CME Journal of Gynecologic Oncology Volume 2 Number 1 March 1997 [antikvár]

Chapter Editor's introduction One great achievement of the past 15 years was the discovery that cancer is a genetic disease, a spectrum of gene mutations. These genetic changes are consistent with current evidence that cancer develops from an accumulation of at least 4-6 genetic alterations in a single cell. Thus cancer is a multi-step process at the cellular level. Gene abnormalities occur in multi- ple combinations, which may result in infinite variations of vir- ulence of the cancer they cause. These changes involve inherit- ed and/or acquired alterations of not only proto-oncogenes and tumour-suppressor genes but of other genes as well, such as DNA mismatch repair genes, etc. The vast majority of these cancer-related genes are responsible for normal cell cycles, function, cellular differentiation or programmed cell death. Molecular genetics has a number of potential clinical implica- tions the practicing gynecologic oncologists need to be familiar with. These include: 1. Detection of submicroscopic disease not detectable by conventional histological methods. This might contribute to more precise staging and to better evalua- tion of the adequacy of the surgical margins. Detection of sub- microscopic disease at the time of second-look laparotomy would certainly increase the clinical utility of this procedure. 2. Understanding the associations between certain gene alter- ations and premalignant lesions, identification of the morpho- logical manifestation of dysplastic lesions due to gene mutation and making a distinction between these lesions and similar dis- eases is crucial, for they have predisposition to cancer. Although the clinical impact of molecular genetic studies of dysplastic lesions has not been clearly defined, such studies can be utilized to identify precancerous lesions in organs in which such dysplastic changes have not been recognized, e.g. the ovaries. This information could have a significant impact on the detection of pre-clinical ovarian cancer. Recognition of can- cer-associated gene mutations in dysplastic lesions is important in the distinction between true pre-malignant precursors and dysplastic lesions that are benign and are not associated with progression to cancer. 3. Applied genetic studies, i.e. genetic analysis of the malignant tumor of the patient to be treated, are becoming a prerequisite of current strategies against cancer. Address correspofideme to Péter Bősze, M.D. Department oi Gynecologic Oncology Siuni Stephen Hospital 1096 Budapc^i, Nagyvárad tér I , Hungary Phone <36 1)275 2172 Fax (36 1)275 2172 E-mail: hos/eCa mail.matav.hu They may provide new prognostic factors reflecting virulence and metastatic behavior of Ihe tumor. These new parameters not only give us an indication of prognosis but would pernni minimally invasive, organ-spearing procedures, many of them as outpatient treatment, as compared to radical surgery with or without irradiation and/or toxic chemotherapy. The study of the biology of the tumor is of particular importance in borderline ovarian neoplasm. 4. With the identification of germhne muta- tions of tumor-susceptibility genes, mainly breast and ovarian cancer genes, such as BRCA-1 and BRCA-2 as well as DNA mismatch-repair genes responsible for the development of HNPCC syndrome, screening for mutation earners who are at high nsk of developing the disease has become available. Such advances will have a dramatic impact on the clinical manage- ment of unaffected members of cancer-prone families. Molecular genetic screening of non-hereditary cancer might be a future alternative to current screening techniques. It may replace conventional cervical cancer screening methods, or may be applied additionally to cytology to reduce the false- negative rates. 5. Various approaches of gene therapy (molecu- lar chemotherapy) have been studied in the research setting, some of them now being in clinical trials. Gene-targeting thera- py is promising in achieving the ultimate goals of cancer genet- ics, i. e. to prevent cancer development and to improve survival and quality of life. It is very likely that genetic therapeutics will be an integral pail of the anticancer armamentarium of gyneco- logic oncologists in the foreseeable future. Developments in cancer genetics have been so rapid that knowledge about the role of molecular genetics both in the development and the management of cancer has out-paced the ability of the cancer physician to incorporate this information into patient care. As well, public awareness of the genetic rel- evance of gynecologic malignant diseases has significantly increased. Gynecologic oncologists must now be familiar with the changes in our understanding of cancer development and the phenotypic consequence of cancer-associated gene mutations. An understanding of molecular genetic terminolo- gy and methodologies is crucial to the practice of gynecologic oncology (1), and therefore the novel, genotype-phenotype correlation-based literature is invaluable in order to translate this molecular revolution into clinical care. "Physicians caring for women with gynecologic malignancies not only need to interpret reports in the literature but process the information in such a way that ii can be conveyed to their patients" (1). This chapter attempts to provide an update on the molecular genetic revolution directly or indirectly related to the malig- nant diseases of the female genital tract and breasts. REFERENCE Skilling JS, Sood Ak. Molecular genetics: implications tor the practising g\ ideo- logic oncologist. CME J Gynecol Oncol 1997 2:6 ( Ml hwrnal of Gynecologic Oncology 5 5