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DNMT3A, a member of the DNA methyltransferases family along with DNMT1 and DNMT3B, is located on chromosome 2p23. Recurrent somatic mutations in DNMT3A are typically heterozygous and found mostly in non-CBF AML, less frequently in MDS and MPN. DNMT3A mutations are reported with other common myeloid mutations including NPM1, FLT3 and IDH1/2. The most canonical DNMT3A mutations are missense alteration in the R882 codon, accounting for >60% of all DNMT3A mutations and they imply dominant negative consequences. Overall, DNMT3A mutations carry a poor prognosis compared to the AML or MDS with wild type (WT) DNMT3A, although data within different subgroups (e.g., incorporating cytogenetic profiles) are conflicting. We hypothesized that molecular consequence of R882 mutations will differ from those of other somatic alterations of DNMT3A and may also result in distinct clinical features and outcomes. To test this theory, we analyzed a cohort of 1174 patients with myeloid neoplasias including 32% AML, 33% MDS, 13% MDS/MPN, 6% MPN and 16% other bone marrow failure disorders. These cases were subjected to multiamplicon targeted deep NGS including all ORFs of DNMT3A and other recurrently mutated genes. After application of various bioanalytic algorithms, confirmatory sequencing and thus stringent exclusion of all artifacts and germline alterations, we identified 140 somatic mutant cases (12% of the cohort), including 89 missense mutations (53 at R882, 19 at R693 and 17 other non-canonical missense alterations) and 51 truncations/frame shifts (all heterozygous). There was an age-related increase in the incidence of DNMT3A mutations, with the peak occurrence at 35-40 yrs. of age. Mutations in DNMT3A were most common in AML (54% in primary (p) AML, 8% in secondary (s) AML) followed by MDS (28%), MDS/MPN (4%), MPN (3%) and other bone marrow failure disorders (3%). Mutation in the R693 codon and truncating mutations were most commonly associated with MDS (p=.013) and sAML (p=.0013) whereas mutation occurring in codon R882 and other non-canonical missense mutations were frequently associated with pAML (p=.00001). For the whole cohort, DNMT3A mutations were most frequently associated with NPM1 (21% vs 8%, p=.014), FLT3 (24% vs. 2%, p=.0001), and IDH1/2 (26% vs. 8%, p=.001), compared to wild type DNMT3A. However, PRC2 complex mutations were less likely to occur in the context of DNMT3A mutations (6% vs. 24%, p=.0006). Canonical R882 mutation was commonly associated with FLT3 (p=.03) mutations, while truncating mutations were not (p=.03). Analyses of clonal hierarchy by ranking of VAF values demonstrated that 53% of DNMT3A mutations were dominant (mean VAF 39%, range 5-93%) (n=74/140). When DNMT3A mutations were dominant, IDH 1/2 (14%), TET2 (9%), ASXL (5%), PRC2 complex (3%) and BCOR (3%) mutations were common secondary events. In subgroup analyses, 55% of mutations in the R693 codon were dominant compared to 45% in R882 and 47% in truncating mutations. TET2 mutations were the most common associated secondary hits in dominant R693 mutations (n=10) compared to truncating (n=24) and R882 mutations (n=23) (40% vs. 8% vs. none, p=.0001). When DNMT3A mutations are secondary (mean VAF 34%, range 1-60%), as in 47% of our cases (n=66/140), then the common first hits were TET2 (10%), U2AF1 (8%) and cohesin complex (RAD21, SMC3, STAG2) mutations (6%). Dominant DNMT3A mutations correlated with MDS/MPN (60%, p=.007), while secondary DNMT3A mutations correlated with sAML (73%, p=.001). DNMT3A mutant myeloid neoplasms showed worse survival (p DNTMT3A mutations often occur as founder lesion in AML. Our study shows that different types of mutations other than canonical R882 alterations may have a differential impact on OS and distinct clinical features. Disclosures Carraway: Celgene Corporation: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

2022Background: Brain metastasis (BM) is a rare but serious neurologic complication of gastro esophageal cancers (GEC). The Disease Specific Graded Prognostic Assessment (DS-GPA) which is based solely on Karnofsky performance scale (KPS) is a commonly used prognostic index in patients with BM. We evaluated DS-GPA and other potential prognostic factors for overall survival (OS) in GECBM at our institution. Methods: With IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify GECBM patients treated between 2002 and 2014. Overall survival (OS) from the diagnosis of GECBM was the primary endpoint. Cox proportional hazards models with stepwise variable selection were used to identify independent prognostic factors. Results: Sixty three patients with median age of 62 years (range; 33-79), were included for analysis. KPS was 90-100 in 22 patients (38%), 70-80 in 30 (52%) and 3 BM in ...

2005Background: Brain metastases (BM) are common serious complication of NSCLC. Activating mutations in EGFR and ALK constitute 10-15% and 5% of NSCLC respectively. Patients with multiple BM (≥4) have inferior outcomes compared to single or limited BM (≤ 3) in wild type NSCLC. There is limited information on impact of number of BM on EGFR and ALK positive NSCLC BM. Methods: With IRB approval, the Cleveland Clinic Neuro-Oncology Center’s database was used to identify patients treated between 2000-2014 for Non-Small Cell Lung Cancer (NSCLC) BM with mutational status (EGFR/ALK/wild). Overall survival (OS) from the diagnosis of BM was the primary end point. Cox proportional hazards models were used for data analysis. Results: 1032 NSCLC patients with BM were included in the analysis. Among 322 NSCLC BM with mutational analysis, 88 were positive for mutation (ALK = 21; EGFR = 67) and 234 were wild type. Median age at diagnosis in EGFR, ALK + NSCLC BM was 59.5 (range 29.8, 82.6) and 50.6% (43 patients) had KPS ...