Mutations in Genes Associated with Familial Predisposition to Myeloid Neoplasms: Their Frequency and Associations with Pretreatment Characteristics in Adult Patients (Pts) with Presumably Sporadic De Novo Acute Myeloid Leukemia (AML)

Abstract 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.

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Mutation Profiling of Therapy-Related Myeloid Neoplasms Using Next-Generation Sequencing Demonstrates Distinct Profiles from De Novo Disease

Blood ◽

10.1182/blood.v124.21.4611.4611 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4611-4611

Author(s):

Alan H. Shih ◽

Franck Rapaport ◽

Stephen S. Chung ◽

Emily K Dolezal ◽

Sean Hobson ◽

...

Keyword(s):

Next Generation Sequencing ◽

Board Of Directors ◽

Tp53 Mutation ◽

Somatic Mutations ◽

De Novo ◽

Next Generation ◽

Advisory Committees ◽

Myeloid Neoplasms ◽

Mutation Profile ◽

Generation Sequencing

Abstract Therapy-related Myeloid Neoplasms (tMN) comprise a poor risk subset of myelodysplastic syndromes and acute myelogenous leukemia, are increasing in incidence, and represent a serious complication following treatment for primary malignancies. In our previous study of 11 genes in 38 tMN patient samples, the data suggested that the mutational spectrum of tMN was distinct from de novo myeloid malignancies. To confirm this finding and to refine the tMN mutation profile, we investigated the mutation profile in samples from 88 patients and 28 genes using Sanger and next-generation sequencing approaches. We performed amplification using RainDance microfluidic PCR, followed by HiSeq next-generation sequencing. Mutations were identified using a modified pipeline for SNP calling employing variant detection software programs. Our study cohort included 88 patients, 71 of whom had complete clinical data for analyses. Patients had a history of epithelial and hematologic malignancies (³2 malignancies n=11; breast n=9; colorectal n=5; head and neck n=4; genital-urinary n=6; lung n=1; lymphoma n=25; melanoma n=2; ovarian n=1; sarcoma n=2; other, n=5). Treatment of primary cancers included chemotherapy alone (n=27), radiation alone (n=8), autologous stem cell transplant (n=11), or chemotherapy plus radiation (n=25). The median latency time between primary malignancy treatment and tMN diagnosis was 5.7yrs (range, 0.7 - 30.9 yrs). Median age at tMN diagnosis was 64yrs (range, 26 - 85 yrs). International Prognostic Scoring System (IPSS) risk group for MDS at tMN diagnosis were Low risk (n=8), Int-1 (n=11), Int-2 (n=30), High risk (n=9). We identified somatic mutations in 56 of 88 (64%) patients (83 patients were evaluated by next-generation sequencing and 5 by Sanger sequencing only). Mutations in TP53 were most common and were detected in 27/88 patients (30.7%), followed by mutations in TET2 in 12/88 (13.6%), DNMT3A in 9/88 (10.2%), NRAS in 8/83 (9.6%), KRAS in 5/83 (6.0%), and KIT in 5/83 (6.0%). Gene mutations detected at lower frequencies included those in ASXL1 in 5/88 (5.7%), RUNX1 in 2/83 (2.4%), EZH2 in 1/88 (1.1%), and SF3B1 in 1/88 (1.1%). Of the 58 patients with complete sequencing and FISH data, 4 patients exhibited biallelic somatic TP53 mutations and 3 patients had TP53 mutation combined with del 17p TP53 loss, demonstrating that 7 of 58 evaluable patients (12.1%) experienced biallelic loss of TP53. We also identified biallelic mutations in TET2 and DNMT3A in 2 separate patients. 25 patients had 2 or more concurrent somatic mutations. The highest number of co-occurring mutations in one patient was 5 mutations; 12 patients had 2 somatic mutations. The most common co-occurrence was TP53 and TET2, which was observed in 5 patients. All 5 ASXL1 mutations co-occurred with additional mutations. By analyzing variant allele frequencies (VAFs) in patients with multiple mutations, we observed that some tMN patients harbored multiple clones with distinct VAFs. This observation was also supported by the co-occurrence of typical class I driver mutations in the same patient, (e.g. KRAS 6% and NRAS 21% VAF; NRAS 9% and KIT 34%; NRAS 26% and KIT 9% in individual patients). The allele frequency data also suggested that ASXL1 is likely an early occurring mutation as the VAF was higher than for other co-occurring mutations (mean VAF ASXL1 50%, other co-occurring genes 23.5%, p<.05 t-test). Because of previous reports on the prognostic significance of point mutations in myeloid malignancies (e.g. TP53 in MDS and TET2 in AML), we tested the impact of individual mutations on prognosis. TP53 mutation or loss was associated with worse prognosis in tMN (OS 17.6 vs 25.2 mos, n=72, p<.11 log-rank test) (Fig A). TET2 mutation and KRAS or NRAS mutations did not predict for a difference in prognosis, although analysis was limited by cohort size. TP53 mutation was also associated with del 5q / monosomy 5 (p<.0001, Chi-square test, n=51). Our data reveal that tMNs display distinct mutation profile compared to de novo disease (Fig B). TP53 mutations and loss are the most common abnormalities and predict for adverse outcome. Epigenetic modifier mutations also occur in tMNs and can serve as disease-initiating mutations. Collectively our results demonstrate that characterizing these mutation profiles can enhance our understanding of disease mechanisms in tMNs and may guide the development of future therapies for these difficult to treat disorders. Figure 1 Figure 1. Disclosures Sekeres: Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees.

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Myelodysplastic Syndrome (MDS)-Determining Clonal Events at Presentation of Aplastic Anemia (AA)

Blood ◽

10.1182/blood.v126.23.1652.1652 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1652-1652

Author(s):

Eiju Negoro ◽

Naoko Hosono ◽

Wenyi Shen ◽

Tetsuichi Yoshizato ◽

Bhumika J. Patel ◽

...

Keyword(s):

Aplastic Anemia ◽

Board Of Directors ◽

Somatic Mutations ◽

De Novo ◽

Initial Presentation ◽

Progression Rate ◽

Advisory Committees ◽

Increased Risk ◽

Slow Expansion ◽

Secondary Mds

Abstract Historically, the evolution rate of aplastic anemia (AA) to MDS approaches 15% in 10 yrs; thus, AA can be considered a major predisposition factor for secondary MDS (sMDS). The likely etiology includes expansion of a preexisting clone or truly late clonogenic events. In both instances, progression can be a result of a clonal escape, but confirmation of the presence of mutant cells at presentation would indicate that initial autoimmune processes may represent a tumor surveillance reaction. We studied 326 patients with AA and 47 patients with paroxysmal nocturnal hemoglobinuria (PNH) and identified 36 cases (progression rate: 11% in median follow up of 6 years) that evolved to MDS or AML (median time to progression: 3.2 yrs.; transplanted patients were not censored). Cytogenetic analysis upon progression showed abnormal karyotype in 83% of cases; 7% had complex karyotype and -7/del(7q) was present in 62% of cases. The presence of a PNH clone was detected in 17% of cases that transformed to sMDS vs. 35% in non-progressors (P=.1). For comparison, we have also analyzed primary de novo cases of MDS (pMDS) with (N=94) and without (N=557) -7/del(7q). In contrast to sMDS, -7/del(7q) was present in 14.4% of cases in pMDS. Because sMDS following AA or PNH included a high proportion of patients with -7/del(7q), we compared sMDS with -7/del(7q) to pMDS with -7/del(7q) for coexisting mutational events. Mutations in RUNX1, CBL, SETBP1 and ASXL1 appeared to be more frequent in sMDS vs. pMDS (28.6% vs. 2.1%, 21.4% vs. 2.1%, 21.4% vs. 5.3%, 21.4% vs. 10.6%, P=.003, P=.02, P=.07, P=.37, respectively). In contrast, TP53 and DMT3A were more common in pMDS (7.1% for sMDS vs. 17%, 0% for sMDS vs. 8.5%, P=.69, P=.59). Similarly, there were several other distinctive differences between all sMDS and pMDS irrespective of the cytogenetics: mutations in SF3B1, SRSF2, NPM1, DNMT3A were common in primary AML but entirely absent from cases after AA; mutations in RUNX1 and SETBP1 appeared to be more frequent in sMDS vs. pMDS (26.3% vs. 8.3%, 21.1% vs. 3.2%, 15.8% vs. 3.9%, P=.03, P=.005, respectively). Whole exome NGS was performed after progression, with confirmed somatic mutations subsequently tracked back by targeted deep NGS applied to serial samples starting at initial presentation. Confirmed mutational events and chromosomal aberrations were found in 19/36 patients with sMDS; 17/19 cases of sMDS had at least 1 confirmed somatic mutation. Remarkably, in retrospective analysis in 6/7 cases studied serially, at least one of the identified mutations was detectable at presentation when deep targeted sequencing (depth 5,000~20,000 reads) was performed. In 5 of these cases the alterations appeared to be ancestral events for sMDS evolution. When anadditional 77 AA or PNH cases were studied by deep sequencing, somatic mutations were present in 48% of AA patients at presentation. Detection of clonal events at presentation was associated with an increased risk of subsequent MDS evolution (14/37 mutant cases vs. 3/40 nonclonal cases evolved, P=.002). Mutations found at both initial presentation and upon evolution were suggestive of a slow expansion of previously cryptic clones (ASXL1, CUX1, TET2, CBL, RUNX1, and SETBP1). Patients with these genes (n=18) had worseoverall survival compared to patients without these mutations (P=.03). To assess the potential impact of immunosuppressive therapies (IST), we also investigated a subset (out of 77) of 53 patients (39 responders and 14 refractory cases) following IST. Clonal somatic events were identified in 27 of them, but there was no association between the response to IST and somatic mutations at presentation. Our results demonstrate that while subclonal mutations indicative of oligoclonal hematopoiesis are frequent in AA, the presence of permissive ancestral somatic events at the outset of AA predisposes patients to sMDS, a feature that had diagnostic and prognostic implications. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees.

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SAMD9 and SAMD9L Germline Disorders in Patients Enrolled in Studies of the European Working Group of MDS in Childhood (EWOG-MDS): Prevalence, Outcome, Phenotype and Functional Characterisation

Blood ◽

10.1182/blood-2018-99-118389 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 643-643

Author(s):

Sushree Sangita Sahoo ◽

Victor Pastor Loyola ◽

Pritam Kumar Panda ◽

Enikoe Amina Szvetnik ◽

Emilia J. Kozyra ◽

...

Keyword(s):

Board Of Directors ◽

In Silico ◽

Somatic Mutations ◽

Germline Mutations ◽

Advisory Committees ◽

Monosomy 7 ◽

Mutational Landscape ◽

Mutational Status ◽

Gata2 Deficiency

Abstract Hereditary predisposition has been ever since implicated in the etiology of childhood myelodysplastic syndromes (MDS). Until recently, GATA2 deficiency prevailed as a major germline cause in pediatric primary MDS. In the past 2 years, we and others identified germline mutations in paralogue genes SAMD9 and SAMD9L residing on chromosome 7q21.2 as new systemic diseases with high propensity for MDS with monosomy 7. Although initially, mutations in SAMD9 and SAMD9L genes were associated with MIRAGE and Ataxia-Pancytopenia syndromes, respectively, with recent reports the phenotypes are becoming more intertwined. Nevertheless, the predisposition to MDS with monosomy 7 (-7) remains a common clinical denominator. Both genes are categorized as negative regulators of cellular proliferation and mutations were shown to be activating. Because of their high evolutionary divergence, classical in silico prediction is erratic, thereby establishing in vitro testing as the current gold standard for pathogenicity evaluation. The objectives of this study were to define the prevalence of SAMD9/9L germline mutations in primary pediatric MDS, and to describe the clinical phenotype and outcome. In addition, we aimed to characterize the somatic mutational architecture and develop a functional scoring system. Within the cohort of 548 children and adolescents with primary MDS diagnosed between 1998 and 2016 in Germany, 43 patients (8%) carried SAMD9/9L mutations that were mutually exclusive with GATA2 deficiency and known constitutional bone marrow (BM) failure. MDS type refractory cytopenia of childhood was diagnosed in 91% (39/43), and MDS with excess blasts in 9% (4/43) of mutated cases. Karyotype at diagnosis was normal in 58%, and -7 was detected in 37% of SAMD9/9L cohort. Within MDS subgroup with -7 (n=74), SAMD9/9L mutations accounted for 22% of patients. Notably, the demographics, familial disease, diagnostic blood and BM findings, overall survival (OS) and the outcome after HSCT were not influenced by mutational status in our study cohort (n=548). At the last follow up, 88% (38/43) of SAMD9/9L MDS patients were alive; 35/43 had been transplanted with a 5-year-OS of 85%. Next, we added 26 additional cases with SAMD9/9L mutations diagnosed in Europe within EWOG-MDS studies. In the total cohort of 69 germline mutated patients we found a total of 75 SAMD9/9L mutations, of which 67 were novel. Of those we tested 47 using a HEK293 cell in vitro system and 45/47 mutants inhibited proliferation. While 53/69 patients carried only single germline mutations (missense in 50/53 and truncating in 3/53), in the remaining 16 patients, 11 additional truncating and 7 missense mutations were found. We did not observe an association between germline mutation and phenotype. Immunological issues (e.g. recurring infections, low Ig) were described in 32%/50% of SAMD9/9L-mutated patients, while physical anomalies were very heterogeneous and reported in ~50% of patients in both mutational groups. Intriguingly, genital phenotypes occurred in 40% of SAMD9L, while neurological problems were present in 30% of SAMD9 - mutational subgroups. To elucidate the somatic mutational landscape, we performed whole exome and deep sequencing of 58 SAMD9/9L patients and identified recurrent somatic mutations in known oncogenes that were earlier associated with pediatric MDS: SETBP1 (10%), RUNX1 (7%), ASXL1 (5%), EZH2 (5%), CBL (3%). The identified somatic mutations occurred in association with monosomy 7 background (18/20). Finally, we utilized the results from functional testing of the 47 SAMD9/9L variants as our test cohort to develop combinatorial in silico scoring. The rationale was to decrease the dependency on functional validation. Based on the results of 20 in silico tools we could concatenate a matrix of 5 algorithms to resolve the pathogenicity of >80% of variants. Using this model, all variants predicted as pathogenic showed also growth-restrictive effect in vitro. In summary, pathogenic SAMD9/9L germline mutations account for 8% of primary pediatric MDS and 22% of MDS/-7. The mutations identified are heterogeneous and their effect can be predicted using a combinatorial in silico - in vitro approach. Finally, the clinical outcome and somatic mutational landscape are not influenced by the mutational status. Disclosures Locatelli: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Niemeyer:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Overall Survival in Patients with JAK2 and ASXL1 Positive Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-128309 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5383-5383

Author(s):

Murtadha Al-Khabori ◽

Shoaib Al-Zadjali ◽

Iman Al Noumani ◽

Khalil Al Farsi ◽

Salam Al-Kindi ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloproliferative Neoplasms ◽

Prognostic Significance ◽

Jak2 V617f ◽

World Health ◽

Prognostic Impact ◽

Advisory Committees ◽

Myeloid Neoplasms ◽

The Impact

Objectives: Mutations in additional sex combs-like transcriptional regulator 1 (ASXL1) have been previously described in myeloid neoplasms (21% in non-Myeloproliferative [MPN; Tefferi A, Leukemia, 2010) and have been associated with a more aggressive disease [Rocquain J et al, BMC Cacer, 2010]. They can also be found in patients with JAK2 positive MPN [Abdel-Wahab O et al, Cancer Research, 2010). Disruption of ASXL1 gene leads to MPN phenotype in zebrafish model (Gjini E, Dis Model Mech, 2019). The co-expression and the prognostic significance of ASXL1 in patients with JAK2 positive MPN are not yet fully defined. We therefore planned to define the prognostic impact of ASXL1 mutations on the Overall Survival (OS) of patients with JAK2 positive MPN. Methods: We included patients with JAK2 V617F positive MPN diagnosed according to the World Health Organization 2016 criteria and treated at the three largest hematology centers in Oman. The entire coding region of ASXL1 gene was sequenced using Next Generation Sequencing (NGS; Ion PGM Sequencer; Thermo Fisher Scientific®). The library was constructed and the templates were prepared using the PGM tool and the variants were annotated using the ClinVar database and the prediction from the Scale-Invariant Feature Transform (SIFT) and or Polymorphism Phenotyping (Polyphen) algorithms. The NGS analysis was done on the frozen diagnostic bone marrow samples. The survival probability was estimated using Kaplan-Meier estimator and Cox regression was used to assess the impact of predictors on the OS outcome. An alpha threshold of 0.05 was used. The R program (version 3.1.2) was used for all statistical analyses. Results: A total of 58 patients with JAK2 V617F positive MPN were included. All of these patients were found to have mutated ASXL1 using the NGS (ASXL1 p.Leu815Pro was found in all patients). The median age of this cohort was 62 years (InterQuartile Range [IQR]: 44 - 70) and female to male ratio was 25:33. The median hemoglobin, hematocrit, white blood cell count and platelet count was 14.7 g/dL, 58%, 11.5 x109/L and 518 x109/L respectively. Out of the 58 patients included, 28 had polycythemia vera, 20 had essential thrombocythemia, 8 had myelofibrosis and 2 had MPN-Unclassified. The median time from diagnosis to last follow up or death was 13 months (IQR: 3-39). During this period, 5 patients died. The probability of OS at 3 years was 88%. The median OS was not reached. In the univariable analysis, age was a statistically significant predictor of OS (p = 0.0355) but not gender (p = 0.434) and MPN subtype (p = 0.7). In the multivariable analysis model of the previous three factors, age remained statistically significant (Hazard ratio = 1.13, p = 0.041). Conclusions: ASXL1 is mutated in high proportion of patients with JAK2 positive MPN. Despite the negative impact of ASXL1 in patients with non-MPN myeloid neoplasms, the patients with combined positivity of JAK2 and ASXL1 in this study had a very good OS probability. Age was a predictor of OS in the univariable and multivariable models. We recommend the development and the assessment of ASXL1 inhibitors as therapeutic strategies in patients with MPN. Disclosures Al-Khabori: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; AstraZeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

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Genetic Predisposition to Therapy-Related Myeloid Neoplasm By Rare, Deleterious Germline Variants in DNA Repair Pathway and Myeloid Driver Genes

Blood ◽

10.1182/blood-2018-99-117815 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1802-1802

Author(s):

Deepak Singhal ◽

Christopher N. Hahn ◽

Cassandra M. Hirsch ◽

Amilia Wee ◽

Monika M Kutyna ◽

...

Keyword(s):

Breast Cancer ◽

Board Of Directors ◽

Research Funding ◽

Somatic Mutations ◽

Germline Mutations ◽

Advisory Committees ◽

Germline Variants ◽

Myeloid Neoplasm ◽

Mutation Profiling ◽

Second Degree

Abstract Therapy-related myeloid neoplasm (t-MN) is considered to be a direct stochastic complication of chemotherapy and/or radiotherapy for primary cancer or autoimmune diseases. However, genetic predisposition is reported in 8-12% of sporadic adult cancer patients [Lu et al Nature Communication 2015 and Huang et al Cell 2018]. Similarly, genetic predispositions to t-MN have also been reported in limited single institute studies of small numbers of patients [Churpek et al Cancer 2016]. In this study, we performed comprehensive germline and somatic mutation profiling in t-MN using next generation sequencing. Matched germline material was available for 62/194 (32%) patients. Mutation profiling was correlated with clinical features including family history in 194 patients enrolled in the South Australian MDS (SA-MDS) registry and Cleveland Clinic (CC). An in-house well established filtering pipeline was used for identification of somatic mutations. Only variants with Genome Aggregation Database (gnomAD) minor allele frequency (MAF) of ≤0.01% and variant allele frequency (VAF) of ≥35% were selected for further analysis of germline variants. Variants reported in in the Catalogue of Somatic Mutations in Cancer database and MDS/AML were excluded from further analysis. Variants reported pathogenic in Breast Cancer Information Core (BIC) database and Leiden Open Variation Database (LOVD) were retained. Other variants were included if truncating (nonsense, indels, splice alterations), CADD>20, or predicted deleterious by >4/6 scoring algorithms (GERP>4, PhyloP>2, SIFT, PolyPhen2, MutationTaster and FATHMM). Forty-one (21%) t-MN patients harbored 45 rare (MAF<0.001) and deleterious germline mutations in the Fanconi anaemia (FA) pathway and driver myeloid genes including frameshift indels and splice site alterations in BRCA1, BRCA2, FANCA, PALB2, RAD51, DDX41 and TP53 (Figure 1A-B). The highest number of FA germline variants were seen in BRCA1 and FANCA (n=5 each) followed by BRCA2 (n=4), ERCC4, PALB2 and FANCC (n=2 each). We also identified 14 rare, deleterious myeloid germline variants in 13/194 (6.7%) of t-MN patients. These germline myeloid variants were identified in TP53, DDX41, GATA2 and MET; genes with well-known drivers of myeloid malignancies. Of the five acute lymphoblastic leukaemia patients with t-MN, 2/5 (40%) had rare myeloid germline variants in TP53, GATA2 and KMT2A. The frequency of these germline mutations in our t-MN cohort is higher than in the general population (gnomAD; Table 1) and in patients with primary malignancies such as breast cancer and lymphoma [Lu et al Nature Communication 2015 and Churpek et al Cancer 2016]. Intriguingly, the frequency of germline FA gene mutations (FAMT) in our therapy-related myelodysplastic syndrome (t-MDS) patients is also higher than those reported in primary MDS patients (18% vs 9%, p=0.02) [Przychodzen et al 2018]. Additionally, of those with available family history, 62% of t-MN patients have first and/or second degree relatives with non-skin cancers. Significantly more patients with FA mutation (FAMT) had first and second degree relatives with cancers compared to patients without FA (FAWT) mutations (82% vs 58%; p=0.03). Additionally, chromosomes 3 and 7 abnormalities, as well as monosomal karyotype, were more frequent in FAMT cases compared to FAWT. Similarly, somatic mutations in GATA2 (10% vs 2%; p=0.02), BCOR (13% vs 4%; p=0.03) and IDH2 (10% vs 2%; p=0.02) were more frequent in FAMT compared to FAWT cases (Figure 1C). In summary, we show that at least one in five t-MN patients harbor deleterious germline mutations, and 82% of FAMT patients have a first or second degree relative with cancers. These findings have implication in management of not only t-MN patients but genetic testing for their family members. Disclosures Branford: Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cepheid: Honoraria. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy. Hiwase:Celgene: Research Funding; Novartis: Research Funding.

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Distinct Features of Chip-Derived and De Novo MDS

Blood ◽

10.1182/blood-2018-99-117763 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2572-2572

Author(s):

Yasunobu Nagata ◽

Hideki Makishima ◽

Cassandra M. Hirsch ◽

Hassan Awada ◽

Abhinav Goyal ◽

...

Keyword(s):

Board Of Directors ◽

Somatic Mutations ◽

De Novo ◽

Meta Analysis ◽

Genetic Alterations ◽

Low Risk ◽

Alternative Methods ◽

Molecular Characteristics ◽

Study Cohort ◽

Advisory Committees

Abstract Subclinical clonal expansions, referred to as clonal hematopoiesis of indeterminate potential (CHIP), are present in blood of otherwise healthy individuals and their frequency increases with age. While many CHIP-associated mutations are present in MDS, only a small proportion of asymptomatic individuals with CHIP progress to MDS. We assumed that: i) a proportion of CHIP mutations will eventually serve as ancestral hits that manifest as MDS upon acquisitions of additional genetic alterations, and ii) MDS from antecedent CHIP may be a MDS disease subtype that is distinct from de novo MDS characterized by more penetrant primary hits. Separating ancestral vs. secondary hits in MDS patients and comparing by meta-analyses their frequencies to those in CHIP may enable molecular and clinical characterizations of CHIP-related MDS. Our study cohort consisted of 1,809 clinically annotated MDS patients. Deep targeted NGS was conducted for a panel of the 36 most frequently mutated "myeloid" genes, which revealed 3,971 somatic mutations in MDS patients after removing SNPs and errors. To discriminate between dominant and subsequent rising secondary mutations, we used a stringent binominal distribution algorithm to define VAFs confidence intervals via loci read counts. Sample maximal VAF mutations were defined as "dominant" and those with overlapping VAF 95% CI were defined as "co-dominant"; mutations with lower non-overlapping 95% CIs were "secondary". These definitions are consistent with those of other methods such as Pyclone, with 95% concordance (1,253/1,317). They yield 1,474 (36%) dominant and 1,372 (35%) secondary mutations. We compared a meta-analysis of frequently mutated genes in 1,693 healthy CHIP individuals with somatic mutations from the CHIP meta-analysis to dominant mutations in MDS patients. Mutations in DNMT3A, TET2, ASXL1, and JAK2 were more frequent in CHIP than MDS [e.g.,DNMT3A; 52% (888/1,693) vs. 6% (110/1,809), p<.001]. Hence MDS patients with dominant mutations in these 4 genes were defined as CHIP-derived MDS (C-MDS). Other dominant mutations such as U2AF1, RUNX1 and STAG2 which were not identified in individuals with CHIP were deemed not CHIP-derived MDS (NC-MDS). And in between, mutations in TP53, SF3B1 and SRSF2, were identified in both cohorts [e.g., TP53; 4% (71/1,693) vs. 5% (97/1,809), p=.11], and such cases will be denoted as C/NC-MDS patients. We set out to compare clinical, molecular and demographic features of C- vs. NC-MDS. There were 459 (25%) C-MDS and 498 (28%) NC-MDS cases out of 1809 MDS patients. 95% of patients with C-MDS (437/459) had at least one TET2 (51%, 234/459), DNMT3A (24%, 110/459) or ASXL1 (20%, 93/459) dominant mutation. The top 5 dominant mutations in patients with de novo MDS were U2AF1 (15%, 75/498), ZRSR2 (10%, 52/498), RUNX1 (9%, 47/498), STAG2 (9%, 43/498), and EZH2 (8%, 40/498). 52% (257/498) of patients with de novo MDS had at least one of these mutations. Focusing on secondary mutations, patients with C-MDS had a significantly higher frequency of secondary TET2 and ZRSR2 mutations than those with de novo [e.g., TET2, 17% (77/459) vs. 8% (41/498), p<.001]. In contrast, secondary ASXL1 mutations were more frequent in NC-MDS [7% (31/459) vs. 18% (88/498), p<.001]. C-MDS cases were older and had more low risk subtypes than NC-MDS cases [(average Age) 72 vs. 69, p<.001, (low risk subtypes) 56% (256/459) vs. 45% (222/498), p<.001]. Patients with C-MDS had better prognosis than those with NC-MDS [hazard ratio .75 (.63-.91), p=.003]. Prospective sequencing of serial samples of CHIP to development of MDS may be needed to fully reveal the landscape of C-MDS. This may not be practical, as over a million healthy donors would need to be followed for years to obtain adequate numbers of C-MDS cases. If our hypothesis that there exist clinical and molecular characteristics of C-MDS is correct, alternative methods that begin with MDS cases could then be employed. Regardless, detecting and monitoring CHIP is warranted, as this will lead to biomarkers that predict risks and thus preventative interventions. Disclosures Nazha: MEI: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Impact and Function of Somatic PHF6 Mutations in Myeloid Neoplasms

Blood ◽

10.1182/blood.v124.21.3581.3581 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3581-3581

Author(s):

Brittney Dienes ◽

Bartlomiej P Przychodzen ◽

Michael Clemente ◽

Wenyi Shen ◽

Chantana Polprasert ◽

...

Keyword(s):

Bone Marrow ◽

Dna Damage ◽

Board Of Directors ◽

Somatic Mutations ◽

Suppressor Gene ◽

Advisory Committees ◽

Nonsense Mutations ◽

Dysmorphic Features ◽

Normal Bone ◽

Myeloid Neoplasms

Abstract Borjeson−Forssman−Lehmann syndrome (BFLS), a hereditary X-linked disorder characterized by mental retardation, truncal obesity, gynecomastia, hypogonadism and other dysmorphic features, is known to be caused by germline (GL) mutations of plant homeo domain finger protein 6 (PHF6). PHF6 is a highly conserved 41kDa protein showing ubiquitous expression in a variety of tissues, including bone marrow, CD34+ cells and blood leukocytes. Human PHF6 is located on chrXq26.2. Recently, rare somatic nonsense mutations and deletions have been detected in patients with T-ALL and AML and found in some T-ALL cell lines. Patients with BFLS with PHF6 mutations have been reported to develop leukemia, suggesting PHF6 mutations may predispose cancer. Although the actual function and molecular pathogenesis is unknown, PHF6 has been suggested to be a tumor suppressor gene involved in the control of myeloid development. In an index case of a young adult female patient with proliferative CMML with dysmorphic features, we have identified remarkable GL mosaicism for PHF6 mutation (p.K44fs), confirmed by deep sequencing of marrow, CD3+ cells and skin tissue. Subsequently, we screened patients with myeloid neoplasms by targeted multi-amplicon sequencing to determine the prevalence and distribution of PHF6 gene alterations. Sequencing results from 1072 cases were analyzed (728 by targeted deep sequencing and 344 by whole exome sequencing). In total, we identified 21 cases with PHF6 mutations, 13 of which were frameshift or nonsense mutations. Previously, PHF6 have been included in screening panels by Haferlach et al., (Leukemia 2014) and Papaemmanuil et al., (Blood 2013) and somatic mutations were found in 24/944 and 21/738 cases of MDS, respectively. These results along with ours suggest that PHF6 mutations are common driver events. The somatic nature of these defects was confirmed by analysis of non-clonal CD3+ lymphocytes, thus, PHF6 mutations occur at a frequency of 2.0% and are most frequently observed among patients with secondary AML (33%, P=.0021). Gender distribution showed a strong male predominance (76%), likely due to the location of PHF6 on chrX and indicating that retention of a single copy of PHF6 may be protective. SNP-array karyotyping showed that deletions of Xq, involving the PHF6 locus (Xq26), were present in about 1.2% of myeloid neoplasms and affect only female patients. As a family, plant homeo domain (PHD) finger genes are affected by mutations associated with various cancers. JARID1A, PHF23, NSD1 and NSD3 were described to serve as fusion partners with the NUP98 in a subset of AML cases. The most frequent chromosomal aberration observed in conjunction with PHF6 mutations was trisomy-8 (P=.08). The most commonly associated somatic mutations were in RUNX1 (N=7; P=.001), U2AF1 (N=5), ASXL1 (N=5), IDH1 (N=4), and DNMT3A (N=4). Interestingly, 6/7 cases with concomitant PHF6 and RUNX1 mutations showed a poor prognosis AML. Subsequent analysis of clonal architecture using variant allelic frequency calculations and serial samples for these cases suggested that PHF6 may function as a founder driver gene while RUNX1 mutations are acquired as secondary events. Recent studies proposed that PHF6 deficiency leads to impaired cell proliferation, cell cycle arrest at G2/M phase and an increase of DNA damage. To examine DNA damage and quantify double stranded breaks (DSBs) in primary cells from PHF6-mutants, those with wild-type (WT) PHF6 and normal bone marrow we used a flow cytometric anti-γH2AX assay, following induction of DNA damage with Camptothecin. As judged by greater percentages of anti-γH2AX labeled cells, DSBs were more common in mutant cases consistent with more DNA damage present in PHF6 mutant compared to WT MDS and normal bone marrow cells. In conclusion, our results indicate that PHF6 mutations are generally present in more aggressive types of myeloid neoplasms, frequently associated with RUNX1 mutations. Our functional in vitro studies along with recently published reports suggest an association of PHF6 deficiency with genomic instability and thereby provide a basis for a mutator phenotype conveyed by ancestral lesions, consistent with its role as a tumor suppressor gene. Disclosures Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees.

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Clinical and Biological Implications of CUX1 Mutations in Myeloid Neoplasms

Blood ◽

10.1182/blood.v128.22.3156.3156 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3156-3156

Author(s):

Mai Aly ◽

Naoko Hosono ◽

Przychodzen Bartlomiej ◽

Hideki Makishima ◽

Nagata Yasunobu ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Somatic Mutations ◽

Myeloproliferative Neoplasms ◽

Loss Of Function ◽

Wild Type ◽

Advisory Committees ◽

Molecular Features ◽

Myeloid Neoplasms ◽

Normal Cytogenetics

Abstract Recurrent somatic mutations of CUX1 are described in myeloid neoplasms. CUX1 is located at chromosome 7q22.1; -7/del(7q) involving CUX1 locus are common abnormalities in myelodysplastic syndromes (MDS). Mutations and loss of heterozygosity involving CUX1 have been also described in breast, lung and uterine cancers. Preliminary functional studies, lack of a mutational hotspot and coincidental deletions suggest loss of function/hypomorphic consequences of these molecular defects. CUX1 (p200), contains 4 evolutionarily conserved DNA-binding domains, including 3 CUT repeats and a CUT homeodomain. Functionally, CUX1 regulates many genes involved in DNA replication and chromosome segregation. Cell-based assays have established a role for CUX1 in the control of cell-cycle progression, cell motility, and invasion .The objective of this study is to assess the molecular context and clinical significance of CUX1 mutations and deletions in myeloid neoplasms. We analyzed a subset of 1478 patients [24% lower-risk MDS, 17% higher-risk MDS, 22% primary (p)AML, 14% secondary AML, 14% MDS/myeloproliferative neoplasms (MPN) and 9% MPN] for the presence of CUX1 mutations and deletions. No CUX1 mutations were found in core binding factor AML. We correlated the presence of these lesions with clinical parameters, cytogenetic abnormalities, and molecular features including clonal architecture and associated somatic mutations. Copy number variation and their boundaries were analyzed by Single Nucleotide Polymorphism (SNP) arrays and mutations by multiamplicon deep sequencing utilizing a panel targeting 60 most commonly mutated genes in myeloid neoplasms. In total cohort 4 % of patients had CUX1 mutations and 6% had locus deletions (affecting ch 7q commonly deleted region: 7q22.1) including 90% of del (7q) cases. Expression of CUX1 is significantly lower in AML with -7/del(7q) compared to AML with normal cytogenetics (p<.00001) and also in MDS with -7/del(7q) compared tohealthy controls (p=.004). Additionally, decreased expression of CUX1 was found in 15% of MDS and 8% of AML patients without -7/del(7q) or related mutations. Cases with lower expression had worse OS compared to patients with higher expression (p=.002). In terms of configuration, most mutations were heterozygous, 5% of mutations were hemizygous and 4% were homozygous (due to UPD). Among 75 somatic CUX1mutations; 72% were missense, 20% where frame shift and 8% where non sense. CUX1 mutations were associated with either lower-risk MDS (p=.0001) and pAML (p=.04) while deletions involving the CUX1 locus were significantly related to higher-risk MDS (p=.05). Heterozygous CUX1 mutations were more commonly associated with normal cytogenetics (p=.01). Patients with -7/del(7q) frequently represented del(5q) (p=.04) and thrombocytopenia (p=.001). The OS of patients with CUX1 mutations was shorter (p=.04) as was that of patients with CUX1/deletions (p=.02) when compared to wild type. We subsequently studied the molecular background of CUX1 alterations. CUX1 mutations (vs. wild type) were associated with TET2 (31% vs. 14%, p=.006), ASXL1 (29% vs. 9%, p=.0005), BCOR (28% vs. 8%, p=.0004), and cohesion mutations (26%, vs. 5%, p=.0005), while NPM1 mutations showed the reverse relationship (1% vs. 7%, p=.03). RAS and CUX1 mutations were mutually exclusive (0% vs. 6%, p=.03). When we analyzed clonal hierarchy in the context of CUX1 mutations; dominant CUX1 mutations (24%; mean VAF=49%); were accomplished by ASXL1 (21%) and SRSF2 (14%) mutations which were the most common secondary events in this context. Phenotypically, dominant CUX1 mutations were associated with MDS/MPN (42%) and MDS (33%). 14% of CUX1 mutant cases did not harbor any other alterations and were not associated with a discernable phenotype. Secondary CUX1 lesions (62%; mean VAF=22%) were found in the context of dominant TET2 mutations (16%). The pathomorphologic context of secondary CUX1 mutation did not differ from that of primary lesions. AML seemed to be underrepresented (p=.006) and MPN overrepresented (p=.019) among dominant CUX1 mutant cases. In conclusion, CUX1 lesions including locus deletions with haploinsuffciency, mutations and a fraction of cases with decreased CUX1 expression can be encountered in MDS and related neoplasms, chiefly AML. CUX1 dysfunction is associated with poor survival likely due to its distinct molecular background. Disclosures Makishima: The Yasuda Medical Foundation: Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA)

Blood ◽

10.1182/blood.2019000937 ◽

2020 ◽

Vol 136 (1) ◽

pp. 24-35 ◽

Cited By ~ 3

Author(s):

Anna L. Brown ◽

Christopher N. Hahn ◽

Hamish S. Scott

Keyword(s):

Somatic Mutations ◽

De Novo ◽

Laboratory Data ◽

Germline Mutations ◽

Model Systems ◽

World Health ◽

Patient Groups ◽

Health Organization ◽

Inherited Mutations

Abstract Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.

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Unexpected High Frequency of Pathogenic Germline Variants in Older Adults with Primary Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2021-154514 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2594-2594

Author(s):

Christopher N Hahn ◽

Simone K. Feurstein ◽

Deepak Singhal ◽

Monika M Kutyna ◽

Rakchha Chhetri ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

High Frequency ◽

Advisory Committees ◽

Germline Variants ◽

Hematological Disorders ◽

Myeloid Neoplasms ◽

History Of ◽

Single Cancer ◽

Telomere Biology

Abstract Background: Germline predisposition is increasingly being recognised in myeloid neoplasms (MN) including primary myelodysplastic syndrome. An unequivocal diagnosis of germline predisposition carries actionable considerations for patient management including donor stem cell source for allogeneic transplantation, dose-reduction of conditioning regimes and screening for extra-hematological disease (such as pulmonary abnormalities in patients with telomere biology disorders). In addition, the identification of MDS predisposition syndromes can avoid misdiagnosis (for example, distinguishing idiopathic thrombocytopenic purpura from thrombocytopenia due to RUNX1 germline variant). However, the prevalence of pathogenic germline variants (PGVs) in unselected pMDS patients presenting at older age remains unknown. Aim: This study assesses frequency and type of pathogenic germline variants in MDS patients and compares with age matched healthy controls and patients with other cancers. Method: We analysed 68 known cancer predisposition genes in germline samples of 146 samples from myeloid neoplasms. Study included primary MDS (n=51) and MDS diagnosed in cancer survivors with (n=77) or without prior exposure to cytotoxic therapy (n=18). Using uniform American College of Medical Genetics and Genomics (ACMG) guidelines for annotating germline mutation, we also compared the frequency of pathogenic germline variants in the same genes with patients with single cancer and age-match healthy controls (>70 years). Results: Pathogenic germline variants (PGVs) were identified in 19% (28/146) patients compared to 4% and 3% patients with single cancer and age-matched controls respectively (P<0.0001) (Fig. 1A). Median age at diagnosis was similar between MN patients with or without PGVs [66 years (19-81) vs. 70 years (33-87); P=0.06]. PGVs were most frequent in DDX41 (n=7, 33%) followed by BRCA1 (n=2, 10%), GATA2 (n=2; 10%) and TP53 (n=2; 10%) (Fig.1B). We also identified pathogenic copy number variations (CNV) in 4 patients. The distribution of PGVs was also different, with DDX41 PGVs absent in single cancers and more prevalent in MN than age-matched controls (35% vs. 4%, P<0.001). The frequency of PGV was not significantly different between P-MN and T-MN/ MC-MN (17% versus 10%, P = 0.32 (Fig.1C). The frequency of PGV was 30%, 6%, 19%, 15% and 18% in patients ≤50, 51-59, 60-69, 70-79 and >80 years of age (Fig. 1D). Phenotypic features such as monocytopenia and mycobacterium infections (MonoMAC; SA460) and personal and family history of pulmonary fibrosis (SA918) were present in only two cases with PGVs. Family history of MDS/AML was present in only in four cases with PGVs, in which PGVs were found in typical myeloid malignancy genes (DDX41, GATA2). Importantly, some patients with family history of solid cancers carried PGVs in genes traditionally associated with solid cancers (e.g. MSH6, NF1, TP53 and BRCA1). SA927 had a PGV in MSH6 and multiple first-degree relatives with solid cancers including colon, renal and brain cancers. Moreover, 41% of adults with hematological disorders and a personal and/or family history of interstitial lung disease had PGVs in telomere biology disorder genes. Hence, family history should not be restricted to hematological disorders, but also solid cancers and non-malignant phenotypes (e.g. hepatic and pulmonary fibrosis). The frequency of PGVs was not different in patients with and without family history of cancer (23% vs. 13%, P=0.32). Conclusion: The frequency of PGVs is significantly high in MN compared to age matched healthy control and other cancer patients. Our observation of a high frequency of PGVs in the older MDS population warrants standardization of germline testing at diagnosis to guide optimal management of patients and their families. Figure 1 Figure 1. Disclosures Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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