The role of the tumour suppressor gene PTEN in the etiology of cancers of the female genital tract

The phosphorylation and dephosphorylation of the tyrosine amino-acids in proteins play an important role in the regulation of many cellular processes in all eukariotic organisms, including the regulation of cell cycle control, growth control, cellular differentiation and gene and synaptic transmission. The involvement of the phosphatase genes in human carcinogenesis was long-suspected, but PTEN is the first important phosphatase gene proven to be a true tumour suppressor. The basic function of normal PTEN is the dephosphorylation of the kinases and inhibition of the integrin and growth factor mediated kinase signalling pathways. The central hypothesis of this study is that PTEN plays an important role in tumours of the upper female genital tract. The involvement of aberrations in the coding regions of this gene was studied in specific gynaecologic tumours and tissues using polymerase chain reaction based mutation analysis. The research model was to study both the malignant tumour and the closest available pre-malignant or benign counterpart to demonstrate different levels of involvement of PTEN in the evolving steps. The PTEN gene was found to be intimately involved in endometrial carcinogenesis. Involvement was demonstrated in hyperplasia and was common in endometroid carcinoma (54%). Pathogenic PTEN mutations were much more common in cancer than in hyperplasia (10%). Multiple mutations were found in some late stage tumours, suggesting that the already malignant tumour cells accumulate more genetic mutations over time. All tumours with more than one pathogenic mutation occurred in African patients. The latter twofindings are unique to the current study. Selective involvement of the PTEN gene was demonstrated in uterine soft tissue tumours. PTEN involvement was neither found in benign soft tissue tumours nor significantly in leiomyosarcoma or endometrial stromal sarcoma. However, PTEN plays a significant role in uterine carcinosarcoma (13%) and specifically in tumours with an endometroid epithelial component, where mutations were found in 17%. This finding is a highly significant and unique research result which supports the hypothesis of the endometrial origin of these tumours. It also supports the observation of a strong link between this gene and endometroid differentiation, with morphology strongly linked to cellular genetics. PTEN gene mutation was demonstrated in ovarian endometroid carcinoma in ~29% of cases investigated. This finding confirms PTEN involvement in carcinogenesis in this tumour type. The finding suggests that PTEN involvement is linked to endometroid epithelial morphology. We could not sufficiently test the involvement of the gene in benign or pre-malignant ovarian endometroid lesions and thus cannot comment on the chronology of mutations in this tissue type. When all tumour types were included, there was a tendency towards a lower frequency ofPTEN mutations in African women. PTEN mutations correlated with endometroid histology. In combination, these results confirm the racial disparity in tumour type distribution or morphology. In summary this study demonstrated significant though highly selective PTEN gene involvement and a strong and interesting association between genotype and histological phenotype was confirmed. The findings enhance our understanding of carcinogenesis and should lead to translational research into new anti-neoplastic drugs. AFRIKAANS: Fosforilering en defosforilering van die tirosien aminosure in proteine speel ‘n belangrike rol in die regulering van sellulêre prosesse in alle eukariotiese organismes. Dit sluit die regulering van selsikluskontrole, groeikontrole, sellulêre differensiasie sowel as genetiese en sinaptiese oordrag in. Dit word lank reeds gespekuleer dat die fosfatase-gene betrokke is in menslike karsinogenese, maar die PTEN geen is die eerste fosfatase geen wat bewys word om ‘n ware tumoronderdrukker geen te wees. As basiese funksie defosforileer normale PTEN die kinases en inhibeer dit die kinase sinjaal kontrolepaaie wat deur integrien en groeifaktor beheer word. Die sentrale hipotese van hierdie studie is dat PTEN ‘n belangrike rol speel in tumore van die boonste genitale traktus. Die frekwensie van abnormaliteite in die koderingsareas van hierdie geen is bestudeer in spesifieke ginekologiese tumore en weefsels met die gebruik van polimerase kettingreaksie gebaseerde mutasie-analise. Die maligne tumore sowel as die mees verwante pre-maligne of benigne weefsel- of tumortipes wat beskikbaar was, is gebruik as navorsingsmateriaal om sodoende die verskillende vlakke van PTEN betrokkenheid in die ontwikkeling van neoplasie te demonstreer.Intieme betrokkenheid van die PTEN geen is gevind in endometriële karsinogenese. PTEN mutasies is in hiperplasie gevind en dit was algemeen in endometroiede karsinoom (54%). Patogene mutasies was baie meer algemeen in kanker as in hiperplasie (10%). Veelvuldige mutasies is in sommige laat stadium tumore aangetoon, wat suggereer dat reeds maligne selle meer genetiese mutasies oor tyd verkry. Alle tumore waar meer as een patogeniese mutasie gevind is het voorgekom by swart pasiënte. Die laaste twee bevindinge is uniek tot hierdie studie.Selektiewe betrokkenheid van die PTEN geen is gevind in die ontwikkeling van sagte weefsel tumore van die uterus. PTEN mutasies is nie in benigne sagte weefsel tumore gevind nie en geen betekenisvolle betrokkenheid is in leiomiosarkome of endometriële stromale sarkome aangetoon nie. PTEN was egter betekenisvol betrokke in karsinosarkome van die uterus (13%) en veral in tumore met ‘n endometrioiede epiteelkomponent waar mutasies in 17% gevind is. Hierdie bevinding is ‘n hoogs betekenisvolle en unieke navorsingsbevinding wat die hipotese ondersteun dat hierdie tumore uit die endometrium ontstaan. Dit onderskryf ook die indruk dat ‘n sterk band bestaan tussen hierdie geen en endometroiede differensiasie, met morfologie sterk gekoppel aan sellulêre genetika.Mutasie in die PTEN geen is aangetoon in ovariële endometroiede karsinoom in ~29% van gevalle wat ondersoek is. Die bevinding bevestig PTEN betrokkenheid in karsinogenese in hierdie tumortipe. Weereens toon die resultaat dat PTEN betrokkenheid gekoppel is aan endometroiede morfologie. Die ondersoek van benign of pre-maligne letsels in hierdie orgaan was nie voldoende om kommentaar oor die tydsberekening van mutasie te kan lewer nie.Met alle tumortipes in ag genome, is daar ‘n tendens aangetoon van minder PTEN mutasies in swart vroue. PTEN mutasies korreleer met endometroiede histologie. In kombinasie bevestig hierdie resultaat ‘n rasse-diskrepansie in die distribusie van tumourtipe of morfologie. In opsomming is die bevinding van hierdie studie dat daar betekenisvolle dog hoogs selektiewe PTEN geen betrokkenheid in boonste genitale traktus tumore is. ‘n Sterk en interessante verband is bevestig tussen genotipe en histologiese fenotipe. Hierdie resultate verbeter die begrip van karsinogenese en behoort ‘n bydrae te lewer in die soeke na nuwe anti-neoplastiese middels.Thesis (PhD)--University of Pretoria, 2011.Obstetrics and Gynaecologyunrestricte

Screening for gynaecologic cancers in genetically predisposed women

Hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colon cancer syndrome are the two most important syndromes responsible for inherited cancers in gynaecology. Genetic testing is available for both these syndromes. Breast cancer gene testing is affordable and easy in women with ancestry where the mutation patterns are known, whereas other population groups need full gene screening. Hereditary non-polyposis colon cancer syndrome can now be diagnosed more frequently with the use of immunohistochemistry. Ovarian cancer risk is high in hereditary breast and ovarian cancer syndromes, and advanced screening techniques should be used when preventive surgery is not an option. Early detection techniques offer less protection than prophylactic removal, but enable women to retain their reproductive organs. Oophorectomy has the advantage of reducing breast cancer risk. In colorectal cancer syndromes, the risk for endometrial and ovarian cancer is much elevated. These risks should be recognised and addressed as these diseases are easy to prevent.http://www.elsevier.com/locate/bpobgynhb2016Obstetrics and Gynaecolog

Ovarian endometriosis as a premalignant condition : epidemiological, histological and molecular evidence

Endometriosis is a common monoclonal benign proliferative disorder that may give rise to pelvic malignancy. Epithelial ovarian carcinoma is responsible for a large proportion of gynaecological cancer-associated deaths. Early diagnosis is difficult and screening is generally unsuccessful. Knowledge of the risk factors for the development of endometriosis and progression to malignancy may assist in identifying women at risk of developing endometriosis-related neoplasia. The associations between infertility, endometriosis and the development of cancer are reviewed in this article. Proliferative growth, metaplasia, hyperplasia and atypia are identified as proliferative disorders in endometriosis and atypia is considered a premalignant lesion. Several endometriosis-related pelvic malignancies have been described, and these all develop from the multipotent Müllerian cell differentiating into epithelial and/or stromal components. The probable histological type depends on the site of the endometriotic lesion and the population group. Cytogenetic and specific gene alterations that are involved in the carcinogenetic process are described briefly and these may help to predict risk of malignancy or to confirm histological subtype. The importance of endometriosis as a precursor of ovarian and related malignancies was probably seriously underestimated in the past. Advances in molecular testing, histology and our understanding of oncogenesis may empower us to help prevent these devastating diseases.http://www.sajgo.co.za/index.php/sajg

Iron deficiency in women’s health : an understated burden with serious health consequences

The importance of iron for overall health in humans cannot be overstated and its extremely widespread biological functions include electron transfer, intercellular signalling, catalysis, and oxygen binding and transport. Iron is found in all cells and is required for the synthesis of iron-sulphur clusters and heme proteins like cytochromes c, b5, and P450, myoglobin, neuroglobin and heme-based sensor proteins.1 It is also an enzyme cofactor that is essential for many important biological processes, and studies have shown that up to 6.5% of all human enzymes are iron-dependant.https://www.obstetricsandgynaecologyforum.comam2023Obstetrics and Gynaecolog

Treatment and outcomes of late stage vulva cancer at Pretoria Academic Hospital Complex, South Africa

Vulva cancer has been regarded as a rare disease in elderly women, diagnosed at a mean age of 70 years. Over the past few decades however, vulva cancer has shown an increasing incidence with a concurrent decreasing mean age. The increased incidence of human papilloma virus (HPV) is believed to be linked with the increasing incidence in younger women.https://journals.co.za/content/journal/medogpm2020Obstetrics and Gynaecolog

Paradigm shift needed for cervical cancer: HPV infection is the real epidemic

In South Africa (SA) the prevalence of cervical cancer is alarmingly high, presentation is late and survival rates are poor. High-risk human papillomavirus (hrHPV) has been established as a prerequisite for the development of cervical cancer, and prevention programmes in many developed countries include primary prevention through immunisation against types 16 and 18 before hrHPV exposure. Two articles in this issue of SAMJ report the outcome of a vaccine demonstration project in rural KwaZulu-Natal (KZN), and high hrHPV prevalence among a large sample of SA women. The editorial discusses optimal cervical cancer prevention programme for a middle-resourced country with an extremely high burden of HPV-associated disease like SA, and proposes initiation of primary school-based HPV vaccination as soon as possible, 10-yearly HPV-based screening, and effective treatment of women with positive screening tests

Paradigm shift needed for cervical cancer : HPV infection is the real epidemic

Thirty years ago the now Nobel Prize winner Harald Zur Hausen first described high-risk human papillomavirus (hrHPV) type 16 in cervical cancer specimens (Fig. 1). Since then, hrHPV infection has been established as a prerequisite for the development of cervical cancer. Cervical cancer prevention programmes in many developed countries already include primary prevention through immunisation against hrHPV types 16 and 18 before hrHPV exposure, combined with secondary prevention via cytology-based screening, often augmented by testing for hrHPV infection. The benefit of acquired knowledge and new technologies must now be extended to developing countries, where 85% of deaths attributable to cervical cancer occur.www.samj.org.zaam201

The effect of human immunodeficiency virus prevalence on the epidemiology of conventional cervical cytological abnormalities : an institutional experience

OBJECTIVES: Despite a shift towards other screening modalities, cervical cytology still has an important screening function in many settings. The worldwide human immunodeficiency virus (HIV) epidemic has impacted severely on cervical cancer, resulting in women presenting at a younger age with more advance disease and poorer prognosis. The objective of this study was to compare different datasets from different time periods to assess the possible impact of HIV infection on the epidemiological characteristics of conventional cervical cytology screening results. DESIGN: The design was a comparative overview of two different cervical cytology datasets collected at different times. SETTINGS AND SUBJECTS: Conventional cervical cytology screening data from non-pregnant patients at the gynaecological outpatient service of the Pretoria Academic Complex from 1991-2000, and data from pregnant patients attending the Kalafong Hospital antenatal clinic in 1993-1994 and 2008, were analysed. OUTCOME MEASURES: Abnormal smear rates, the distribution of different abnormal smears and HIV prevalence in pregnant women taking part in the annual, National Antenatal Sentinel HIV and Syphilis Prevalence Survey. RESULTS: The high prevalence of HIV in South Africa is associated with a higher prevalence of abnormal smears. It is also associated with a change in the distribution of detected abnormalities. High-grade squamous intraepithelial lesions (HSIL) are now much more common than low-grade squamous intraepithelial lesions (LSIL). The most pronounced change has been a shift in the ratio of LSIL to HSIL, where the value has changed from > 1 to < 1. CONCLUSION: The rate of abnormal smears as well as the distribution of abnormalities of conventional cervical cytology in South Africa has changed. It is possible that this change is associated with the high prevalence of HIV infection.http://www.sajgo.co.za/index.php/sajgoam201

Challenges in preventative care and research in primary healthcare facilities : information obtained during implementation of a cervical cancer screening project in the Tshwane Health District

OBJECTIVES: The aim was to identify challenges to conducting research and obstacles to successful cervical cancer screening in public sector primary healthcare clinics (PHCs). DESIGN: Qualitative research was conducted, using semi-structured interviews. SETTING AND SUBJECTS: Study staff and healthcare workers involved in the implementation of a large screening study conducted in existing primary healthcare facilities were interviewed during the study period. OUTCOME MEASURES: The outcome measure was qualitative data on problems and obstacles to research and cervical cancer screening in public health facilities. RESULTS: Twenty-one participants were interviewed at intervals over three years. It was found that clinical research could only be conducted in PHC facilities if no additional burden was placed on the staff or facilities. Preventative care was not found to be part of the focus of the clinics, which rather concentrated on disease. The need for gynaecological examinations was identified as an important obstacle to screening at PHC clinics. Self-sampling was widely accepted, as was cervical sampling for human papillomavirus. Reporting of screening results to patients presented a huge challenge to PHC facilities. Ineffective communication of the results was identified as another major obstacle to effective screening. CONCLUSION: Future cervical cancer screening methods should include sampling, without the need for an intimate examination. Finding new ways of calling women in for structured screening at regular intervals and reporting the results to them requires urgent attention.http://www.sajgo.co.za/index.php/sajgoam201

Tubal ectopic pregnancy 4 years after hysterectomy : a case report

BACKGROUND : Ectopic pregnancy after hysterectomy is a rare event. To date there are 73 definitive cases of post-hysterectomy ectopic pregnancy. The first case was reported by Wendler in 1895. CASE : A 31 year old P2G4 (one miscarriage) presented with a history of severe lower abdominal pain of three days duration. She previously had a subtotal hysterectomy four years prior her current presentation for a septic miscarriage with multiple organ dysfunction. She had a background history of being HIV reactive on antiretroviral therapy initiated two days before her presentation. Her CD4 count was 54 cells/uL, negative cryptococcal latex test. She was first diagnosed with HIV in 2015, however had not been on antiretroviral therapy since then. On clinical examination she was hemodynamically stable, normal blood pressure and pulse, afebrile and no stigmata of AIDS. She had an acute abdomen and on pelvic examination a cervical stump was palpable with no blood from the cervical os. Her haemoglobin was 13.4g/dl. Urine pregnancy test was positive. Her quantitative beta-HCG of 3979 IU/L. Pelvic ultrasound showed fluid collection in the pelvis, no definite masses seen, no uterus seen and ovaries could also not be visualised. Abdominal ultrasound did not show any abnormalities in the rest of the abdomen. The patient was counselled for surgery. Preparation with multidisciplinary consultation was done. Intraoperatively, 100ml haemoperitoneum was found. There were dense pelvic adhesions. Adhesiolysis was done and a bleeding right fallopian tube ampullary pregnancy was found. The right ovary was grossly normal. The contralateral adnexa could not be identified. A right salpingectomy was done. Total blood loss was 100ml. She recovered well post operatively and was discharged three days later to continue her antiretroviral therapy. DISCUSSION : A rare case of tubal ectopic pregnancy after hysterectomy is presented. Access to the peritoneal cavity and fallopian tube through the cervical canal, we postulated as the mechanism in this case. Ectopic pregnancies after hysterectomy are classified into early and late. The former being associated with a pregnancy (or viable gametes) that was present at the time of hysterectomy. These present soon after the hysterectomy. The latter present long after the hysterectomy. Conception can occur after hysterectomy through access via a prolapsed fallopian tube, a fistula or defect in the vault. Cervical stump pregnancy is also described. Surgical intervention is the most common intervention described amongst the case reports. CONCLUSION : Pregnancy after a hysterectomy is a rare possibility with possible adverse outcomes. Clinicians must have a strong index of suspicion for a possible ectopic pregnancy in patients that present with abdominal pain after hysterectomy.https://journals.co.za/journal/medogam2022Obstetrics and Gynaecolog