Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. FindingsOf 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1•84, 95% CI 1•53-2•21), male sex (1•63, 1•07-2•48), smoking status (former smoker vs never smoked: 1•60, 1•03-2•47), number of comorbidities (two vs none: 4•50, 1•33-15•28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3•89, 2•11-7•18), active cancer (progressing vs remission: 5•20, 2•77-9•77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2•93, 1•79-4•79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0•24, 0•07-0•84) or the US-Midwest (0•50, 0•28-0•90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.

Protein phosphatase 2A (PP2A) has been implicated to exert its tumor suppressive function via a small subset of regulatory subunits. In this study, we reported that the specific B regulatory subunits of PP2A B56c1 and B56c3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56c protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56c protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56c3-mediated inhibition of cell proliferation and cell transformation. These results suggest a molecular mechanism for B56c-mediated tumor suppression and provide a potential route for regulation of B56c-specific PP2A complex function.

Earlier studies have demonstrated a functional link between B56␥-specific protein phosphatase 2A (B56␥-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56␥-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation. Although an enhanced interaction between p53 and B56␥ is observed after DNA damage, the underlying mechanism and its significance in PP2A tumor-suppressive function remain unclear. In this study, we show that the increased interaction between B56␥ and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56␥3-induced inhibition of cell proliferation, induction of cell cycle arrest in G 1 , and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56␥ interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56␥ interaction and the modulation of p53 tumor suppressor activity by PP2A. We also show an important link between ATM activity and the tumor-suppressive function of B56␥-PP2A.Protein phosphatase 2A (PP2A) is a very important family of holoenzyme complexes that functions within a diversity of signaling pathways inside the cell (9,21,26,27). PP2A consists of either a core complex containing a catalytic (C) subunit and scaffolding (A) subunit (29) or a trimer containing the AC core with one of many possible regulatory (B) subunits bound to it (30). The known B subunits have been divided into four gene families based on sequence homology: the B (B55 or PR55), BЈ (B56 or PR61), BЉ (PR48/59/72/130), and Bٞ (PR93/110) families (25). Each of these many B subunits can combine with the PP2A core to form complexes with distinct activities and substrate specificities. As such, PP2A is able to perform various functions in multiple regulatory pathways, depending on which B subunit is bound.In the past, PP2A was thought to have primarily dull housekeeping functions inside the cell. Recent studies, however, suggest that PP2A may have more-active regulatory roles and may actually function as a tumor suppressor under certain conditions. It is believed that a small subset of B subunits is most likely responsible for promoting this function of PP2A. In support of this view, at least two B56 subunit family members have been implicated in conferring tumor-suppressive functions on the holoenzyme. The B56 family consists of five different genes, ␣ (PPP2R5A), ␤ (PPP2R5B), ␥ (PPP2R5C), ␦ (PPP2R5D), and ε (PPP2R5E) (5, 16). In addition, the B56␥ gene encodes four differentially spliced forms, PP2A B56␥1, -␥2, -␥3 and -␥4 (17, 19). B56␦-specific PP2A was shown to function in a mitotic checkpoint in Xenopus laevis (15) and B56␥3-specific PP2A in blocking the proliferation of lung cancer cell lines (3). Importantly, evidence from our laboratory indicates that B56␥-PP2A participates in the activation of the tumor suppressor protein p53 af...

Earlier studies have demonstrated both p53-dependent and -independent tumor suppressive functions of B56γ-specific protein phosphatase 2A (B56γ-PP2A). In the absence of p53, B56γ-PP2A can inhibit cell proliferation and cell transformation by an unknown mechanism. In the presence of p53, upon DNA damage, a complex including B56γ-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and inhibition of cell proliferation. Despite its significance in inhibition of cell proliferation, no B56γ mutations have been linked to human cancer to date. In this study, we first differentiate between the p53-dependent and -independent functions of B56γ-PP2A by identifying a domain of the B56γ protein required for interaction with p53. Within this region we identify a B56γ mutation, F395C, in lung cancer that disrupts the B56γ-p53 interaction. More importantly, we show that F395C is unable to promote p53 Thr55 dephosphorylation, transcriptional activation of p21, and the p53-dependent tumor suppressive function of PP2A. This finding provides a mechanistic basis for the p53-dependent and -independent functions of B56γ-PP2A and establishes a critical link between B56γ-PP2A p53-dependent tumor suppressive function and tumorigenesis.

The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets.