small subset of B cells/ CD8: Cytotoxic T cells, subset of thymocytes, and some NK cells
- PRIMARILY B-CELL ASSOCIATED: CD10: Pre-B cells and germinal-center B cells; also called CALLA/ CD19: Pre-B cells and mature B cells but not plasma cells/ CD20: Pre-B cells after CD19 and mature B cells but not plasma cells/ CD21: EBV receptor; mature B cells and follicular dendritic cells/ CD23: Activated mature B cells/ CD79a: Marrow pre-B cells and mature B cells
- PRIMARILY MONOCYTE- OR MACROPHAGE-ASSOCIATED: CD11c: Granulocytes, monocytes, and macrophages; also expressed by hairy cell leukemias CD13: Immature and mature monocytes and granulocytes/ CD14: Monocytes/ CD15: Granulocytes; Reed-Sternberg cells and variants/ CD33: Myeloid progenitors and monocytes/ CD64: Mature myeloid cells
- PRIMARILY NK-CELL ASSOCIATED: CD16: NK cells and granulocytes/ CD56: NK cells and a subset of T cells
- PRIMARILY STEM CELL–AND PROGENITOR CELL–ASSOCIATED: CD34: Pluripotent hematopoietic stem cells and progenitor cells of many lineages
- ACTIVATION MARKERS: CD30: Activated B cells, T cells, and monocytes; Reed-Sternberg cells and variants
- PRESENT ON ALL LEUKOCYTES: CD45: All leukocytes; also known as leukocyte common antigen (LCA)
What are the markers of T cells?
- CD1: Thymocytes and Langerhans cells/ CD3: Thymocytes, mature T cells/ CD4: Helper T cells, subset of thymocytes/ CD5: T cells and a small subset of B cells/ CD8: Cytotoxic T cells, subset of thymocytes, and some NK cells
What are the markers of B cell?
- CD10: Pre-B cells and germinal-center B cells; also called CALLA/ CD19: Pre-B cells and mature B cells but not plasma cells/ CD20: Pre-B cells after CD19 and mature B cells but not plasma cells/ CD21: EBV receptor; mature B cells and follicular dendritic cells/ CD23: Activated mature B cells/ CD79a: Marrow pre-B cells and mature B cells
CD45 is negative in................
What are the markers for PreB cell ALL?
t(9;22), t(4;11), t(1;19)
What are the uses of Molecular Diagnosis in cancer?
- Diagnosis of malignant neoplasms
- Prognosis of malignant neoplasms
- Detection of minimal residual disease
- Diagnosis of hereditary predisposition to cancer
What are some examples of molecular diagnosis for diagnosis of cancer?
- Differentiating benign (polyclonal) proliferations of T or B cells from malignant (monoclonal) proliferations (Clonal rearrangements of antigen receptor genes) --> PCR–based detection of T-cell receptor or immunoglobulin
- Detection of translocations in leukemia lymphoma--> by routine cytogenetic analysis or by FISH technique
- PCR, can detect residual disease in cases that appear negative by conventional analysis
- Diagnosis of sarcomas with characteristic translocations (because chromosome preparations are often difficult to obtain from solid tumors) [t(11;22)(q24;q12)] translocation, established by PCR, in one of these tumors confirms the diagnosis of Ewing sarcoma
- Spectral karyotyping-->detect all types of chromosomal rearrangements in tumor cells, even small, cryptic translocations and insertions/ also detect the origin of unidentified chromosomes, called marker chromosomes, seen in many hematopoietic malignancies
- comparative genomic hybridization, now more conveniently converted to microarray format--> analysis of chromosomal gains and losses in tumor cells
- The use of DNA microarrays, either tiling arrays, which cover the entire human genome, or single-nucleotide polymorphism arrays (SNP chips), also allows analysis of genomic amplifications and deletions at very high resolution.
Translocations in leukemia and lymphoma are detected by..................
cytogenetic analysis or by FISH technique
Translocations in sarcoma are detected by................
What are the uses of spectral karyotyping in cancer diagnosis?
- Spectral karyotyping has great sensitivity and allows the examination of all chromosomes in a single experiment.
- This technique, which is based on 24-color chromosomal painting with a mixture of fluorochromes, can detect all types of chromosomal rearrangements in tumor cells, even small, cryptic translocations and insertions. It can also detect the origin of unidentified chromosomes, called marker chromosomes, seen in many hematopoietic malignancies
...................is for detecting the origin of the unidentified chromosome (marker) seen in hematologic malignancies
comparative genomic hybridization, now more conveniently converted to microarray format, allows the analysis of ...........................
chromosomal gains and losses in tumor cells
How can molecular diagnosis be used for Prognosis of malignant neoplasms?
- For example, amplification of the N-MYC gene and deletions of 1p bode poorly for patients with neuroblastoma, while amplification of HER-2/NEU in breast cancer is an indication that therapy with antibodies against the ERBB2 receptor may be effective.
- These can be detected by routine cytogenetics and also by FISH or PCR assays.
- Oligodendrogliomas in which the only genomic abnormality is the loss of chromosomes 1p and 19q respond well to therapy and are associated with long-term survival when compared to tumors with intact 1p and 19q but with EGF receptor amplification
How can molecular diagnosis be used for Detection of minimal residual disease?
- After treatment of patients with leukemia or lymphoma, the presence of minimal disease or the onset of relapse can be monitored by PCR-based amplification of nucleic acid sequences unique to the malignant clone. For example, detection of BCR-ABL transcripts by PCR gives a measure of the residual leukemia cells in treated patients with CML.
- Similarly, detection of specific KRAS mutations in stool samples of persons previously treated for colon cancer can alert the clinician to the possible recurrence of the tumor.
- The prognostic importance of minimal disease has been established in acute lymphoblastic leukemia, and is being evaluated in other neoplasms
The prognostic importance of minimal disease has been established in .....................
How can molecular diagnosis be used for Diagnosis of hereditary predisposition to cancer?
Such analysis usually requires detection of a specific mutation (e.g., RET gene) or sequencing of the entire gene. The latter is necessitated when several different cancer-associated mutations are known to exist
The most common method for large-scale analysis of gene expression in use today is based on ...............technology
What are the two methods for expression analysis?
Either PCR products from cloned genes or oligonucleotides homologous to genes of interest are spotted onto a glass slide
What are the steps for gene analysis?
- The gene chip is then hybridized to “probes” prepared from tumor and control samples (the probes are usually complementary DNA copies of RNAs extracted from tumor and uninvolved tissues) that have been labeled with a fluorochrome.
- After hybridization the chip is read using a laser scanner; sophisticated software has been developed to measure the intensity of the fluorescence for each spot
What are Steps required for the analysis of global gene expression by DNA microarray?
- RNA is extracted from tumor and normal tissue.
- Complementary DNA (cDNA) synthesized from each preparation is labeled with fluorescent dyes (in the example shown, normal tissue cDNA is labeled with a green dye; tumor cDNA is labeled with a red dye).
- The array consists of a solid support in which DNA fragments from many thousands of genes are spotted.
- The labeled cDNAs from tumor and normal tissue are combined and hybridized to the genes contained in the array.
- Hybridization signals are detected using a confocal laser scanner and downloaded to a computer for analysis (red squares, expression of the gene is higher in tumor; green squares, expression of the gene is higher in normal tissue; black squares, no difference in the expression of the gene between tumor and normal tissue). In the display the horizontal rows correspond to each gene contained in the array; each vertical row corresponds to single samples
hierarchical clustering can be used to divide variants of a tumor based on gene expression to produce a ..........
A major problem in the analysis of gene expression in tumors is the heterogeneity of the tissue. In addition to the heterogeneity of the tumor cells, samples may contain variable amounts of stromal connective tissue, inflammatory infiltrates, and normal tissue cells. One way to overcome this problem is to .................................
obtain nearly pure tumor cells or small tumors free from associated stroma using laser capture microdissection. In this technique, the dissection of tumor cells is made under a microscope through a focused laser. The dissected material is then captured or “catapulted” into a small cap and processed for RNA and DNA isolation
Array-based comparative genomic hybridization can be used to look for alterations in genomic structure, ...........................
such as amplifications and deletions.
What are the uses of SNP and tiling array method?
- So-called single nucleotide polymorphism (SNP) chips, which include SNPs that span the entire genome, have been used in genome-wide linkage analysis and association studies to identify genes associated with increased risk of cancer.
- Arrays tiled across the entire genome can be used to look for novel transcripts, novel promoters, and novel splice variants.
- These tiling arrays can also be used to identify epigenetic events, such as DNA methylation, and, when combined with a technique called chromatin immunoprecipitation, can map the genomic site of chromatin marks, as well as genomic binding sites of transcription factors
True or False: Biochemical assays for tumor-associated enzymes, hormones, and other tumor markers in the blood can be used for definitive diagnosis of cancer
What are the major roles of tumor markers?
they contribute to the detection of cancer and in some instances are useful in determining the effectiveness of therapy or the appearance of a recurrence
What are the problems with PSA?
- Although PSA levels are often elevated in cancer, PSA levels also may be elevated in benign prostatic hyperplasia. Furthermore, there is no PSA level that ensures that a person does not have prostate cancer.
- Thus, the PSA test suffers from both low sensitivity and low specificity
What are some hormonal tumor markers?
- HCG--> Trophoblastic tumors, nonseminomatous testicular tumors
- Calcitonin---> MTC
- Catecholamine and metabolites---> Pheochromocytoma and related tumors
What are some ONCOFETAL ANTIGENS as tumor markers?
- α-Fetoprotein: Liver cell cancer, nonseminomatous germ cell tumors of testis (yolk sac)
- Carcinoembryonic antigen: Carcinomas of the colon, pancreas, lung, stomach, and heart
What are some ISOENZYMES that are used as tumor markers?
- Prostatic acid phosphatase: Prostate cancer
- Neuron-specific enolase: Small-cell cancer of lung, neuroblastoma
What are some SPECIFIC PROTEINS that are used as tumor markers?
- Immunoglobulins: Multiple myeloma and other gammopathies
- Prostate-specific antigen and prostate-specific membrane antigen: Prostate cancer
What are some MUCINS AND OTHER GLYCOPROTEINS that are used as tumor markers?
- CA-125: Ovarian cancer
- CA-19-9: Colon cancer, pancreatic cancer
- CA-15-3: Breast cancer
What are some new molecular markers ?
- p53, APC, RAS mutants in stool and serum: Colon cancer
- p53 and RAS mutants in stool and serum: Pancreatic cancer
- p53 and RAS mutants in sputum and serum: Lung cancer
- p53 mutants in urine: Bladder cancer
What are the involved genes in lung cancer?
- C-KIT (40–70%),MYCN and MYCL (20–30%), p53 (90%), 3p (FHIT) (100%), RB (90%), and BCL2 (75–90%) are most commonly involved in small cell lung carcinoma.
- EGFR (25%),KRAS (10–15%), p53 (50%), p16 INK4a (70%) are the ones most commonly affected in non-small cell lung carcinoma.
What gene is involved in all lung cancers?
What gene is involved in 100% of small cell lung cancer?
What are some molecular targeted therapies for cancer?
- All-trans retinoic acid (ATRA)--> Inhibits transcriptional repression by PML-RARalpha (Acute promyelocytic leukemia M3 AML; t(15;17))
- Imatinib ,Dasatinib, Nilotinib--> Blocks ATP binding to tyrosine kinase active site (CML/GIST)
- Sunitinib--> Inhibits activated c-Kit and PDGFR in GIST; inhibits VEGFR in RCC (GIST/RCC)
- Sorafenib --> Targets VEGFR pathways in RCC (RCC/HCC)
- Erlotinib -->Competitive inhibitor of the ATP-binding site of the EGFR (Non-small cell lung cancer; pancreatic cancer)
- Gefitinib -->Inhibitor of EGFR tyrosine kinase(Non-small cell lung cancer)
- Bortezomib --> Inhibits proteolytic degradation of multiple cellular proteins by inhibition of proteasome (MM)
- Trastuzumab --> Binds HER2 on tumor cell surface and induces receptor internalization (breast)
- Cetuximab/ Panitumumab --> Binds extracellular domain of EGFR and blocks binding of EGF and TGF-; induces receptor internalization (CRC/SCC of H and N)
- Rituximab--> direct induction of tumor cell apoptosis and immune mechanisms(bind CD20) (B cell lymphomas and leukemias that express CD20)
- Alemtuzumab (CD52)--> CLL
- Bevacizumab --> Inhibits angiogenesis by high-affinity binding to VEGF
What are the translocations implicated in MALTOMA?
t(11;18) and the less common t(1;14) and t(14;18)
What is the mc translocation in MALTOMA?
- brings together the apoptosis inhibitor 2 (API2) gene on chromosome 11 with the “mutated in MALT lymphoma,” or MLT, gene on chromosome 18. This creates a chimeric API2-MLT fusion gene that encodes an API2-MLT fusion protein
..................is the most frequently inactivated tumor suppressor gene in pancreatic cancer/ ...............is the most frequently altered oncogene in pancreatic cancer
p16/CDKN2A---The KRAS gene (chromosome 12p)
What are the four most important genes involved in pancreatic cancer?
- KRAS 12p
- p16/CDKN2A 9p
- TP53 17p
- SMAD4 18q
What is the most involved gene in RCC?
loss of sequences on the 3p (VHL)
What are the genetic features of seminoma?
- Isochromosome 12p,
- Express OCT3/4 and NANOG
- Increased c-KIT expression
What are the common genetic changes in urothelial cancers?
- Chromosome 9 monosomy or deletions of 9p and 9q (9p contain p16)
- Deletions of 17p, including the region of the p53 gene
- The first pathway is initiated by deletions of tumor suppressor genes on 9p and 9q, leading to superficial papillary tumors, a few of which may then acquire p53 mutations and progress to invasion; a second pathway, possibly initiated by p53 mutations, leads to CIS and, with loss of chromosome 9, progression to invasion
What are the molecular genetics of endometrial carcinoma?
- Type 1--> PTEN (early) PIK3CA (invasive) KRAS MSI β-catenin p53 (late)
- Type 2---> missense mutations in P53 (very common)
What is the molecular genetics of ovarian serous carcinoma?
- low-grade tumors arising in serous borderline tumors have mutations in the KRAS or BRAF oncogenes, with only rare mutations in p53.
- In contrast, the high-grade tumors(including BRCA1,2) have a high frequency of mutations in the p53 gene but lack mutations in either KRAS or BRAF
What is the major mutation in mucinous tumor of ovary?
What are the genetic alterations in prostate cancer?
- One very common type of somatic mutation in prostate cancer gives rise to chromosomal rearrangements that juxtapose the coding sequence of an ETS family transcription factor gene (most commonly ERG or ETV1) next to the androgen-regulated TMPRSS2 promoter. These rearrangements place the involved ETS gene under the control of the TMPRSS2 promoter and lead to their over-expression in an androgen-dependent fashion. Over-expression of ETS transcription factors makes normal prostate epithelial cells more invasive, possibly through the upregulation of matrix metalloproteases.
- The most common epigenetic alteration in prostate cancer is hypermethylation of glutathione S-transferase (GSTP1) gene which down-regualtes GSTP1 expression. Located on chromosome 11q13 its role is to prevent damage from carcinogens
Approximately 40% of somatotroph cell adenomas bear ..................................................
GNAS mutations that abrogate the GTPase activity of Gsα
What is the genetic of FTC?
- Approximately one third to one half of follicular thyroid carcinomas harbor mutations in the PI-3K/AKT signaling pathway, resulting in constitutive activation of this oncogenic pathway.
- This subset of cases includes tumors with gain-of-function point mutations of RAS and PIK3CA, tumors with amplification of PIK3CA, and those with loss-of-function mutations of PTEN, a tumor suppressor gene and negative regulator of this pathway
What is the major genetic changes in PTC?
- Activation of the MAP kinase pathway is a feature of most papillary carcinomas and can occur by one of two major mechanisms.
- The first mechanism involves rearrangements of RET or NTRK1 (neurotrophic tyrosine kinase receptor 1), both of which encode transmembrane receptor tyrosine kinases, and the second mechanism involves activating point mutations in BRAF, whose product is an intermediate signaling component in the MAP kinase pathway
What type of mutation is seen in MTC?
RET mutation (not rearrangement)
What are the two important genetic change in parathyroid adenoma?
- Cyclin D1 gene inversions
- MEN1 mutations
What are the genes associated with pheochromocytoma ?
.........is mutated or silenced in most esophageal cancers
Chromosomal abnormalities and mutation or overexpression of ........are present at early stages of esophageal adenocarcinoma
What are the genetic changes seen in astrocytoma?
- LG astrocytomas --> p53 and overexpression of PDGF-A and its receptor.
- The transition to HG astrocytoma --> RB and p16/CDKNaA
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