Molecular biology of gynaecologic cancer - MTCC

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Molecular biology of gynaecologic cancer - MTCC Powered By Docstoc
					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 [38].
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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posted:8/25/2011
language:English
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