Sex bias of females in survival from cancer and infections. Is X the answer?

Major differences in survival of men and women from infectious diseases and cancers have been highlighted by death rates from COVID-19 infections. In cancer, attention has been focussed on differences in gene expression from X chromosomes in men and women with a preponderance of genes involved in immune responses being expressed in women. Important findings have been that some of the genes are important epigenetic regulators that play fundamental roles in immune responses.Subject terms: Cancer epigenetics, Oncology

One of the striking features of the coronavirus disease 2019 (COVID-19) outbreak has been the higher death rates in men even though the infection rates seem similar between men and women.¹ Similar findings were reported from Wuhan where men had 2.4 times the death rate of women² and in New York where press releases stated twice the death rate of men compared with women.³ Although men had higher rates of comorbidities, these differences were not considered sufficient to explain the higher death rates and other explanations have been sort. Women are considered to have stronger immune responses against infective diseases and a higher rate of autoimmune diseases, so this has questioned whether the lower death rate may have an immune basis.A sex bias is not only seen in infections, but also in cancers where a strong sex bias in survival from cancer is well documented.^4,5 For example, women in Australia have approximately half the death rates from melanoma as males.⁶ A number of explanations have been proposed to account for these major differences in melanoma, such as higher sun exposure in males⁷ and higher mutation rates⁸ in melanoma from males. When stringent statistical analyses are carried out, however, female sex remains as the major contributor to longer survival.⁴Melanoma is not the only cancer to show improved survival in females and previous researchers have asked whether this may be due to differences in the sex chromosomes between male and females. In a mammoth study, Dunford and colleagues examined information in The Cancer Genome Atlas (TCGA) from 21 different tumour types from 4100 cancers.⁵ They found that 6 out of 783 X chromosome genes had loss-of-function mutations with tumour-suppressive function in males but not in females. There were no similar differences in 18,055 non-X autosomal genes. Importantly, four of the six genes were known epigenetic regulators, such as KDM6A (lysine-specific demethylase 6A), KDM5C (lysine-specific demethylase 5C), ATRX (Alpha thalassaemia/mental retardation syndrome X-linked) and DDX3X (DEAD-box helicase 3 X-linked).⁵These findings point to important differences in X chromosomes between the sexes. The Y chromosome codes mainly for genes that determine male sex, but X chromosomes are quite large and code for >800 genes many of which are involved in immune responses.⁹ To equalise the number of genes between the sexes, one of the X chromosomes in females undergoes inactivation (Xi) of its genes.¹⁰ The silencing process is, however, not perfect and between 10 and 20% of the genes on the X may be expressed in females depending on the tissue involved. It is probably of significance that failure to silence genes may be particularly high in activated lymphocytes.¹¹ As a result of this phenomenon, females have double expression of many genes involved in immune responses compared with males. Biologists have speculated that this is an evolutionary mechanism to protect the species by enhancing immune responses in females against harmful infections.Analysis of data in the TCGA on 458 melanoma patients revealed that KDM6A expression was strongly related to improved survival from melanoma in female patients. ATRX had prognostic significance in both sexes. Analysis of another series of 678 patients with earlier melanoma referred to as the Leeds Melanoma Cohort confirmed the association with KDM6A expression and also identified KDM5C and DDX3X as being related to improved survival.¹² Immune responses are known to be critical in survival from melanoma and the TCGA analysis allowed us to link high KDM6A to components of the immune system considered important in killing of melanoma. This was particularly so in the production of interferon γ in female patients which is a key cytokine needed by the immune system to kill cancer cells. Gene set analysis also showed downregulation of Myc and other oncogenic pathways that may have contributed to the improvement in survival.¹²These data add to a number of studies implicating KDM6A in immune responses against viral infections and in autoimmune diseases.¹³ At a molecular level, KDM6A is known to have an opposing role to EZH2 (enhancer of Zeste homologue 2) in the PRC2 complex in methylation of Lys 27 on H3 histone. This role may explain some of the effects of KDM6A on the immune system in that we previously reported that EZH2 was associated with the repression of several genes associated with antigen presentation and chemokines involved in T cell responses.¹⁴Although these studies are compelling in linking KDM6A to immune responses, it is still questionable whether it has a role in immune responses against COVID-19. If this was the case, we would expect that women being treated for severe COVID-19 infections in intensive care would have lower KDM6A expression than those with infections not requiring such care.¹⁵ We examined the RNA-seq data from blood samples of 102 COVID-19 patients. This included 38 women and 64 men, where 17 women and 34 men were admitted to intensive care unit. The analysis of KDM6A levels in the women showed that treatment in intensive care unit was associated with higher KDM6A expression ({"type":"entrez-geo","attrs":{"text":"GSE157103","term_id":"157103"}}GSE157103,¹⁵ data not shown). Although this was unexpected, it may indicate that KDM6A expression was linked to stronger responses causing higher inflammation in organs such as the lungs. No differences in KDM6A levels were detected in men irrespective of whether they were admitted to intensive care or not.Female patients with bi-allelic expression of KDM6A may induce the expression of interferon γ pathways which enhance anti-tumour immunity by recruiting immune modulatory cells (Fig. 1). These results point to the need for a better understanding of the role of X-linked genes in immune responses and whether EZH2-mediated suppression of immune modulatory genes have a role in infections as well as in cancer. In cancers and infections that have worst outcomes in males versus females, one approach might be to target (inhibit) the EZH2 epigenetic regulator that opposes KDM6A (Fig. 1). Another option may be to increase levels of KDM6A by administration of oestrogens. Oestrogen α receptors are expressed in practically all lymphocytes and were shown to physically interact with KDM6A to create a permissive chromatin state on endoplasmic reticulum (ER) targets such as C-X-C chemokine motif receptor 4.¹⁶ It was transactivated by ER to form a feed-forward loop. Administration of 17β-oestradiol has been suggested by others as treatment for COVID-19 infections.¹⁷Open in a separate windowFig. 1Proposed model of sex-biased role of the X-linked KDM6A gene in promoting immunity.Males harbour one X chromosome with no functional Y chromosome homologue. Hence, mutation in the X-linked epigenetic modifier KDM6A with tumour-suppressive or immunomodulatory role will probably lead to cancer or infection in males. Immune-related genes will be repressed by EZH2-mediated H3K27me3 deposition resulting in low KDM6A protein and immune evasion in male patients. In females, with two X chromosome, [one active (Xa) and one inactive (Xi)], a single mutation (m) in KDM6A is less likely to develop cancer or infections since another functional allele escapes X inactivation. Cells with high KDM6A level would be expected to demethylate H3K27me3 resulting in activation of the interferon γ pathway resulting in inactivation of natural killer (NK), dendritic or cytotoxic T cells to induce anti-tumour immunity and adaptive immunity against virus-infected cells.These studies have therefore raised many questions that require more detailed study to identify how the powerful survival benefits of the X-linked epigenetic regulators might be used to improve the therapeutic outcome in patients.     

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.Subject terms: Acute myeloid leukaemia, Targeted therapies     

Effects of cancer screening restart strategies after COVID-19 disruption

Background Many breast, cervical, and colorectal cancer screening programmes were disrupted due to the COVID-19 pandemic. This study aimed to estimate the effects of five restart strategies after the disruption on required screening capacity and cancer burden.Methods Microsimulation models simulated five restart strategies for breast, cervical, and colorectal cancer screening. The models estimated required screening capacity, cancer incidence, and cancer-specific mortality after a disruption of 6 months. The restart strategies varied in whether screens were caught up or not and, if so, immediately or delayed, and whether the upper age limit was increased.Results The disruption in screening programmes without catch-up of missed screens led to an increase of 2.0, 0.3, and 2.5 cancer deaths per 100 000 individuals in 10 years in breast, cervical, and colorectal cancer, respectively. Immediately catching-up missed screens minimised the impact of the disruption but required a surge in screening capacity. Delaying screening, but still offering all screening rounds gave the best balance between required capacity, incidence, and mortality.Conclusions Strategies with the smallest loss in health effects were also the most burdensome for the screening organisations. Which strategy is preferred depends on the organisation and available capacity in a country.Subject terms: Health policy, Population screening, Cancer screening, Cancer screening     

Chromosome 1q21 abnormalities in multiple myeloma

Gain of chromosome 1q (+1q) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM), occurring in approximately 40% of newly diagnosed cases. Although it is often considered a poor prognostic marker in MM, +1q has not been uniformly adopted as a high-risk cytogenetic abnormality in guidelines. Controversy exists regarding the importance of copy number, as well as whether +1q is itself a driver of poor outcomes or merely a common passenger genetic abnormality in biologically unstable disease. Although the identification of a clear pathogenic mechanism from +1q remains elusive, many genes at the 1q21 locus have been proposed to cause early progression and resistance to anti-myeloma therapy. The plethora of potential drivers suggests that +1q is not only a causative factor or poor outcomes in MM but may be targetable and/or predictive of response to novel therapies. This review will summarize our current understanding of the pathogenesis of +1q in plasma cell neoplasms, the impact of 1q copy number, identify potential genetic drivers of poor outcomes within this subset, and attempt to clarify its clinical significance and implications for the management of patients with multiple myeloma.Subject terms: Cancer genomics, Myeloma, Myeloma     

Long-term Implications of Tracheostomy in Cardiac Surgery Patients: Decannulation and Mortality

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The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAF^V600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.Subject terms: CNS cancer, Metastasis, Melanoma, Tumour biomarkers, Cancer     

Postprocedural Antiplatelet Treatment after Emergent Carotid Stenting in Tandem Lesions Stroke: Impact on Stent Patency beyond Day 1

BACKGROUND AND PURPOSE:Postprocedural dual-antiplatelet therapy is frequently withheld after emergent carotid stent placement during stroke thrombectomy. We aimed to assess whether antiplatelet regimen variations increase the risk of stent thrombosis beyond postprocedural day 1.MATERIALS AND METHODS:Retrospective review was undertaken of all consecutive thrombectomies for acute stroke with tandem lesions in the anterior circulation performed in a single comprehensive stroke center between January 9, 2011 and March 30, 2020. Patients were included if carotid stent patency was confirmed at day 1 postprocedure. The group of patients with continuous dual-antiplatelet therapy from day 1 was compared with the group of patients with absent/discontinued dual-antiplatelet therapy.RESULTS:Of a total of 109 tandem lesion thrombectomies, 96 patients had patent carotid stents at the end of the procedure. The early postprocedural stent thrombosis rate during the first 24 hours was 14/96 (14.5%). Of 82 patients with patent stents at day 1, in 28 (34.1%), dual-antiplatelet therapy was either not initiated at day 1 or was discontinued thereafter. After exclusion of cases without further controls of stent patency, there was no significant difference in the rate of subacute/late stent thrombosis between the 2 groups: 1/50 (2%) in patients with continuous dual-antiplatelet therapy versus 0/22 (0%) in patients with absent/discontinued dual-antiplatelet therapy (P = 1.000). In total, we observed 88 patient days without any antiplatelet treatment and 471 patient days with single antiplatelet treatment.CONCLUSIONS:Discontinuation of dual-antiplatelet therapy was not associated with an increased risk of stent thrombosis beyond postprocedural day 1. Further studies are warranted to better assess the additional benefit and optimal duration of dual-antiplatelet therapy after tandem lesion stroke thrombectomy.

In around 15% of endovascular procedures for anterior circulation stroke,¹ there is a tight stenosis or occlusion of the cervical carotid artery in addition to the intracranial artery occlusion. The optimal endovascular management of tandem lesions has yet to be defined; however, there is mounting evidence^2,3 that emergent stent placement in the carotid artery associated with at least 1 antiplatelet agent could lead to better recanalization rates and improved clinical outcomes. A more definitive answer should be provided by the Thrombectomy In TANdem lesions (TITAN) randomized multicenter trial,⁴ designed to assess the safety and efficacy of emergent internal carotid artery stent placement in tandem lesion thrombectomy. This study recently enrolled the first patient in early 2020.In patients undergoing emergent carotid stent placement, there is no consensus regarding the optimal periprocedural antiplatelet therapy. Many groups^5,6 chose to avoid dual-antiplatelet therapy (DAPT) during the first 24 hours in an attempt to reduce the risk of hemorrhagic transformation. Conversely, less aggressive antiplatelet regimens might increase the risk of carotid stent thrombosis.Stent thrombosis was recently identified as a predictor of unfavorable clinical outcome.^7,8 To date, available data regarding stent patency rates remain scarce. Most case series of endovascular management for tandem lesions^5,9-11 do not report postprocedural stent patency, while some publications^12-15 offer partial data for a subgroup of patients for whom carotid imaging controls were available. Reported rates of stent thrombosis ranged between 1.2% and 22.0%.^{6-8,12-14,16,17}To date, no study has attempted to differentiate between early (first 24 hours) and subacute/late postprocedural stent thrombosis. During the first 24 hours, protection against stent thrombosis is conferred by antiplatelet agents administered during the procedure (periprocedural antiplatelets). Beyond 24 hours, the recommended antiplatelet regimen is DAPT for 4–12 weeks,^9,17 but in reality, antiplatelets are often tailored in view of neurological and extra-neurological hemorrhagic events. It is currently unknown whether discontinuation of DAPT is associated with an increased risk of late stent thrombosis.Thus, we aimed to describe the variations in the postprocedural antiplatelet regimen in a large consecutive cohort of tandem lesion thrombectomies with emergent carotid artery stent placement and to assess whether discontinuation of DAPT was associated with an increased risk of carotid stent thrombosis.