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Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

Akiko Shimamura and colleagues report the identification of dominant-negative germline variants in ETV6 that cause thrombocytopenia and hematologic malignancies in the affected members of three families. All three mutations alter conserved amino acids in the transcriptional repressor encoded by ETV6 and affect its DNA binding. We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.

Post-transcriptional diversification of RNA transcripts mediated by complex processing machinery, including DEAD-box ATPases, establishes and maintains cellular phenotypes. For example, DDX41 controls RNA splicing, innate immune signaling, and genome stability. Although heterozygous DDX41 germline genetic variation occurs in familial myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the DDX41 contributions to splicing globally, biological processes, and pathogenic mechanisms are incompletely defined. Using a genetic rescue system with Ddx41 +/− myeloid progenitors, we established global wildtype DDX41 and pathogenic variant mechanisms. Differing from pathogenic variants of other RNA splicing regulators, DDX41 deficiency compromised multiple splicing steps. DDX41-regulated transcripts encoded factors controlling RNA splicing, including Cdc2-like kinase 3 (CLK3). DDX41 regulated Clk3 transcripts, and elevated CLK3 during myeloid differentiation. Loss-of-function analysis revealed DDX41-regulated splicing commonly, but not always, required CLK3. Thus, through a mechanism utilizing a splicing factor kinase that itself is DDX41-regulated, DDX41 establishes transcript ensembles in myeloid progenitors. Although DDX41 genetic variation occurs in myelodysplastic syndrome and acute myeloid leukemia, the pathogenic mechanisms remained unclear. Here, the authors found DDX41 regulates CLK3-dependent alternative splicing to establish transcript ensembles, while pathogenic variants limit the activity.

Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies. However, identification of these syndromes in routine pathology practice is often challenging, as characteristic findings associated with these diagnoses at baseline are frequently absent, nonspecific, or impossible to evaluate in the setting of a myeloid malignancy. Here we review the formally classified germline predisposition syndromes associated with myeloid malignancies and summarize practical recommendations for pathologists evaluating a new myeloid malignancy diagnosis. Our intent is to empower clinicians to better screen for germline disorders in this common clinical setting. Recognizing when to suspect a germline predisposition syndrome, pursue additional ancillary testing, and ultimately recommend referral to a cancer predisposition clinic or hematology specialist, will ensure optimal patient care and expedite research to improve outcomes for these individuals.

Background Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents. Methods We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito). Results Three (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m 2 ), and 17 (85%) received the target level of 80 mg (~ 50 mg/m 2 ). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%), cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction. Conclusion The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/m 2 /day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination. Trial registration ClinicalTrials.gov , NCT02573363 . Registered October 5, 2015

Current therapies for high-grade TP53 -mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53 -mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender ( P  = 0.026), ≥2 autosomal monosomies ( P  < 0.001), −17/17p ( P  = 0.011), multi-hit TP53 allelic state ( P  < 0.001) and CUX1 co-alterations ( P  = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies ( P  = 0.004), TP53 VAF > 25% ( P  = 0.002), TP53 splice junction mutations ( P  = 0.007) and antecedent treated myeloid neoplasm ( P  = 0.001). In addition, mutations/deletions in CUX1 , U2AF1 , EZH2 , TET2 , CBL , or KRAS (‘ EPI6 ’ signature) predicted inferior OS24 (HR = 2.0 [1.5–2.8]; P  < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals ( N  = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival ( P  < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

The initiation and evolution of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are driven by genomic events that disrupt multiple genes controlling hematopoiesis. Human genetic studies have discovered germline mutations in single genes that instigate familial MDS/AML. The best understood of these genes encode transcription factors, such as GATA-2, RUNX1, ETV6, and C/EBPα, which establish and maintain genetic networks governing the genesis and function of blood stem and progenitor cells. Many questions remain unanswered regarding how genes and circuits within these networks function in physiology and disease and whether network integrity is exquisitely sensitive to or efficiently buffered from perturbations. In familial MDS/AML, mutations change the coding sequence of a gene to generate a mutant protein with altered activity or introduce frameshifts or stop codons or disrupt regulatory elements to alter protein expression. Each mutation has the potential to exert quantitatively and qualitatively distinct influences on networks. Consistent with this mechanistic diversity, disease onset is unpredictable and phenotypic variability can be considerable. Efforts to elucidate mechanisms and forge prognostic and therapeutic strategies must therefore contend with a spectrum of patient-specific leukemogenic scenarios. Here we illustrate mechanistic advances in our understanding of familial MDS/AML syndromes caused by germline mutations of hematopoietic transcription factors.

Comprehensive genomic profiling of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cases have enabled the detection and differentiation of driver and subclonal mutations, informed risk prognostication, and defined targeted therapies. These insights into disease biology, and management have made multigene-acquired mutation testing a critical part of the diagnostic assessment of patients with sporadic MDS and AML. More recently, our understanding of the role of an increasing number of inherited genetic factors on MDS/AML risk and management has rapidly progressed. In recognition of the growing impact of this field, clinical guidelines and disease classification systems for both MDS and AML have recently incorporated familial MDS/AML predisposition syndromes into their diagnostic algorithms. In this perspective piece, we contemplate the advantages, disadvantages, and barriers that would need to be overcome to incorporate inherited MDS/AML genetic testing into the upfront molecular diagnostic work-up of every MDS/AML patient. For centers already performing panel-based tumor-only testing, including genes associated with familial forms of MDS/AML (e.g., RUNX1, CEBPA, GATA2, TP53), we advocate optimizing these tests to detect all types of germline variants in these genes and moving toward upfront paired tumor/germline testing to maximize detection and streamline patient care.

African Americans have a disproportionate burden of aggressive young-onset breast cancer. Genomic testing for inherited predisposition to breast cancer is increasingly common in clinical practice, but comprehensive mutation profiles remain unknown for most minority populations. We evaluated 289 patients who self-identified as African American with primary invasive breast cancer and with personal or family cancer history or tumor characteristics associated with high genetic risk for all classes of germline mutations in known breast cancer susceptibility genes using a validated targeted capture and multiplex sequencing approach. Sixty-eight damaging germline mutations were identified in 65 (22 %, 95 % CI 18–28 %) of the 289 subjects. Proportions of patients with unequivocally damaging mutations in a breast cancer gene were 26 % (47/180; 95 % confident interval [CI] 20–33 %) of those with breast cancer diagnosis before age 45; 25 % (26/103; 95 % CI 17–35 %) of those with triple-negative breast cancer (TNBC); 29 % (45/156; 95 % CI 22–37 %) of those with a first or second degree relative with breast cancer before age 60 or with ovarian cancer; and 57 % (4/7; 95 % CI 18–90 %) of those with both breast and ovarian cancer. Of patients with mutations, 80 % (52/65) carried mutations in BRCA1 and BRCA2 genes and 20 % (13/65) carried mutations in PALB2, CHEK2, BARD1, ATM, PTEN , or TP53 . The mutational allelic spectrum was highly heterogeneous, with 57 different mutations in 65 patients. Of patients meeting selection criteria other than family history (i.e., with young age at diagnosis or TNBC), 48 % (64/133) had very limited information about the history of cancer in previous generations of their families. Mutations in BRCA1 and BRCA2 or another breast cancer gene occur in one in four African American breast cancer patients with early onset disease, family history of breast or ovarian cancer, or TNBC. Each of these criteria defines patients who would benefit from genomic testing and novel therapies targeting DNA repair pathways.

Women who inherit a BRCA1 or BRCA2 mutation have an increased risk of breast cancer. Preliminary evidence suggests they may also have defects in bone marrow function. To test this hypothesis, we conducted a multicenter, retrospective, matched cohort study, comparing women with localized breast cancer requiring cytotoxic chemotherapy who carried an inherited BRCA1 or BRCA2 mutation to similar wild‐type patients treated between 1995 and 2017 and matched based on age, race, site, and chemotherapy regimen. The proportion who developed specific hematologic toxicities, timing of these toxicities, and patterns of blood count fluctuations over time were compared among BRCA1 carriers vs matched wild‐type patients and among BRCA2 carriers vs matched wild‐type patients. 88 BRCA1 carriers and 75 BRCA2 carriers were matched to 226 and 242 wild‐type patients, respectively. The proportions and timing of experiencing any grade or grade 3/4 cytopenias during chemotherapy were not significantly different for BRCA1 carriers or BRCA2 carriers vs matched wild‐type patients. Proportions requiring treatment modifications and time to first modification were also similar. Patterns of blood count fluctuations over time in mutation carriers mirrored those in wild‐type patients overall and by the most common regimens. Women with an inherited mutation in BRCA1 or BRCA2 experience similar frequency, severity, and timing of hematologic toxicities during curative intent breast cancer chemotherapy as matched wild‐type patients. Our findings suggest that BRCA1 or BRCA2 haploinsufficiency is sufficient for adequate bone marrow reserve in the face of short‐term repetitive hematopoietic stressors. In this multicenter, retrospective, matched cohort study, we investigated whether women with an inherited mutation in BRCA1 or BRCA2 experience more severe hematologic toxicities during curative intent chemotherapy for breast cancer than similar women without a mutation. We found that the frequency, severity, and timing of toxicities were similar in these two groups. This study is reassuring that women with an inherited mutation are able to tolerate the repetitive bone marrow stress of modern chemotherapy regimens with usual supportive care measures as well as those without a mutation.