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A pilot study was conducted to determine whether 3-monthly groin ultrasonography could eliminate groin dissection after a negative bilateral groin ultrasound in three groups of patients: (i) Those with a unifocal stage 1B squamous cell carcinoma of up to 20 mm in diameter. (ii) Those with an ipsilateral squamous cell carcinoma of any size which extended to within 1 cm either side of the midline. These patients underwent ipsilateral inguinofemoral lymphadenectomy and ultrasonic surveillance of the contralateral groin. (iii) Patients with multifocal invasive lesions with the largest individual focus 20 mm or less in diameter. Three additional patients were added because they either refused groin dissection or were considered unfit for surgery. All ultrasonically positive nodes were confirmed histologically. Thirty-two patients were entered, and no patients were lost to follow-up. Forty-three groins were followed. With a median follow-up of 37 months, three positive nodes (9.4%) were detected. One patient died of her recurrence (3.1%), and 39 groins (90.7%) were preserved. The overall sensitivity of ultrasonic surveillance was 100% (95% CI: 44-100%), with a specificity of 97% (95% CI: 83-99%) and a negative predictive value of 100% (95% CI: 88-100%). This pilot justifies a larger study on serial ultrasonography in lieu of groin dissection in selected patients with vulvar cancer.
Subject(s)
Genital Neoplasms, Female , Female , Humans , Genital Neoplasms, Female/therapy , Societies, MedicalABSTRACT
Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were divided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score <2) had a higher fraction of the genome altered by copy number changes compared to PR-high tumors (p = 0.001), with cancer genes affected within specific loci linked to altered peptidyl-tyrosine kinase, MAP-kinase, and PI3-kinase signaling. Cox regression analysis showed that ER-high (p = 0.02), PR-high (p = 0.03), stage III disease (p = 0.02), low residual disease burden (p = 0.01) and normal p16 expression (p<0.001) were all significantly associated with improved overall survival. This study provides evidence that genomic aberrations are linked to ER/PR expression in primary LGSOC.
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BACKGROUND: Lower limb lymphedema is a long-term complication of inguino-femoral lymphadenectomy and is related to the number of lymph nodes removed. Our hypothesis was that lymph nodes lateral to the femoral artery could be left in situ if the medial nodes were negative, thereby decreasing this risk. METHODS: We included patients with vulvar cancer of any histological type, even if the cancer extended medially to involve the urethra, anus, or vagina. We excluded patients whose tumor extended (i) laterally onto the thigh, (ii) posteriorly onto the buttocks, or (iii) anteriorly onto the mons pubis. After resection, the inguinal nodes were divided into a medial and a lateral group, based on the lateral border of the femoral artery. RESULTS: Between December 2010 and July 2018, 76 patients underwent some form of groin node dissection, and data were obtained from 112 groins. Approximately one-third of nodes were located lateral to the femoral artery. Positive groin nodes were found in 29 patients (38.2%). All patients with positive nodes had positive nodes medial to the femoral artery. Five patients (6.6%) had positive lateral inguinal nodes. The probability of having a positive lateral node given a negative medial node was estimated to be 0.00002. CONCLUSION: Provided the medial nodes are negative, medial inguino-femoral lymphadenectomy may suffice and should reduce lower limb lymphedema without compromising survival.
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OBJECTIVE: Most guidelines advise no adjuvant radiotherapy in vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis. However, several recent studies have questioned the validity of this recommendation. The aim of this study was to analyze the groin recurrence rate in patients with a single intracapsular positive lymph node treated without adjuvant radiotherapy. METHODS: Patients with a single clinically occult intracapsular lymph node metastasis, treated without adjuvant radiotherapy, formed the basis for this study. Groin recurrences, and the risk of death, were analyzed in relation to the size of the metastasis in the lymph node and the lymph node ratio. Data were analyzed using SPSS, version 26.0 for Windows. RESULTS: After a median follow-up of 64 months, one of 96 patients (1%) was diagnosed with an isolated groin recurrence and another two (2.1%) were diagnosed with a combination of a local and a groin recurrence. The only isolated groin recurrence occurred in a contralateral lymph node negative groin. Size of the metastasis and lymph node ratio had no impact on the groin recurrence risk, nor on survival. The 5-year actuarial disease-specific and overall survivals were 79% and 62.5% respectively. The 5-year actuarial groin recurrence-free survival was 97%. CONCLUSION: Because of the low risk of groin recurrence and the excellent groin recurrence-free survival, we recommend that adjuvant radiotherapy to the groin in patients with vulvar squamous cell carcinoma and a single occult intracapsular lymph node metastasis can be safely omitted to prevent unnecessary toxicity and morbidity.
Subject(s)
Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/surgery , Vulvar Neoplasms/pathology , Vulvar Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Australia/epidemiology , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/radiotherapy , Female , Humans , Lymph Nodes/pathology , Lymph Nodes/surgery , Lymphatic Metastasis , Middle Aged , Neoplasm Recurrence, Local/pathology , Netherlands/epidemiology , Radiotherapy, Adjuvant , Retrospective Studies , Vulvar Neoplasms/mortality , Vulvar Neoplasms/radiotherapyABSTRACT
For the last 30 years at the Royal Hospital for Women, unifocal vulvar squamous cancers have been treated by radical local excision, aiming to achieve a histopathological margin of ≥8 mm, equating to a surgical margin of 1 cm. The need for a margin of this width has recently been challenged. We aimed to determine the long-term outcome following this conservative approach, and the relationship between vulvar recurrences and surgical margins. Data were obtained retrospectively on 345 patients treated primarily with surgery for squamous vulvar cancer between 1987 and 2017. Median follow-up was 93 months. Five-year disease-specific survival was 86%. Of 78 vulvar recurrences, 33 (42.3%) were at the primary site and 45 (57.7%) at a remote site. In multivariable analysis, a margin < 5 mm showed a higher risk of all vulvar (Hazard ratio (HR), 2.29; CI, 1.12-4.70), and primary site recurrences (subdistribution hazard ratio (SHR), 15.20; CI, 5.21-44.26), while those with a margin of 5 to <8 mm had a higher risk of a primary site recurrence (SHR, 8.92; CI, 3.26-24.43), and a lower risk of remote site recurrence. Excision margins < 8 mm treated by re-excision or radiation therapy had a significantly decreased risk of recurrence. Guidelines should continue to recommend a surgical margin of 1 cm.
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INTRODUCTION: The International Cancer Benchmarking Partnership demonstrated international differences in ovarian cancer survival, particularly for women aged 65-74 with advanced disease. These findings suggest differences in treatment could be contributing to survival disparities. OBJECTIVE: To compare clinical practice guidelines and patterns of care across seven high-income countries. METHODS: A comparison of guidelines was performed and validated by a clinical working group. To explore clinical practice, a patterns of care survey was developed. A questionnaire regarding management and potential health system-related barriers to providing treatment was emailed to gynecological specialists. Guideline and survey results were crudely compared with 3-year survival by 'distant' stage using Spearman's rho. RESULTS: Twenty-seven guidelines were compared, and 119 clinicians completed the survey. Guideline-related measures varied between countries but did not correlate with survival internationally. Guidelines were consistent for surgical recommendations of either primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery with the aim of complete cytoreduction. Reported patterns of surgical care varied internationally, including for rates of primary versus interval debulking, extensive/'ultra-radical' surgery, and perceived barriers to optimal cytoreduction. Comparison showed that willingness to undertake extensive surgery correlated with survival across countries (rs=0.94, p=0.017). For systemic/radiation therapies, guideline differences were more pronounced, particularly for bevacizumab and PARP (poly (ADP-ribose) polymerase) inhibitors. Reported health system-related barriers also varied internationally and included a lack of adequate hospital staffing and treatment monitoring via local and national audits. DISCUSSION: Findings suggest international variations in ovarian cancer treatment. Characteristics relating to countries with higher stage-specific survival included higher reported rates of primary surgery; willingness to undertake extensive/ultra-radical procedures; greater access to high-cost drugs; and auditing.
Subject(s)
Carcinoma, Ovarian Epithelial/therapy , Gynecology/methods , Medical Oncology/methods , Ovarian Neoplasms/therapy , Practice Guidelines as Topic , Adult , Aged , Australia , Canada , Europe , Female , Health Services Accessibility , Humans , Middle Aged , New Zealand , Surveys and QuestionnairesABSTRACT
BACKGROUND: Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms. METHODS: Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. RESULTS: These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. CONCLUSIONS: These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Carcinoma, Basal Cell/genetics , Carcinoma, Basal Cell/metabolism , Inhibitor of Differentiation Proteins/genetics , Inhibitor of Differentiation Proteins/metabolism , Animals , Apoptosis/physiology , Breast Neoplasms/pathology , Carcinoma, Basal Cell/pathology , Cell Differentiation/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Chromatin/genetics , Chromatin/metabolism , DNA Damage , Female , Heterografts , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Prognosis , Proteogenomics , Tumor Cells, CulturedABSTRACT
OBJECTIVE: To investigate the prognostic significance of HPV status in vulvar squamous cell carcinomas (VSCC) and to determine whether preoperative determination of p16 or p53 status would have clinical relevance. METHODS: Patients treated for VSCC at a tertiary hospital in Sydney, Australia, from 2002 to 2014, were retrospectively evaluated (n = 119). Histological specimens were stained for p53 and p16 expression, and HPV status was determined by PCR detection of HPV DNA. RESULTS: HPV DNA was detected in 19%, p16 expression in 53%, and p53 expression in 37% of patients. Kaplan-Meier survival estimates indicated that p16/HPV-positive patients had superior five-year disease-free survival (76% versus 42%, resp., p = 0.004) and disease-specific survival (DSS) (89% versus 75% resp., p = 0.05) than p53-positive patients. In univariate analysis, nodal metastases (p < 0.001), tumor size >4 cm (p = 0.03), and perineural invasion (p = 0.05) were associated with an increased risk of disease progression and p16 expression with a decreased risk (p = 0.03). In multivariable analysis, only nodal metastases remained independent for risk of disease progression (p = 0.01). For DSS, lymph node metastases (p < 0.001) and tumor size (p = 0.008) remained independently prognostic. CONCLUSION: The p16/HPV and p53 status of VSCC allows separation of patients into two distinct clinicopathological groups, although 10% of patients fall into a third group which is HPV, p16, and p53 negative. p16 status was not independently prognostic in multivariable analysis. Treatment decisions should continue to be based on clinical indicators rather than p16 or p53 status.
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BACKGROUND: Malignant mixed Mullerian tumors of endometrial (MMMT-E) and ovarian (MMMT-O) origin are associated with poor prognosis. Suggestively epithelial-driven tumors, their treatment has shifted from anthracycline or ifosfamide-based towards taxane-based chemotherapy. It remains unclear whether this change associates with better outcomes. PATIENTS AND METHODS: A conjoined Australian and Swiss patient cohort of MMMT-E (N = 103) and MMMT-O (N = 17) was compared to patients with adenocarcinoma of the endometrium (EC, N = 172) and ovary (OC, N = 189). Clinicopathological characteristics, FIGO stage, first-line treatment, and patient outcomes were analyzed. The generated hypothesis was verified in an US-American cohort with high-grade serous ovarian cancer (HGSOC, N = 1290) and MMMT-O (N = 450) using immunohistochemistry and next-generation sequencing. RESULTS: Early stage I/II MMMT-E showed a survival plateau after 2.5 years, with no recurrence or death observed afterwards. Relapse-free survival was significantly worse in MMMT-E treated with platinum/taxanes (P = 0.024) compared to non-taxane regimen. Hypothesizing that also MMMT-O might benefit from an adjuvant non-paclitaxel regimen, a second independent cohort of MMMT-O and HGSOC patients was examined. p53 mutations dominated in both cancers with comparable frequency. PI3KCA and KRAS mutations were less frequent: they were more frequent in MMMT-O than in HGSOC (P = 0.015 and P = 0.018, respectively). MMMT-O responded better to a combination of carboplatin with anthracyclines than with taxanes (73.9% vs. 39.4%). CONCLUSION: Early stage I/II MMMT-E patients have excellent prognosis if no recurrence has appeared within the first 2.5 years. In MMMT-E, platinum/anthracycline or ifosfamide regimen associated with better outcomes than platinum/taxanes regimens. This might also apply to MMMT-O.
Subject(s)
Antineoplastic Agents/therapeutic use , Chemotherapy, Adjuvant/methods , Endometrial Neoplasms/drug therapy , Mixed Tumor, Mullerian/drug therapy , Ovarian Neoplasms/drug therapy , Taxoids/therapeutic use , Adult , Aged , Female , Humans , Middle AgedABSTRACT
Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.
Subject(s)
Adenocarcinoma, Mucinous/genetics , Carcinoma, Ovarian Epithelial/genetics , Gene Expression Profiling/methods , Ovarian Neoplasms/genetics , Adenocarcinoma, Mucinous/classification , Adenocarcinoma, Mucinous/metabolism , Carcinoma, Ovarian Epithelial/classification , Carcinoma, Ovarian Epithelial/metabolism , Cohort Studies , Female , Gene Expression Regulation, Neoplastic , Humans , Mutation , Ovarian Neoplasms/classification , Ovarian Neoplasms/metabolism , Sequence Analysis, DNA/methods , Survival AnalysisABSTRACT
Purpose: The stage of disease is one of the strongest prognostic factors in epithelial ovarian cancer. The International Federation of Gynecology and Obstetrics (FIGO) classification was revised in 2013; stage IC was subdivided into IC1 (intraoperative surgical spill), IC2 (capsule rupture before surgery or tumor on surface), and IC3 (positive peritoneal washing or ascites). Our aim was to compare the outcome of patients in the new FIGO stage I subgroups, as this might influence adjuvant therapy decisions. Patients and methods: Patient databases of three gynecological oncology centers were retrospectively analyzed. Patients with FIGO stage I ovarian cancers were restaged according to the revised classification, based on operative and pathological reports, and determined patient outcomes. Results: We analyzed 128 patients with ovarian cancers. In FIGO IA, we found 11.3% recurrences and 4.2% deaths. In FIGO IC, 21.8% of the patients recurred and 7.3% died. There was a trend toward a shorter time to recurrence when comparing IA to IC (P=0.076). Within all new subgroups of FIGO IC, there was no difference in time to recurrence (P=0.59). There was also no significant difference in survival when FIGO IA was compared to FIGO IC in comparison with the new individual classifications (IA to IC, IA to IC1, 2, or 3; P=0.60, P=0.15, P=0.61, P=0.66, respectively) or within the different subgroups (P=0.56). Platinum-based chemotherapy was given to the majority (82.6%, n=38/46) of the FIGO IC patients compared to 30.9% in FIGO IA (n=17/55). There was no significant difference within the new subgroups of FIGO IC (P=0.88). Conclusion: In our retrospective analysis, the new FIGO staging of IC ovarian cancers did not predict prognosis, but the use of adjuvant chemotherapy in 82.6% of the stage IC patients may have biased the outcome.
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The relationship between ABO blood groups (BG) and risk of incidence in cancers including gynecological cancers has been widely studied, showing increased incidence risk for BG A patients. As available data are inconsistent we investigated whether BG and their anti-glycan antibodies (anti-A and anti-B) have prognostic values in gynecological cancers. We retrospectively evaluated 974 patients with gynecological cancers in three cancer centers (Switzerland and Australia) between 1974 and 2014 regarding the relationships between clinico-pathological findings and the BG. Time to disease recurrence was significantly influenced by BG in patients with ovarian (n = 282) and vulvar (n = 67) cancer. BG O or B patients showed a significantly increased risk for ovarian cancer relapse compared to A, 59% and 82%, respectively (p = 0.045; HR O vs A = 1.59 (CI 1.01-2.51) and (p = 0.036; HR A vs B = 0.55 (CI 0.32-0.96). Median time to relapse for advanced stage (n = 126) ovarian cancer patients was 18.2 months for BG O and 32.2 for A (p = 0.031; HR O vs A = 2.07 (CI 1.07-4.02)). BG also significantly influenced relapse-free survival in patients with vulvar cancer (p = 0.002), with BG O tending to have increased relapse risk compared to A (p = 0.089). Blood groups hence associate with recurrence in ovarian and vulvar cancer: women with BG O seem to have a lower ovarian cancer incidence, however are more likely to relapse earlier. The significance of the BG status as a prognostic value is evident and may be helpful to oncologists in prognosticating disease outcome and selecting the appropriate therapy.
Subject(s)
ABO Blood-Group System , Adenocarcinoma/pathology , Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/pathology , Vulvar Neoplasms/pathology , Adenocarcinoma/blood , Adenocarcinoma/therapy , Australia , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/therapy , Ovarian Neoplasms/blood , Ovarian Neoplasms/therapy , Prognosis , Retrospective Studies , Survival Rate , Vulvar Neoplasms/blood , Vulvar Neoplasms/therapyABSTRACT
BACKGROUND: Gynaecological cancers may be the sentinel malignancy in women who carry a mutation in BRCA1 or 2, a mis-match repair gene causing Lynch Syndrome or other genes. Despite published guidelines for referral to a genetics service, a substantial number of women do not attend for the recommended genetic assessment. The study aims to determine the outcomes of systematic follow-up of patients diagnosed with ovarian or endometrial cancer from Gynaecologic-oncology multidisciplinary meetings who were deemed appropriate for genetics assessment. METHODS: Women newly diagnosed with gynaecological cancer at the Royal Hospital for Women between 2010 and 2014 (cohort1) and 2015-2016 (cohort 2) who were identified as suitable for genetics assessment were checked against the New South Wales/Australian Capital Territory genetic database. The doctors of non-attenders were contacted regarding suitability for re-referral, and patients who were still suitable for genetics assessment were contacted by mail. Attendance was again checked against the genetics database. RESULTS: Among 462 patients in cohort 1, flagged for genetic assessment, 167 had not consulted a genetic service at initial audit conducted in 2014. 86 (18.6%) women whose referral was pending clarification of family history and/or immunohistochemistry did not require further genetic assessment. Letters were sent to 40 women. 7 women (1.5%) attended hereditary cancer clinic in the following 6 months.The audit conducted in 2016 identified 148 patients (cohort 2) appropriate for genetic assessment at diagnosis. 66 (44.6%) had been seen by a genetics service, 51 (34.5%) whose referral was pending additional information did not require further genetic assessment. Letters were sent to 15 women, of whom 9 (6.1%) attended genetics within 6 months. CONCLUSIONS: To improve the effectiveness of guidelines for the genetic referral of women newly diagnosed with ovarian cancer, clinicians need to obtain a thorough family history at diagnosis; arrange for reflex MMR IHC according to guidelines; offer BRCA or panel testing to all women with non-mucinous ovarian cancer prior to discharge and systematically follow up all women referred to genetics at the post-op visit.
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BACKGROUND: Endometrial, ovarian and breast cancers are paradigms for global health disparity. Women living in the developing world continue to present in later stages of disease and have fewer options for treatment than those in developed countries. Risk reducing surgery is of proven benefit for women at high risk of gynaecological cancer. There is no specific model for identification and management of such women in the developing world. METHODS: We have integrated data from our published audit of a major gynaecological oncology centre at Royal Hospital for Women in Australia, with data from our survey and a focus group discussion of Nepalese gynaecological health care professionals regarding genetic testing, and findings from the literature. These data have been used to identify current barriers to multidisciplinary gynaecological oncology care in developing nations, and to develop a model to integrate hereditary cancer services into cancer care in Nepal, as a paradigm for other developing nations. RESULTS: The ability to identify women with hereditary gynaecological cancer in developing nations is influenced by their late presentation (if active management is declined or not appropriate), limited access to specialised services and cultural and financial barriers. In order to include genetic assessment in multidisciplinary gynaecological cancer care, education needs to be provided to all levels of health care providers to enable reporting of family history, and appropriate ordering of investigations. Training of genetic counsellors is needed to assist in the interpretation of results and extending care to unaffected at-risk relatives. Novel approaches will be required to overcome geographic and financial barriers, including mainstreaming of genetic testing, telephone counselling, use of mouth swabs and utilisation of international laboratories. CONCLUSION: Women in Nepal have yet to receive benefits from the advances in early cancer diagnosis and management. There is a potential of extending the benefits of hereditary cancer diagnosis in Nepal due to the rapid fall in the cost of genetic testing and the ability to collect DNA from a buccal swab through appropriate training of the gynaecological carers.
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In the era of precision medicine, the tailoring of cancer treatment is increasingly important as we transition from organ-based diagnosis towards a more comprehensive and patient-centric molecular diagnosis. This is particularly the case for high-grade serous adenocarcinomas of the ovary and peritoneum, which are commonly diagnosed at an advanced stage, and collectively treated and managed similarly. We characterized the N- and O-glycome of serous ovarian (OC) and peritoneal cancer (PC) tissues using PGC-LC-ESI-IT-MS/MS profiling and validated the discriminatory glycans and their corresponding glyco-gene expression levels using cell lines and transcriptomic data from 232 patients. Overall, the N- and O-glycan repertoires of both cancer types were found to comprise mostly of α2,6-sialylated glycan structures, with the majority of N-glycans displaying the biantennary mono- and disialylation as well as bisecting-type biantennary glycans. The MS profiling by PGC-LC also revealed several glycan structural isomers that corresponded to LacdiNAc-type (GalNAcß1-4GlcNAc) motifs that were unique to the serous ovarian cancers and that correlated with elevated gene expression of B4GALNT3 and B4GALNT4 in patients with serous cancer. Statistical evaluation of the discriminatory glycans also revealed 13 N- and 3 O-glycans (P < 0.05) that significantly discriminated tumour-sampling sites, with LacdiNAc-type N-glycans (m/z 1205.02- and m/z 1059.42- ) being associated with ovarian-derived cancer tissue and bisecting GlcNAc-type (m/z 994.92- ) and branched N-glycans (m/z 1294.02- and m/z 1148.42- ) upregulated at the metastatic sites. Hence, we demonstrate for the first time that OC and PC display distinct molecular signatures at both their glycomic and transcriptomic levels. These signatures may have potential utility for the development of accurate diagnosis and personalized treatments.
Subject(s)
Cystadenocarcinoma, Serous/genetics , Glycomics , Ovarian Neoplasms/genetics , Peritoneal Neoplasms/genetics , Polysaccharides/analysis , Polysaccharides/genetics , Transcriptome , Cell Line, Tumor , Cystadenocarcinoma, Serous/pathology , Female , Humans , N-Acetylgalactosaminyltransferases/genetics , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/pathology , Tandem Mass Spectrometry/methodsABSTRACT
BACKGROUND: Glycosphingolipids are important compounds of the plasma membrane of mammalian cells and a number of them have been associated with malignant transformation and progression, reinforcing tumour aggressiveness and metastasis. Here we investigated the levels of naturally occurring anti-glycan antibodies to Globo H in blood plasma obtained from high-grade serous ovarian cancer patients (SOC) and women without gynaecological malignancies (control) using suspension glycan array technology employing chemically synthesized glycans as antibody targets. RESULTS: We found that anti-human Globo H IgG antibodies were able to significantly discriminate SOC from controls (P < 0.05). A combination with the clinically used tumour marker CA125 increased the diagnostic performance (AUC 0.8711). We next compared suspension array with standard flow cytometry in plasma samples and found that the level of anti-Globo H antibodies highly correlated (r = 0.992). The incubation of plasma-derived anti-glycan antibodies with chemically synthesized (presented on fluorescence microspheres) and native Globo H (expressed on Globo H-positive cell lines) revealed strong reactivity of naturally occurring human anti-Globo H antibodies towards its antigen expressed on ovarian cancer cells. CONCLUSIONS: Our data demonstrate that human plasma-derived antibodies to Globo H as well as the presence of the antigen might be considered as therapeutic option in ovarian cancer.