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Supplementary Methods, Supplementary References Supplementary Table S1: Inherited regions of homozygosity in >1% of 1,798 non-leukemic individuals Supplementary Table S2: Acquired uniparental disomies detected in 425 cytogenetically normal AML patients Supplementary Table S3. Associations between recurrent UPDs with pretreatment patient characteristics for patients with cytogenetically normal acute myeloid leukemia Supplementary Table S5. Variant allele fraction of gene mutations that co-occurred with UPDs Supplementary Table S6. Allelic ratio of FLT3 internal tandem duplications that co-occurred with UPDs Supplementary Table S7: Copy number gains and losses in 425 patients with cytogenetically normal acute myeloid leukemia

Purpose:Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.Results:We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P < 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.Conclusions:LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.

Mutations detected in 425 CN-AML patients

BackgroundPapillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination of low penetrance variants. A recent genome-wide association study revealed the association of PTC with a missense variant, rs6793295, at 3q26 in a gene called Leucine Repeat Rich Containing 34 (LRRC34).MethodsWe report the mechanisms of PTC risk at 3q26 using a combination of overexpression, mass spectroscopy, knockdown, transcriptome profiling, migration assays and genetic analysis.ResultsWe observed differential binding of wild-type and missense LRRC34 to RANBP1. Overexpression of missense LRRC34 reduced RanGTP levels and increased apoptosis. We also identified a second linkage disequilibrium (LD) block upstream of LRRC34 containing regulatory variants with allele-specific expression. Transcriptome profiling of LRRC34 knockdown cells showed changes in genes involved with cellular movement. LRRC34 knockdown reduced the migration of thyroid cancer cell lines. Lastly, we assessed the relative contribution of PTC risk from each locus using haplotype analysis.ConclusionsOur study demonstrates two separate mechanisms, one in G protein signalling and the other in transcriptional control, dictating PTC risk at 3q26 using both biochemical and genetic techniques.

Purpose:Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.Results:We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P < 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.Conclusions:LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.

Background: Thyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease. Methods: Whole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAF(V600E), NRAS(Q61R), and HRAS(Q61R) in AA patients whose primary tumor samples were available (28/55). Results: TG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAF(V600E) appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of

Although ∼80% of adult patients with cytogenetically normal acute myeloid leukemia (CN-AML) achieve a complete remission (CR), more than half of them relapse. Better identification of patients who are likely to relapse can help to inform clinical decisions. We performed RNA sequencing on pretreatment samples from 268 adults with de novo CN-AML who were younger than 60 years of age and achieved a CR after induction treatment with standard “7+3” chemotherapy. After filtering for genes whose expressions were associated with gene mutations known to impact outcome (ie, CEBPA, NPM1, and FLT3-internal tandem duplication [FLT3-ITD]), we identified a 10-gene signature that was strongly predictive of patient relapse (area under the receiver operating characteristics curve [AUC], 0.81). The signature consisted of 7 coding genes (GAS6, PSD3, PLCB4, DEXI, JMY, NRP1, C10orf55) and 3 long noncoding RNAs. In multivariable analysis, the 10-gene signature was strongly associated with relapse (P < .001), after adjustment for the FLT3-ITD, CEBPA, and NPM1 mutational status. Validation of the expression signature in an independent patient set from The Cancer Genome Atlas showed the signature’s strong predictive value, with AUC = 0.78. Implementation of the 10-gene signature into clinical prognostic stratification could be useful for identifying patients who are likely to relapse.

To identify and characterize the functional variants, regulatory gene networks, and potential binding targets of SMAD3 in the 15q22 thyroid cancer risk locus. We performed linkage disequilibrium (LD) and haplotype analyses to fine map the 15q22 locus. Luciferase reporter assays were applied to evaluate the regulatory effects of the candidate variants. Knockdown by small interfering RNA, microarray analysis, chromatin immunoprecipitation (ChIP) and quantitative real-time polymerase chain reaction assays were performed to reveal the regulatory gene network and identify its binding targets. We report a 25.6-kb haplotype within SMAD3 containing numerous single-nucleotide polymorphisms (SNPs) in high LD. SNPs rs17293632 and rs4562997 were identified as functional variants of SMAD3 by luciferase assays within the LD region. These variants regulate SMAD3 transcription in an allele-specific manner through enhancer elements in introns of SMAD3. Knockdown of SMAD3 in thyroid cancer cell lines revealed its regulatory gene network including two upregulated genes, SPRY4 and SPRY4-IT1. Sequence analysis and ChIP assays validated the actual binding of SMAD3 protein to multiple SMAD binding element sites in the region upstream of SPRY4. Our data provide a functional annotation of the 15q22 thyroid cancer risk locus.

Background: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in APC is controversial. Methods: Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. Results: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in APC. Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Conclusions: Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.

Papillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination of low penetrance variants. A recent genome-wide association study revealed the association of PTC with a missense variant, rs6793295, at 3q26 in a gene called Leucine Repeat Rich Containing 34 (We report the mechanisms of PTC risk at 3q26 using a combination of overexpression, mass spectroscopy, knockdown, transcriptome profiling, migration assays and genetic analysis.We observed differential binding of wild-type and missense LRRC34 to RANBP1. Overexpression of missense LRRC34 reduced RanGTP levels and increased apoptosis. We also identified a second linkage disequilibrium (LD) block upstream ofOur study demonstrates two separate mechanisms, one in G protein signalling and the other in transcriptional control, dictating PTC risk at 3q26 using both biochemical and genetic techniques.

Background: Inactivation of DNA mismatch repair (MMR) and the resulting microsatellite instability (MSI) are frequently observed in endometrial, stomach, and colorectal cancers, as well as more rarely in other solid tumor types. The prevalence of MSI in thyroid cancer has not been explored in depth, although recent studies utilizing data from large cancer sequencing efforts such as The Cancer Genome Atlas indicate that MSI is absent or at least very rare in the most common and most well studied histologic subtype, papillary thyroid carcinoma. This study aimed to determine the prevalence of MSI in thyroid cancer by using a large series comprising all major histological subtypes. Methods: A total of 485 thyroid cancer patients were screened for MSI/MMR deficiency, including all major histologic subtypes (195 papillary thyroid carcinoma, 156 follicular thyroid carcinoma [FTC], 50 anaplastic thyroid carcinoma, 65 medullary thyroid carcinoma, and 17 poorly differentiated thyroid carcinomas) by using a combination of polymerase chain reaction–based detection, immunohistochemistry, and next-generation sequencing. Results: A total of four tumors were MSI-high and had loss of MMR protein expression, all of which were from FTC patients. Whole-exome sequencing was performed on two MSI-high FTCs and revealed a hemizygous loss of function mutation in MSH2 in one tumor. Conclusions: Based on these data, it is estimated that the overall prevalence of MSI in FTC is 2.5%, and MSI is either entirely absent or rare in other histology subtypes of thyroid carcinoma. These findings highlight the importance of testing for MSI in FTC.

Approximately 20% of CN-AML patients (pts) younger than 60 years treated with current standard intensive combination chemotherapy regimens have primary refractory disease, and among pts who achieve a complete remission (CR), over half relapse. Thus, early detection of pts with low likelihood of achieving a CR and those with a high likelihood of relapsing is of crucial importance. To identify molecular profiles associated with achieving and maintaining CR, we performed total transcriptome RNA sequencing and targeted DNA sequencing of 82 cancer- and leukemia-associated genes on pretreatment blood or bone marrow samples from 341 CN-AML pts less than 60 years old, similarly treated with intensive chemotherapy on Cancer and Leukemia Group B / Alliance for Clinical Trials in Oncology therapeutic trials. Pts who died within 30 days of diagnosis were excluded. Pts were classified into 3 mutually exclusive outcome groups: primary refractory (n=55, 16% of pts), pts who achieved a CR but later relapsed (n=165, 48%) and pts who remained in CR for the duration of this study (n=121, 35%). Gene-level differential expression analysis between the 3 groups was performed after removing low-expressed genes, and a set of 385 genes met significance criteria (adjusted P < 0.05 and at least 1.5-fold increase or decrease between 2 groups). Hierarchical clustering pts using these 385 genes revealed 5 distinct pt clusters (Figure A). There were significant differences between the 5 clusters in the proportions of pts in the 3 outcome groups (P Pts in cluster 1 (n=47 pts) almost all had bi-allelic CEBPA mutations (96%), and comparatively good outcome (all but one pt achieved a CR, and 49% achieved and maintained CR). In contrast, 94% of cluster 3 (n=69) pts harbored FLT3-internal tandem duplications (ITDs), and most pts either failed to achieve a CR (36%), or relapsed (51%). Cluster 2 (n=138) and cluster 4 (n=39) had intermediate outcomes compared to the other clusters (11% and 8% primary refractory pts, respectively; 40% and 51% pts who relapsed after CR, respectively). Notably, within cluster 2, there was a sub-cluster of 24 poor-risk pts who were less like to achieve CR and maintain CR compared to the rest of the cluster 2 pts (P Finally, pts in cluster 5 (n=35) had a less distinct mutation pattern compared to other clusters. Most pts in cluster 5 did poorly. 23% were primary refractory and 67% achieved a CR then relapsed. Because no obvious mutations were detected that would drive this cluster, we performed gene set enrichment analysis (GSEA) for oncogenic signatures using the Broad Institute's GSEA and MSigDB software. Compared to the rest of the pts, those in cluster 5 were significantly enriched in genes shown to be downregulated by oncogenic KRAS expression (false discovery rate q Our study shows that expression analysis can identify different outcome groups in younger CN-AML pts. We identified clusters of AML pts with poor CR rates and high incidences of relapse not associated with recurrent gene mutations, who were characterized by upregulation of lncRNAs, or enriched in KRAS signaling gene sets. These may represent new poor-risk subsets of AML pts requiring alternative treatment strategies. Support: UG1CA23333801, U10CA180821, U10CA180882, U10CA180861, U24CA196171 ClinicalTrials.gov identifiers: NCT00048958 (8461), NCT00900224 (20202) https://acknowledgments.alliancefound.org Figure Disclosures Powell: Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Kolitz:Astellas: Research Funding; Boeringer-Ingelheim: Research Funding; Roche: Research Funding. Byrd:TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau.

Introduction: The vast majority of solid tumors and half of leukemias and lymphomas possess an abnormal number of chromosomes. Individuals with congenital trisomy 21 have an increased risk of developing leukemia and respond differently to treatment when compared to leukemic individuals without congenital aneuploidies. Curiously, the chromosomes that most frequently undergo non-disjunction in malignancy are similar to the chromosomes that occur as trisomies in utero. We aimed to characterize the molecular landscapes of individuals with congenital trisomies to elucidate what changes may lead to an increased risk of cancer development in these individuals. Methods: We extracted DNA and RNA from fibroblasts of 14 individuals with congenital trisomies, including trisomy 8, 9, 13, 18 and 21 (obtained from Coriell Biorepository). DNA and RNA sequencing were performed with AmpliSeq for Illumina Comprehensive Panel v3. Variants were detected in the DNA using VarScan and annotated with SnpEff, while Kallisto was used for mRNA expression analysis. We applied mRNA context mapping methodology developed by the Computational Cancer Analysis Lab (University of California, San Diego). We used quantitative PCR and Western blotting to validate RB1 and MET expression. Results: Identification of transcripts highly expressed in multiple trisomies was performed. AXL was the only transcript that was highly expressed in all five trisomy groups, while ACBD5 and CCDC6 were each highly expressed in four. Interestingly, the number of unique highly expressed transcripts differed drastically by trisomy, ranging from n=0 for trisomy 9 to n= 111 for trisomy 13. We then generated a context map of the samples and observed that they cluster together by trisomy, with the exception of two samples. RB1 and MET were up-regulated in eleven samples, and down-regulated in the remaining three samples. We were able to validate these findings at the mRNA and protein level. Finally, we are in the process of identifying rare genetic variants that are unique to or enriched in this population. Conclusion: Our data indicate that several genes with well-described roles in cancer might also be differentially expressed in individuals with trisomies. RB1 is a tumor suppressor and previous studies have shown that pRB loss leads to centromere dysfunction and chromosomal instability, which could imply dysregulated RB1 plays a role in trisomy acquisition. MET is a proto-oncogene and is implicated as the major driver of oncogenesis in papillary renal carcinomas with chromosomal gain. Further studies that compare congenital trisomy with malignancy-associated trisomy may improve our understanding of non-disjunction and mechanisms of oncogenesis that occur in congenital trisomy patients. Citation Format: Maryam A. Bainazar, Sophia E. Maharry, Christopher J. Walker, Luke K. Genutis, Albert de la Chapelle, Ann-Kathrin Eisfeld. Genomic and transcriptomic characterization of congenital trisomy reveal possible role for RB1 and MET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1753.

// Jerneja Tomsic 1, 7 , Rebecca Fultz 1 , Sandya Liyanarachchi 1 , Luke K. Genutis 1 , Yanqiang Wang 1 , Wei Li 1 , Stefano Volinia 2 , Krystian Jazdzewski 3, 4 , Huiling He 1 , Paul E Wakely Jr. 5 , Leigha Senter 6 , Albert de la Chapelle 1 1 Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 2 Deptartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy 3 Genomic Medicine, Medical University of Warsaw, Warsaw, Poland 4 Laboratory of Human Cancer Genetics, Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland 5 Department of Pathology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA 6 Department of Internal Medicine, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 7 Division of Biomarkers Early Detection Prevention, City of Hope, Duarte, CA, USA Correspondence to: Albert de la Chapelle, email: albert.delachapelle@osumc.edu Keywords: genetics, predisposition, miRNA, thyroid, variants Received: July 15, 2016 Accepted: December 16, 2016 Published: December 23, 2016 ABSTRACT Papillary Thyroid Carcinoma (PTC) displays one of the highest familiality scores of all cancers as measured by case-control studies, yet only a handful of genes have been implicated until now. Variants in microRNAs have been associated with the risk of several cancers including PTC but the magnitude of this involvement is unclear. This study was designed to test to what extent genomic variants in microRNAs contribute to PTC risk. We used SOLiD technology to sequence 321 genomic regions encoding 427 miRNAs in one affected individual from each of 80 PTC families. After excluding variants with frequency ≥ 1% in 1000 Genomes Phase 1 ( n = 1092) we detected 1978 variants. After further functional filtering steps 25 variants in pre-miRs remained. Co-segregation was observed for six out of 16 tested miRNA variants with PTC in the families, namely let-7e, miR-181b, miR-135a, miR-15b, miR-320, and miR-484. Expression of miR-135a and miR-181b was tested in normal thyroid and tumor tissue from patients that carry the variants and a decrease in expression was observed. In vitro assays were applied to measure the effect of the variants on microRNAs’ maturation. Four out of six variants were tested. Only the let-7e and miR-181b variants showed an effect on processing leading to lower levels of mature miRNA. These two variants were not detected in 1170 sporadic PTC cases nor in 1404 controls. Taken together, our data show that high penetrance germline sequence variants of miRNAs potentially predispose to a fraction of all PTC but are not common.

The effects of germline variants in the development of myeloid neoplasms, including AML, were largely neglected for decades. However, several myeloid neoplasms with germline predisposition have been recently recognized as separate entities in the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. In addition to genes whose mutations are associated with bone marrow failure syndromes, and are long-known contributors to Mendelian disorders that have myelodysplastic syndromes/AML as the main clinical feature (e.g., germline CEBPA, GATA2 and RUNX1 mutations), 3 more genes were included: ANKRD26, DDX41 and SRP72. Mutations in these genes were described in few families, and are thus considered to be very rare. However, it is possible that their frequency might be underestimated, because the associated phenotypes are often vague and family history not routinely considered. To establish the frequency of ANKRD26, DDX41 and SRP72 mutations, and to characterize molecular and clinical features associated with these mutations, we determined mutational status of 83 cancer- and leukemia-associated genes using 2 targeted sequencing panels in diagnostic samples of 1,021 clinically well-characterized adult pts with de novo AML AML treated on trials conducted by the Alliance for Clinical Trials in Oncology. Mutations in the 3 familial genes were found in 46 pts (4.5%), specifically, mutations in ANKRD26 in 15, DDX41 in 17 and SRP72 in 19 pts. Three pts had mutations in either 2 or all 3 genes. Mutations occurred at varying variant allele fractions (VAFs, median: 0.47; range: 0.10-0.98), with 76% of mutations observed with VAFs >35%. Mutations were found throughout the genes. Pts harboring mutations in any of the 3 genes were predominantly younger (median age, 54 years; range, 19-77), 65% of them were male, and 48% belonged to the 2017 European LeukemiaNet (ELN) favorable genetic risk group. The co-mutation profiles partially differed among the genes. NPM1 mutations were the most frequent co-mutations, occurring in 47%, 41%, and 42% of pts with mutations in ANKRD26, DDX41, and SRP72, respectively. However, ANKRD26-mutated pts frequently harbored FLT3-ITD and mutations in DNMT3A, IDH2 and SRSF2 genes (each detected in 20% of pts). DDX41-mutated pts commonly had mutations in NRAS (18%), SMARCA2 (12%) and TP53 (12%). SRP72-mutated pts often had mutations in TET2 (26%), CEBPA (23%) and IDH1 (21%). With the exception of a higher complete remission rate in ANKRD26-mutated pts (93% compared with 73% for DDX41- and 81% for SRP72-mutated pts), the clinical outcomes were very similar. Considering all 3 genes combined, the median 3-year disease-free survival rate of 25% and median 3-year overall survival rate of 44% resembled those of pts belonging to the ELN intermediate risk group. We next tested whether the variants detected in our cohort of pts with presumably sporadic AML were of germline or somatic origin. We performed Sanger sequencing on germline material (buccal swab or remission samples) of 28 pts who had mutations detected at VAF>35% and material available. Germline origin was determined for the mutations detected in 24 of 28 pts tested (86%; ANKRD26, 9/10 tested pts; SRP72, 9/11 pts; DDX41, 8/10 pts). Of the detected germline changes, 7/9 ANKRD26 mutations, 6/10 DDX41 mutations and 5/9 SRP72 mutations were predicted to have deleterious effects on the respective proteins via Polyphen. The 1 pt with mutations in all 3 genes were found to be somatic mutations. Additional genes whose germline mutations are known to occur in families, such as GATA2, CEBPA and RUNX1, were sequenced for somatic mutations in our pt cohort, but not yet tested for potential germline origin in our analysis. Thus, it is likely that the frequency of familial AML mutations is even higher in our cohort. To our knowledge, this is the first study that tested the frequency of 3 leukemia-predisposing gene mutations in a large cohort of adults with presumably sporadic AML. The relatively high number of germline mutations in these 3 genes highlights the importance of testing for germline mutations. Thus, inclusion of those genes in diagnostic sequencing panels should be considered, and critical consideration of obtained family history should be strongly encouraged for providers taking care of pts with myeloid malignancies. Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171 Disclosures Mims: Novartis: Consultancy; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kolitz:Magellan Health: Consultancy, Honoraria.