151 results found
Saner FAM, Takahashi K, Budden T, et al., 2023, Concurrent RB1 loss and BRCA -deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma., medRxiv
BACKGROUND: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 ( BRCA ). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. PATIENTS AND METHODS: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. RESULTS: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 × 10 -7 ), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC ( P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 x10 -6 ) compared to patients with either alteration alone, and their median OS was three times lon
Masood M, Ding Q, Cawte AD, et al., 2023, Genetic screening for anticancer genes highlights FBLN5 as a synthetic lethal partner of MYC, Cell Communication and Signaling, Vol: 21, ISSN: 1478-811X
Background: When ectopically overexpressed, anticancer genes, such as TRAIL, PAR4 and ORCTL3, specifically destroy tumour cells without harming untransformed cells. Anticancer genes can not only serve as powerful tumour specific therapy tools but studying their mode of action can reveal mechanisms underlying the neoplastic transformation, sustenance and spread. Methods: Anticancer gene discovery is normally accidental. Here we describe a systematic, gain of function, forward genetic screen in mammalian cells starting with over 30,000 transcripts in order to isolate novel anticancer genes of human origin. FBLN5 was chosen, as a proof of principle, for mechanistic gene expression profiling, comparison pathways analyses and functional studies. Results: Sixteen novel anticancer genes were isolated; these included non-coding RNAs, protein-coding genes and novel transcripts, such as ZNF436-AS1, SMLR1, TMEFF2, LINC01529, HYAL2, NEIL2, FBLN5, YPEL4 and PHKA2-processed transcript. FBLN5 selectively caused inhibition of MYC in COS-7 (transformed) cells but not in CV-1 (normal) cells. MYC was identified as synthetic lethality partner of FBLN5 where MYC transformed CV-1 cells experienced cell death upon FBLN5 transfection, whereas FBLN5 lost cell death induction in MCF-7 cells upon MYC knockdown. Conclusions: Sixteen novel anticancer genes are present in human genome including FBLN5. MYC is a synthetic lethality partner of FBLN5.
Aboelnasr LS, El-Bahrawy M, 2023, Epithelioid trophoblastic tumor, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, ISSN: 1048-891X
Kobel M, Kang E-Y, Weir A, et al., 2023, p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study, JOURNAL OF PATHOLOGY CLINICAL RESEARCH, Vol: 9, Pages: 208-222
Kang E-Y, Weir A, Meagher NS, et al., 2023, CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study, CANCER, Vol: 129, Pages: 697-713, ISSN: 0008-543X
Kasaven L, Jones BP, Ghaem-Maghami S, et al., 2022, Study protocol for a randomised controlled trial on the use of intra-operative Ultrasound Guided Laparoscopic Ovarian Cystectomy (UGLOC) as a method of fertility preservation in the management of benign ovarian cysts, BMJ Open, Vol: 12, ISSN: 2044-6055
Introduction: The lifetime risk of women undergoing surgery for the presence of benign ovarian pathology in the united kingdom (UK) is 5-10%. Despite minimally invasive surgical techniques, evidence suggests a number of healthy ovarian follicles and tissues are resected intraoperatively, resulting in subsequent decline of ovarian reserve. As such, there is an increasing demand for the implementation of fertility preservation surgery (FPS). This study will evaluate the effect on ovarian reserve following two different surgical interventions for the management of benign ovarian cysts. Methods and analysis: We will conduct a two-armed randomised controlled trial comparing laparoscopic ovarian cystectomy, considered gold standard treatment as per the Royal College of Obstetricians and Gynaecologists (RCOG) Green Top guidelines for the management of benign ovarian cysts, with ultrasound guided laparoscopic ovarian cystectomy (UGLOC), a novel method of FPS. The study commencement date was October 2021 and completion date October 2024. The primary outcome will be the difference in anti-Mullerian hormone (pmol/L) (AMH) and antral follicle count (AFC) measured 3 and 6 months post operatively from the pre-operative baseline. Secondary outcomes include assessment of various surgical and histopathological outcomes including: duration of hospital stay (days), duration of surgery (mins), presence of intra-operative cyst rupture (yes/no), presence of ovarian tissue within the specimen (yes/no) and the grade of follicles excised with specimen (grade 0-4). We aim to randomise 94 patients over 3 years to achieve power of 80% at an alpha level of 0.05.Ethics and dissemination: Findings will be published in peer reviewed journals and presented at national and international conferences and scientific meetings. The Chelsea NHS Research and Ethics Committee have awarded ethical approval of the study (21/LO/036).Trial registration number: NCT05032846
Kasaven L, Jones B, Saravelos S, et al., 2022, Reproductive outcomes in women with Borderline Ovarian Tumours. Does fertility treatment increase the risk of disease recurrence?, 38th Hybrid Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: I113-I113, ISSN: 0268-1161
Uthayanan L, El-Bahrawy M, 2022, Potential roles of claudin-3 and claudin-4 in ovarian cancer management, JOURNAL OF THE EGYPTIAN NATIONAL CANCER INSTITUTE, Vol: 34, ISSN: 1110-0362
Kang EY, Millstein J, Popovic G, et al., 2022, MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma, VIRCHOWS ARCHIV, Vol: 480, Pages: 855-871, ISSN: 0945-6317
Heinze K, Nazeran TM, Lee S, et al., 2022, Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas, JOURNAL OF PATHOLOGY, Vol: 256, Pages: 388-401, ISSN: 0022-3417
Uthayanan L, Wang Z, El-Bahrawy M, 2022, Expression of Claudin 3 and Claudin 4 in Serous Borderline Ovarian Tumours and Low-Grade Serous Ovarian Carcinomas, Virtual 4th Joint Winter Meeting of the Pathological-Society-of-Great-Britain-and-Ireland and the Royal-Society-of-Medicine, Publisher: WILEY, Pages: S12-S12, ISSN: 0022-3417
Kasaven L, Chawla M, Jones B, et al., 2022, Fertility sparing surgery and borderline ovarian tumours, Cancers, Vol: 14, ISSN: 2072-6694
o determine the oncological outcomes following fertility-sparing surgery (FSS) for the management of Borderline Ovarian Tumours (BOTs). A retrospective analysis of participants diagnosed with BOTs between January 2004 and December 2020 at the West London Gynaecological Oncology Centre was conducted. A total of 172 women were diagnosed; 52.3% (90/172) underwent FSS and 47.7% (82/172) non-FSS. The overall recurrence rate of disease was 16.9% (29/172), of which 79.3% (23/29) presented as the recurrence of serous or sero-mucinous BOTs and 20.7% (6/29) as low-grade serous carcinoma (LGSC). In the FSS group, the recurrence rate of BOTs was 25.6% (23/90) presenting a median 44.0 (interquartile range (IQR) 41.5) months, of which there were no episodes of recurrence presenting as LGSC reported. In the non-FSS group, all recurrences of disease presented as LGSC, with a rate of 7.7% (6/78), following a median of 47.5 months (IQR 47.8). A significant difference between the type of surgery performed (FSS v Non-FSS) and the association with recurrence of BOT was observed (Pearson Chi-Square: p = 0.000; x = 20.613). Twelve women underwent ultrasound-guided ovarian wedge resection (UGOWR) as a novel method of FSS. Recurrence of BOT was not significantly associated with the type of FSS performed (Pearson Chi- Square: x = 3.166, p = 0.379). Non-FSS is associated with negative oncological outcomes compared to FSS, as evidenced by the higher rate of recurrence of LGSC. This may be attributed to the indefinite long-term follow up with ultrasound surveillance all FSS women undergo, enabling earlier detection and treatment of recurrences.
Montinaro A, Areso Zubiaur I, Saggau J, et al., 2022, Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers, Cell Death and Differentiation, Vol: 29, Pages: 492-503, ISSN: 1350-9047
Primary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from a broad range of cancers, importantly without inducing detectable adverse events. Remarkably, the combination of TRAIL with CDK9 inhibition was also highly effective on cancers resistant to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Dynamic BH3 profiling revealed that, mechanistically, combining TRAIL with CDK9 inhibition induced a drastic increase in the mitochondrial priming of cancer cells. Intriguingly, this increase occurred irrespective of whether the cancer cells were sensitive or resistant to chemo- or targeted therapy. We conclude that this pro-apoptotic combination therapy has the potential to serve as a highly effective new treatment option for a variety of different cancers. Notably, this includes cancers that are resistant to currently available treatment modalities.
Zhou Y, El-Bahrawy M, 2021, Gene fusions in tumourigenesis with particular reference to ovarian cancer, JOURNAL OF MEDICAL GENETICS, Vol: 58, Pages: 789-795, ISSN: 0022-2593
Khalid S, El-Bahrawy M, 2021, Primary lesions of the appendix in patients undergoing cytoreductive surgery for gynaecological malignancies, 13th Joint Meeting of the British Division of the International Academy of Pathology and the Pathological Society of Great Britain & Ireland, Publisher: Pathological Society of Great Britain and Ireland, Pages: S23-S23, ISSN: 0022-3417
BackgroundThe incidence of neoplasms of the appendix is low and accounts for 1% of all cancers.It is often an incidental finding, detected in 0.2 - 0.3% of all appendicectomyspecimens.PurposeWe studied the incidence of primary lesions of the appendix in a cohort of patientswho underwent appendicectomy as part of cytoreductive surgery for gynaecologicalmalignancies.MethodsA total of 182 cases were identified from the database of the Department ofHistopathology over the course of 6 years (2015-2020). The histopathology reports forthese cases were reviewed, and data including patient age, primary gynaecologicalcancer type, macroscopic abnormality in appendix, presence of a primary lesion of theappendix and its type was collated.ResultsThe median age of the entire cohort was 54 years (range 17-83 years). An appendiceallesion was identified in 12/182 cases (0.5%), whose median age was 61years (range48-77 years).The appendiceal pathology included low grade appendiceal neoplasm in 4/12 (33%),well differentiated (grade 1) neuroendocrine tumour in 2/12 (17%), sessile serratedlesion with no dysplasia in 4/12 (33%) and hyperplastic polyp in 2/12 (17%) cases.There was no association with any particular gynaecological cancer type with thepresence of appendiceal lesions. A macroscopic abnormality in the form of dilatationof appendix was noted in one of the 12 cases (8%). A tumour nodule was identifiedgrossly in another case whilst metastatic tumour deposits were confirmedmicroscopically in 4/12 cases (33%).ConclusionAppendicectomy in the course of cytoreductive surgery provides an opportunity toidentify occult primary appendiceal lesions, particularly in patients over the age of 45.Appendiceal lesions are most often an incidental finding and given the poorcorrelation between gross appearance of the appendix and microscopic findings in themajority of these lesions, the entire appendix should be submitted for histologicalassessment.
Southern A, El-Bahrawy M, 2021, Advances in understanding the molecular pathology of gynecological malignancies: the role and potential of RNA sequencing, International Journal of Gynecological Cancer, Vol: 31, Pages: 1159-1164, ISSN: 1048-891X
For many years technological limitations restricted the progress of identifying the underlying genetic causes of gynecologicalcancers. However, during the past decade, high-throughput next-generation sequencing technologies have revolutionized cancer research. RNA sequencing has arisen as a very useful technique in expanding our understanding of genome changes in cancer. Cancer is characterized by the accumulation of genetic alterations affecting genes, including substitutions, insertions, deletions, translocations, gene fusions, and alternative splicing. If these aberrant genes become transcribed, aberrations can be detected by RNA sequencing, which will also provide information on the transcript abundance revealing the expression levels of the aberrant genes. RNA sequencing is considered the technique of choice when studying gene expression and identifying new RNA species. This is due to the quantitative and qualitative improvement that it has brought to transcriptome analysis, offering a resolution that allows research into different layers of transcriptome complexity. It has also been successful in identifying biomarkers, fusion genes, tumor suppressors, and uncovering new targets responsible for drug resistance in gynecological cancers. To illustrate that we here review the role of RNA sequencing in studies that enhanced our understanding of the molecular pathology of gynecological cancers.
Olusoji MJ, Magdy N, Wang J, et al., 2021, Expression of MEL-CAM and HSD3B1 in cervical carcinoma, Pathology International, Vol: 71, Pages: 561-563, ISSN: 1320-5463
Bennett JA, Young RH, Howitt BE, et al., 2021, A distinctive adnexal (usually paratubal) neoplasm often associated with peutz-jeghers syndrome and characterized by STK11 alterations (STK11 adnexal tumor): a report of 22 cases., American Journal of Surgical Pathology, Vol: 45, Pages: 1061-1074, ISSN: 0147-5185
We describe 22 examples of a novel, usually paratubal, adnexal tumor associated with Peutz-Jeghers syndrome in nearly 50% of cases that harbored STK11 alterations in all tested (n=21). The patients ranged from 17 to 66 years (median=39 y) and the tumors from 4.5 to 25.5 cm (median=11 cm). Most (n=18) were paratubal, with metastases noted in 11/22 (50%) and recurrences in 12/15 (80%). Morphologically, they were characterized by interanastomosing cords and trabeculae of predominantly epithelioid cells, set in a variably prominent myxoid to focally edematous stroma, that often merged to form tubular, cystic, cribriform, and microacinar formations, reminiscent of salivary gland-type tumors. The tumor cells were uniformly atypical, often with prominent nucleoli and a variable mitotic index (median=9/10 HPFs). The tumors were usually positive to a variable extent for epithelial (CAM5.2, AE1/AE3, cytokeratin 7), sex cord (calretinin, inhibin, WT1), and mesothelial (calretinin, D2-40) markers, as well as hormone receptors. PAX8, SF1, and GATA-3 were rarely positive, while claudin-4, FOXL2, and TTF-1 were consistently negative. All sequenced tumors (n=21) harbored alterations in STK11, often with a loss of heterozygosity event. There were no other recurrently mutated genes. Recurrent copy number alterations included loss of 1p and 11q, and gain of 1q, 15q, and 15p. Despite an extensive morphologic, immunohistochemical, and molecular evaluation, we are unable to determine with certainty the histogenesis of this unique tumor. Wolffian, sex cord stromal, epithelial, and mesothelial origins were considered. We propose the term STK11 adnexal tumor to describe this novel entity and emphasize the importance of genetic counseling in these patients as a significant number of neoplasms occur in association with Peutz-Jeghers syndrome.
Senn D, Videira H, Haagsma B, et al., 2021, Sex Cord Tumour with Annular Tubules-An Unusual Case of Abdominal Pain, JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA, Vol: 43, Pages: 361-364, ISSN: 1701-2163
Al Harbi R, McNeish IA, El-Bahrawy M, 2021, Ovarian sex cord-stromal tumors: an update on clinical features, molecular changes, and management, International Journal of Gynecological Cancer, Vol: 31, Pages: 161-168, ISSN: 1048-891X
Sex cord stromal-tumors are rare tumors of the ovary that include numerous tumor subtypes of variable histological features and biological behavior. Surgery is the main therapeutic modality for the management of these tumors, while chemotherapy and hormonal therapy may be used in some patients with progressive and recurrent tumors. Several studies investigated molecular changes in the different tumor types. Understanding molecular changes underlying the development and progression of sex cord-stromal tumors provides valuable information for diagnostic and prognostic biomarkers and potential therapeutic targets for these tumors. In this review, we provide an update on the clinical presentation, molecular changes, and management of sex cord-stromal tumors.
Masood M, Grimm S, El-Bahrawy M, et al., 2020, TMEFF2: A transmembrane proteoglycan with multifaceted actions in cancer and disease, Cancers, Vol: 12, Pages: 1-25, ISSN: 2072-6694
Transmembrane protein with an EGF-like and two Follistatin-like domains 2 (TMEFF2) is a 374-residue long type-I transmembrane proteoglycan which is proteolytically shed from the cell surface. The protein is involved in a range of functions including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 is methylated in numerous cancers, and an inverse correlation with the stage, response to therapy and survival outcome has been observed. Moreover, TMEFF2 methylation increases with breast, colon and gastric cancer progression. TMEFF2 is methylated early during oncogenesis in breast and colorectal cancer, and the detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Interestingly, through binding the amyloid β protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer’s disease. Despite undergoing extensive investigation over the last two decades, the primary literature regarding TMEFF2 is incoherent and offers conflicting information, in particular, the oncogenic vs. onco-suppressive role of TMEFF2 in prostate cancer. For the first time, we have compiled, contextualised and critically analysed the vast body of TMEFF2-related literature and answered the apparent discrepancies regarding its function, tissue expression, intracellular localization and oncogenic vs. onco-suppressive role.
Jones GG, Del Rio IB, Sari S, et al., 2020, The SHOC2 phosphatase complex as a therapeutic target for ERK-pathway inhibition in RAS-driven tumors., AACR Special Conference on Targeting RAS-Driven Cancers, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 65-66, ISSN: 1541-7786
Bennett J, Meserve E, Howitt B, et al., 2020, Unusual Adnexal Tumors with Recurring STK11 Mutations: A Clinicopathological Study of 11 Cases Including 4 in Patients with Peutz-Jeghers Syndrome, 109th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP), Publisher: NATURE PUBLISHING GROUP, Pages: 1016-1017, ISSN: 0023-6837
Sharma H, Turner CE, Siggins MK, et al., 2019, Toxic shock syndrome toxin-1 evaluation and antibiotic impact in a transgenic model of staphylococcal soft tissue infection, mSphere, Vol: 4, ISSN: 2379-5042
Nonmenstrual toxic shock syndrome (nmTSS), linked to TSST-1-producing CC30 Staphylococcus aureus, is the leading manifestation of toxic shock syndrome (TSS). Due to case rarity and a lack of tractable animal models, TSS pathogenesis is poorly understood. We developed an S. aureus abscess model in HLA class II transgenic mice to investigate pathogenesis and treatment. TSST-1 sensitivity was established using murine spleen cell proliferation assays and cytokine assays following TSST-1 injection in vivo. HLA-DQ8 mice were infected subcutaneously with a tst-positive CC30 methicillin-sensitive S. aureus clinical TSS-associated isolate. Mice received intraperitoneal flucloxacillin, clindamycin, flucloxacillin and clindamycin, or a control reagent. Abscess size, bacterial counts, TSST-1 expression, and TSST-1 bioactivity were measured in tissues. Antibiotic effects were compared with the effects of control reagent. Purified TSST-1 expanded HLA-DQ8 T-cell Vβ subsets 3 and 13 in vitro and instigated cytokine release in vivo, confirming TSST-1 sensitivity. TSST-1 was detected in abscesses (0 to 8.0 μg/ml) and draining lymph nodes (0 to 0.2 μg/ml) of infected mice. Interleukin 6 (IL-6), gamma interferon (IFN-γ), KC (CXCL1), and MCP-1 were consistent markers of inflammation during infection. Clindamycin-containing antibiotic regimens reduced abscess size and TSST-1 production. Infection led to detectable TSST-1 in soft tissues, and TSST-1 was detected in draining lymph nodes, events which may be pivotal to TSS pathogenesis. The reduction in TSST-1 production and lesion size after a single dose of clindamycin underscores a potential role for adjunctive clindamycin at the start of treatment of patients suspected of having TSS to alter disease progression.
Meagher NS, Wang L, Rambau PF, et al., 2019, A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases, Modern Pathology, Vol: 32, Pages: 1834-1846, ISSN: 0893-3952
Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7−/CK20+/CDX2+/PAX8−. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1–50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this wa
Jones GG, del Rio IB, Sari S, et al., 2019, SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers, Nature Communications, Vol: 10, Pages: 1-16, ISSN: 2041-1723
Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors.
Huang GS, Merritt MA, Hutson A, et al., 2019, Sex hormone, insulin, and insulin-like growth factor signaling in recurrence of high stage endometrial cancer: Results from the NRG Oncology/Gynecologic Oncology Group 210 trial., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Wang J, Gerrard G, Poskitt B, et al., 2019, Targeted next generation sequencing of pancreatic solid pseudopapillary neoplasms show mutations in Wnt signaling pathway genes, Pathology International, Vol: 69, Pages: 193-201, ISSN: 1320-5463
Solid pseudopapillary neoplasms of the pancreas are rare neoplasms that have been shown to harbor recurrent somatic pathogenic variants in the beta-catenin gene, CTNNB1. Here, we used targeted next generation sequencing to analyze these tumors for other associated mutations. Six cases of solid pseudopapillary neoplasms were studied. DNA extracted from formalin-fixed paraffin embedded tissue blocks was analyzed using the Ion Torrent platform, with the 50-gene Ampliseq Cancer Hotspot Panel v2 (CHPv2), with further variant validation performed by Sanger sequencing. Four tumors (67%) were confirmed to harbor mutations within CTNNB1, two with c.109T > G p.(Ser37Ala) and two with c.94G > A p.(Asp32Asn). One case showed a frameshift deletion in the Adenomatous Polyposis Coli gene, APC c.3964delG p.(Glu1322Lysfs*93) with a variant allele frequency of 42.6%. Sanger sequencing on non-tumoral tissue confirmed the variant was somatic. The patient with the APC mutation developed metastasis and died. In addition to the four cases harboring CTNNB1 variants, we found a case characterized by poor outcome, showing a rare frameshift deletion in the APC gene. Since the APC product interacts with beta-catenin, APC variants may, in addition to CTNNB1, contribute to the pathogenesis of solid pseudopapillary neoplasms via the Wnt signaling pathway.
Atinga A, El-Bahrawy M, Stewart V, et al., 2019, Superficial myofibroblastoma of the genital tract: a case report of the imaging findings, BJR Case Reports, Vol: 5, Pages: 1-4, ISSN: 2055-7159
Superficial angiomyofibroblastomas are mesenchymal tumours that occur in the genital tract and are well described pathologically. This case report reviews the imaging appearances and highlights the MRI findings, which have not been previously described. We describe the occurrence of this lesion in a vaginal cyst, which to the authors’ knowledge, has also not been previously described. The histological findings are also presented here.IntroductionMesenchymal tumours of the female genital tract are well described pathologically but the imaging findings are less well documented. We present a case of an unusual mesenchymal tumour of the female genital tract, highlight the key sonographic and MRI findings and summarise the current diagnostic and management approach.Clinical historyA 50-year-old female presented with a history of prolonged menstrual bleeding and right iliac fossa discomfort. Her past medical history of note included endometriosis, a partially septate uterus and two previous lower segment cesarean sections. She had no allergies and denied any relevant drug history such as tamoxifen or hormonal therapy use.Imaging findingsInitial pelvic ultrasound demonstrated normal uterus and ovaries, but detected a 13 mm vascular soft tissue nodule in a 28 × 20 × 25 mm cystic lesion in the left posterior vaginal fornix (Figure 1). The differential diagnosis at this time included a cervical or high vaginal polyp or an endometrioma, although the solid vascular component was unusual for the latter.
Rambau PF, Vierkant RA, Intermaggio MP, et al., 2018, Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study, Journal of Pathology: Clinical Research, Vol: 4, Pages: 250-261, ISSN: 2056-4538
We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6,525 ovarian carcinomas including 4,334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (N=2,280) mostly representing HGSC (N=2,010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell (HR: 2.02, 95%CI 1.47-2.77, p< 0.001) and endometrioid (HR: 1.88, 95%CI 1.30- 2.75, p=0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95%CI 1.61-5.38, p=0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition. This article is protected by copyright. All rights reserved.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.