H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair

Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets—a narrative review

Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo- or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosis-associated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinum-resistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future

Prognostic significance and predictors of the neutrophil-to-lymphocyte ratio in ovarian cancer

Objective: To investigate the neutrophil-to-lymphocyte ratio (NLR) from peripheral blood, a general measure of inflammation, in ovarian cancer. Methods: White cell counts and CA125 levels before treatment, tumor features, and questionnaire data on 519 women with ovarian cancer at two Boston hospitals were recorded. Counts were log-transformed and effects on these by tumor features and epidemiologic variables assessed by analysis of variance and generalized linear models. Cox proportional hazards models were used to assess effects on overall survival. Results: Greater NLR was associated with higher tumor stage and grade, presence of ascites, and bilateral disease and correlated with risk factors including Jewish ethnicity, taller height, more ovulatory cycles, and family history of cancer in premenopausal women and talc use in all women. CA125 was positively correlated with neutrophil count, monocyte count, and NLR and inversely correlated with lymphocyte count. In a multivariate adjusted analysis, high NLR predicted poorer survival and high lymphocyte count better survival. Conclusion: An elevated NLR before treatment signals more aggressive disease and correlates with risk factors for ovarian cancer. CA125 directly correlates with neutrophils which may reflect secretion of both CA125 and neutrophilic growth factors by the tumor. CA125 inversely correlates with lymphocytes which may reflect the ability of some neutrophilic factors to induce lymphopenia and/or binding of CA125 to lymphocytes removing CA125 from the serum pool. Links between NLR, CA125, and epidemiologic factors may provide new clues about the pathogenesis and progression of ovarian cancer

Changes of health-related quality of life 6 months after high-risk oncological upper gastrointestinal and hepatobiliary surgery: a single-centre prospective observational study (ChangeQol Study)

Introduction Postoperative health-related quality of life (HRQoL) is an essential outcome in oncological surgery, particularly for elderly patients undergoing high-risk surgery. Previous studies have suggested that, on average, HRQoL returns to premorbid normal levels in the months following major surgery. However, the averaging of effect over a studied cohort may hide the variation of individual HRQoL changes. The proportions of patients who have a varied HRQoL response (stable, improvement, or a deterioration) after major oncological surgery is poorly understood. The study aims to describe the patterns of these HRQoL changes at 6 months after surgery, and to assess the patients and next-of-kin regret regarding the decision to undergo surgery.Methods and analysis This prospective observational cohort study is carried out at the University Hospitals of Geneva, Switzerland. We include patients over 18 years old undergoing gastrectomy, esophagectomy, pancreas resection or hepatectomy. The primary outcome is the proportion of patients in each group with changes in HRQoL (improvement, stability or deterioration) 6 months after surgery, using a validated minimal clinically important difference of 10 points in HRQoL. The secondary outcome is to assess whether patients and their next-of-kin may regret their decision to undergo surgery at 6 months. We measure the HRQoL using the EORTC QLQ-C30 questionnaire before and 6 months after surgery. We assess regret with the Decision Regret Scale (DRS) at 6 months after surgery. Key other perioperative data include preoperative and postoperative place of residence, preoperative anxiety and depression (HADS scale), preoperative disability (WHODAS V.2.0), preoperative frailty (Clinical Frailty Scale), preoperative cognitive function (Mini-Mental State Examination) and preoperative comorbidities. A follow-up at 12 months is planned.Ethics and dissemination The study was first approved by the Geneva Ethical Committee for Research (ID 2020-00536) on 28 April 2020. The results of this study will be presented at national and international scientific meetings, and publications will be submitted to an open-access peer-reviewed journal.Trial registration number NCT04444544

Prior appendectomy does not protect against subsequent development of malignant or borderline mucinous ovarian neoplasms

Background Due to concern that mucinous malignant or borderline ovarian neoplasms (MON) may represent metastatic deposits from appendiceal primaries, gynecologic oncologists routinely perform appendectomy in these cases. However, a multidisciplinary critique of this practice is lacking. Methods The New England Case-Control study database was utilized to compare the effect of prior appendectomy against known risk factors for MON. Pathology and operative reports of local cases of MON were reviewed to estimate the frequency of microscopic mucinous lesions in the appendix. Protein expression patterns among mucinous ovarian, colorectal, and appendiceal cancers were compared by immunohistochemistry. Results From the New England Case-Control study, 287 cases of MON were compared against 2,339 age-matched controls. Prior appendectomy did not reduce the risk of MON (OR 1.28, 95% CI 0.83–1.92, p=0.23), while prior tubal ligation, parity, and breastfeeding were each protective against MON. Active smoking (OR 2.04, 95% CI 1.48–2.80, p<0.001) was associated with an increased risk of MON. Among 196 mucinous adnexal tumors, appendectomy did not reclassify any MON as appendiceal in origin. By immunohistochemistry, mucinous ovarian carcinomas tended to be CK7+/CK20-/MUC2-/CDX2-, whereas mucinous colorectal and appendiceal adenocarcinomas were typically CK7-/CK20+/MUC2+/CDX2+, although with some overlap in immunophenotype. Additionally, PAX8 was positive in a subset of MOC and negative in all appendiceal carcinomas. Conclusion Prior appendectomy is not protective against development of malignant or borderline MON. Routine appendectomy during surgery for MON seldom reveals an unsuspected GI primary in early stage tumors but may aid in final diagnosis in advanced stage cases

Elafin drives poor outcome in high grade serous ovarian cancers and basal-like breast tumors

High grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirmed that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies, and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting

H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours.

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair

Primordial germ cells as a potential shared cell of origin for mucinous cystic neoplasms of the pancreas and mucinous ovarian tumors

Mucinous ovarian tumors (MOTs) morphologically and epidemiologically resemble mucinous cystic neoplasms (MCNs) of the pancreas, sharing a similar stroma and both occurring disproportionately among young females. Additionally, MOTs and MCNs share similar clinical characteristics and immunohistochemical phenotypes. Exome sequencing has revealed frequent recurrent mutations in KRAS and RNF43 in both MOTs and MCNs. The cell of origin for these tumors remains unclear, but MOTs sometimes arise in the context of mature cystic teratomas and other primordial germ cell (PGC) tumors. We undertook the present study to investigate whether non-teratoma-associated MOTs and MCNs share a common cell of origin. Comparisons of the gene expression profiles of MOTs [including both the mucinous borderline ovarian tumors (MBOTs) and invasive mucinous ovarian carcinomas (MOCs)], high-grade serous ovarian carcinomas, ovarian surface epithelium, Fallopian tube epithelium, normal pancreatic tissue, pancreatic duct adenocarcinomas, MCNs, and single-cell RNA-sequencing of PGCs revealed that both MOTs and MCNs are more closely related to PGCs than to either eutopic epithelial tumors or normal epithelia. We hypothesize that MCNs may arise from PGCs that stopped in the dorsal pancreas during their descent to the gonads during early human embryogenesis, while MOTs arise from PGCs in the ovary. Together, these data suggest a common pathway for the development of MCNs and MOTs, and suggest that these tumors may be more properly classified as germ cell tumor variants

Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer

Patients with cancer experience a higher burden of SARS-CoV-2 infection, disease severity, complications, and mortality, than the general population. SARS-CoV-2 mRNA vaccines are highly effective in the general population; however, few data are available on their efficacy in patients with cancer. Using a prospective cohort, we assessed the seroconversion rates and anti-SARS-CoV-2 spike protein antibody titers following the first and second dose of BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines in patients with cancer in US and Europe from January to April 2021. Among 131 patients, most (94%) achieved seroconversion after receipt of two vaccine doses. Seroconversion rates and antibody titers in patients with hematological malignancy were significantly lower than those with solid tumors. None of the patients with history of anti-CD-20 antibody in the 6 months before vaccination developed antibody response. Antibody titers were highest for clinical surveillance or endocrine therapy groups and lowest for cytotoxic chemotherapy or monoclonal antibody groups