First Tirana Mediterranean Cancer Congress Tirana international Hotel, April 29-30, 2011 Majlinda Buba Ikonomi Overview I. Genetics Overview 1. Translocations 2. Deletions 3. Point mutations 4. Amplification II. Oncogenes III. Tumor Suppressor Genes IV. Mismatch Repair Genes Genetic Alterations Translocations and Inversions Early event, rarely singular Chromosomal Deletions (LOH) Most common for solid tumors p53 tumor suppressor deletion of 17p Point Mutations – Especially if regulatory or coding region Gene Amplification Amplification of her-2/neu Cervical cancer The epidemiologic and experimental data undoubtedly points to the human papillomavirus (HPV) as the primary causal agent in development of cervical carcinoma. Its carcinogenic role continues to represent the main field of research on the molecular biology of cervical cancer. Cervical cancer The transition from normal cervical epithelium to dysplasia to invasive disease is well-defined histologically A useful framework upon which molecular alterations can be evaluated. “Malignant transformation” HPV viral integration into host genome DNA is associated with progression from polyclonal to monoclonal status in cervical intraepithelial neoplasia (CIN), and these events play a fundamental role in the progression from low- to high-grade cervical neoplasia Normal cell LGCIN HGCIN Cancer HPV infection Viral Neoplastic persistence progression Viral clearance Viral DNA Genetic integration instability High levels Defects in Type-specific of E6,E7 antigen imunity presentation Cervical cancer During HPV DNA integration, the viral genome usually breaks in the E1/E2 region. The break generally leads to loss of the E1 and E2 regions. Loss of E2 results in uncontrolled and increased expression of E6 and E7 oncogenic proteins. Increased expression of E6 and E7, meanwhile, has been observed to lead to malignant transformation of host cells and to tumor formation . Cervical cancer Changes in expression patterns that accompany progression to cervical cancer J. DOORBAR Clinical Science (2006) 110, 525–541 Cervical cancer • Overexpression of the cyclin dependent kinase inhibitor p16 INK4A • Visualisation of p16 INK4A in routine applicable technologies • Cells that have acquired the transforming mode are to a higher risk for neoplastic progression. Epigenetic alterations in cervical cancer The two most widely studied epigenetic changes are DNA methylation and histone acetylation Endometrial cancer Evaluation of the molecular features of EC is still an area of predominant interest in the field of research. Some aspects could have practical usefulness at present or in the near future. Therapy Dualistic model of Endometrial carcinoma based on a classification system hypothesized by Bokhman in 1983. Molecular biology of dualistic model Aside from their morphologic and clinical features, type 1 and type 2 endometrial cancers are further distinguished by genetic alterations Evaluation of precursor lesions Rritje e agresivitetit MLH-1 immunostaining in evaluation of atypical complex hyperplasia in endometrial biopsies EIN serous type Nomenclature and potential new classification to endometrial neoplasia Targeted therapies Diagnosis of HNPCC in a patient with EC Microsatellite instability (MI) is seen in cancers (colonic, endometrial and others) of patients with hereditary non-polyposis colon cancer (HNPCC), but is also seen in 25–30% of sporadic EC HNPCC patients with EC have an inherited germ-line mutation in MLH-1, MSH-2, MSH-6 or PMS-2 (“first hit”); but EC develops only after the instauration of a deletion or mutation in the contralateral MLH-1,MSH- 2, MSH-6 or PMS-2 allele (“second hit”) in endometrial cells Diagnosis of HNPCC in a patient with EC Immunostaining for mismatch repair genes (MLH-1, MSH-2, MSH-6 or PMS-2), as well as evaluation of microsatellite instability, is of obvious interest in studying EC patients with suspected features of HNPCC Results should be confirmed by identifying the germ- line mutation in the responsible gene (MLH-1, MSH-2, MSH-6 or PMS-2) in DNA obtained from normal tissue or peripheral blood. Ovarian epithelial cancer Are they biologically the same? OVARY ENDOMETRIUM SEROUS ENDOMETRIOID CLEAR CELL Dualistic model of OSC Ovarian a heterogenous group of neoplasms, each with a different underlying pathogenesis and natural behaviour. There is considerable interobserver variation in the distinction between high-grade serous and endometrioid adenocarcinomas. Most poorly differentiated ovarian adenocarcinomas are serous in type; WT1 immunohistochemical staining may be useful in confirmation. PrognostiC molecular factors New technologies are being introduced that allow the simultaneous measurement of multiple signalling pathways. Gene expression analysis has identified ovarian cancer signatures that predict optimal cytoreductive surgery, poor overall survival and chemoresistance, CONCLUSIONS The morphologic and molecular genetic data support different pathways of development for each of the major histologic types of ovarian carcinoma Low- and high-grade serous carcinoma most probably arise via different pathways, the former progressing along an adenoma–borderline tumor–carcinoma sequence involving mutations in KRAS and BRAF the latter from alterations in surface epithelial inclusion glands involving mutations of TP53 and dysfunction of BRCA1 and/or BRCA2. CONCLUSIONS Mucinous carcinomas most probably arise via an adenoma–borderline tumor–carcinoma sequence with mutations of KRAS. Endometrioid carcinomas arise from endometriosis with mutations of CTNNB1 (the gene encoding - catenin) and PTEN. The genetic alterations in clear cell carcinoma are the least investigated but also support an origin from endometriosis. THE DETAILED UNDERSTANDING OF DISEASE SPECIFIC MOLECULAR BASIS WILL IMPROVE OUTCOMES OF THESE MALIGNANCIES IN SEVERAL CLINICAL APPLICATIONS GENETIC SCREENING EARLY DIAGNOSIS NOVEL DIRECTED TARGETED THERAPIES Thank you!
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