Systematic Screening for Familial Leukemia Based on Somatic Genomic Profiling Results

Abstract The incidence of familial acute leukemias (AL) and myelodysplastic syndrome (MDS) in the adult population is not well characterized, though recent estimates report that up to 4% of newly diagnosed individuals have a familial syndrome. Recognizing these syndromes is critical to proper clinical management of patients with an inherited susceptibility, and for genetic screening of family members. Within our tertiary care academic institution, less than 1% of AL/MDS cases are referred to genetic counseling, presenting an opportunity for improvement in practice. With the integration of next generation sequencing into standard clinical practice, we recently initiated a bi-monthly meeting to review these sequencing results, with the intent to detect possible familial AL/MDS syndromes and increase appropriate genetic counseling referrals. Here, we describe the potential value of this approach, through a retrospective analysis of somatic genomic profiling results in AL/MDS patients. We performed a retrospective, single-center analysis of all patients who underwent somatic genomic profiling with FoundationOne Heme for AL and MDS between May 2015 and July 2018. Genomic alterations implicated in familial leukemias or familial cancers and included in the FoundationOne Heme panel were as follows: RUNX1, CEBPA, ETV6, GATA2, TERC/TERT, PAX5, CHEK2, and TP53. We recorded baseline characteristics including age, sex, and diagnosis. The presence of the suspected germline variant and up 6 other genomic alterations were recorded. We described whether a comprehensive family history, defined as whether a family history of bleeding tendency, low blood counts, or cancers, was documented for all patients. All patients with a positive family history had the malignancies and blood disorders reported. Finally, we observed if a genetic counseling referral was placed. A total of 108 patients underwent genomic profiling during the study period. Pathogenic variants implicated in familial AL/MDS or familial cancers were detected in 41 of those patients. The number of patients under the age of 50 was 7. Twenty-nine patients had a diagnosis of AML and 12 patients had MDS. Of the reported relevant pathogenic variants, TP53 was seen in 20 patients, RUNX1 in 14 patients, CEBPA in 4 patients, ETV6 in 4 patients, and GATA2 in 3 patients. There were 5 patients that had 2 pathogenic variants noted on their genetic testing. Among the patients with positive pathogenic variant, 22/41 had a comprehensive family history performed. Family history was positive for malignancy in 26/41 patients. Of those 26, 9 patients had a first degree relative with a history of hematologic malignancy including leukemia. Only 2 patients overall were referred to genetic counseling. In AL/MDS patients who underwent somatic genomic profiling at our institution, nearly half of patients with suspected germline variants for familial AML-MDS syndromes had either a family history of malignancy or development of their malignancy at an earlier age, warranting genetic counseling referral. There also is room to improve comprehensive family history collection. Beginning in March 2018, we initiated a bi-monthly meeting to review somatic genomic profiling results in AL/MDS patients with a licensed geneticist. If a suspected germline variant is discovered, we now issue a statement to the primary oncologist to clarify family history if needed, and recommend a referral for formal genetic counseling in the presence of a suggestive family history or on the basis of age. In future investigations, we plan to study how this changes the rate of genetic counseling referrals, and whether this results in an increase in the detection of familial AL/MDS or familial cancer syndromes among this patient group. Disclosures Atallah: Abbvie: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Jazz: Consultancy; Novartis: Consultancy.

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Eculizumab discontinuation in atypical hemolytic uremic syndrome: TMA recurrence risk and renal outcomes

Clinical Kidney Journal ◽

10.1093/ckj/sfab005 ◽

2021 ◽

Author(s):

Gema Ariceta ◽

Fadi Fakhouri ◽

Lisa Sartz ◽

Benjamin Miller ◽

Vasilis Nikolaou ◽

...

Keyword(s):

Family History ◽

Hemolytic Uremic Syndrome ◽

Univariate Analysis ◽

Atypical Hemolytic Uremic Syndrome ◽

Renal Response ◽

Pathogenic Variants ◽

Increased Risk ◽

History Of ◽

Uremic Syndrome

ABSTRACT Background Eculizumab modifies the course of disease in patients with atypical hemolytic uremic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited. Methods Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated hematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analyzed. The primary endpoint was the proportion of patients suffering thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: eGFR changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function. Results We analyzed 151 patients with clinically diagnosed aHUS who had evidence of hematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants, or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; 7 (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation. Conclusions Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

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DDX41 Mutations in Myeloid Neoplasms and Acute Leukemias

Blood ◽

10.1182/blood-2020-143456 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-13

Author(s):

Yang Zhang ◽

Fang Wang ◽

Xue Chen ◽

Hong Liu ◽

Xiaoliang Wang ◽

...

Keyword(s):

Family History ◽

Germline Mutation ◽

Mrna Splicing ◽

The Other ◽

Biallelic Mutation ◽

Acute Leukemias ◽

Myeloid Neoplasms ◽

Uncertain Significance ◽

History Of ◽

The Dead

DDX41 is thought to be a tumor suppressor gene involved in pre-mRNA splicing, innate immunity and rRNA processing. Myeloid neoplasms with germline DDX41 mutations have been included as a new diagnostic category in the 2016 WHO classification. However, there are limited studies describing the mutation profile of myeloid neoplasms and acute leukemias associated with DDX41 mutation. We analyzed the prevalence and characteristics of DDX41 mutations in an unselected cohort of 1764 patients with myeloid neoplasms and acute leukemias, including 720 subjects with AML, 91 with MDS, 41 with MPN, 16 with MDS/MPN, 760 with ALL, and 42 with MPAL. Next-generation sequencing was performed on 86 genes closely related to hematologic neoplasms. The fingernail specimens or blood samples in remission were taken as control samples to verify the mutation from possible germline sources. We identified 21 different DDX41 mutations in 16 unrelated patients (6 MDS/AML, 1 CMML, 9 ALL) that were classified as causal (n=17) and uncertain significance (n=4) variants. The acquisition of a somatic DDX41 mutation was also considered as a very strong criterion for causality, the uncertain significance variants were excluded. Nine causal variants have not been reported. 53% of variants were located on the DEAD domain and 24% on the Helicase C domain, the rest were located upstream of the DEAD domain. Ten variants were germline that the majority (80%) were located upstream of the Helicase C domain, 7 variants were somatic and were scattered. In 6 patients with MDS/AML and DDX41 mutations, the median age was 49 years (range, 28-78y) and 57% were male. None of the patients had del 5/5q. Five (83%) patients had personal history of cytopenia prior to MDS/AML diagnosis, while only one patient had a family history of anemia and one patient's aunt died of leukemia. Four (67%) patients harbor DDX41 germline/somatic biallelic mutation, two with typical biallelic mutation (N-terminal germline nonsense and C-terminal somatic missense), the other two with atypical biallelic mutation (N-terminal germline missense and C-terminal somatic missense). The average age of patients with DDX41 atypical biallelic mutation (48y) seems lower than that with typical biallelic mutation (74y). The rest two patients harbor single germline mutations and one of them concomitant with SF3B1 mutation, which is a component of spliceosome complex also involving in mRNA splicing. DDX41 mutations were identified in 7 patients with B-ALL and one with T-ALL. The median age was 9 years (range, 4-2 y) and 56% were male. None of the patients had a family history of hematological malignancy and del 5/5q. Unlike in myeloid neoplasms, no DDX41 biallelic mutations were identified that 5 patients had single somatic mutation (3 missenses, 1 nonsense) and 4 had single germline mutation (all are missenses). Among MDS/AML patients with DDX41 biallelic mutation, only one received treatment who relapsed after HSCT and received second HSCT, the time of overall survival (OS) was 74 months, the other 3 quite after diagnosed. In patients with MDS/AML and DDX41 single germline mutation, one received 4 courses of treatment with decitabine and half-dose CAG regimen, then transformed to AML and abandoned, the other one received 10 courses of chemotherapy and showed continuous no remission. The time of OS was 17 and 31 months, respectively. Among ALL patients with DDX41 single somatic mutation, 80% (4/5) received HSCT, 80% (4/5) were in complete remission (CR), one died of post-transplant infection, the median OS was 25 months. Among ALL patients with DDX41 single germline mutation, all the three patients received HSCT and were in CR, the median OS was 37 months. The genotype-phenotype correlations regarding germline DDX41 mutations should be clarified more specifically, the most prevalent loss of function mutations, predisposes to myeloid disease at the same age as sporadic disease, whereas point mutations in the DEAD domain (this study) or helicase C domain (previous report) were speculated to cause earlier onset disease. Moreover, this study reported for the first time that DDX41 mutations have also been found in ALL, which expanded its phenotypic spectrum. The characteristics of DDX41 mutation in ALL are different from myeloid neoplasm, the age of onset is young, and no germline/somatic biallelic mutation have been observed, suggesting that it might be involved in different pathogenesis mechanisms. Disclosures No relevant conflicts of interest to declare.

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Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-020-00160-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Kodai Abe ◽

Arisa Ueki ◽

Yusaku Urakawa ◽

Minoru Kitago ◽

Tomoko Yoshihama ◽

...

Keyword(s):

Pancreatic Cancer ◽

Family History ◽

Genetic Analysis ◽

Pathogenic Variant ◽

Familial Pancreatic Cancer ◽

Case Presentation ◽

Pathogenic Variants ◽

Pancreatic Cancers ◽

Epidemiological Surveys ◽

History Of

Abstract Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

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Internet use is associated with utilization of genetic counseling for BRCA 1/2 mutations in women with a family history of breast or ovarian cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10654 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10654-10654 ◽

Cited By ~ 1

Author(s):

K. Armstrong ◽

S. Gray ◽

S. Domchek

Keyword(s):

Ovarian Cancer ◽

Genetic Counseling ◽

Family History ◽

Cancer Risk ◽

Health Information ◽

Internet Use ◽

The Internet ◽

Frequent Use ◽

Brca 1 ◽

History Of

10654 Background: Women obtain breast cancer risk information from a variety of sources including mass media, the internet and personal and professional sources. Little is know about how internet use for health information influences choices about breast cancer risk evaluation and decision making. Methods: Case control study of 408 women with a family history of breast or ovarian cancer, of whom 217 underwent genetic counseling for BRCA 1/2 testing (cases) and 191 women who did not (controls). Participants received primary care within a large health system in greater Philadelphia, PA. Results: Women with a family history of breast or ovarian cancer who reported frequent use of the internet for health information (>1–2 times a month) were significantly more likely to undergo genetic counseling for BRCA 1/2 testing than women that rarely used the internet to obtain health information (<2 times a year) (odds ratio 2.6; 95% CI 1.7–4.0). This association persisted after adjustment for age, race, education and Gail risk (adjusted odds ratio 2.1; 95% CI 1.05–4.2) Conclusions: Frequent use of the internet for health care information is associated with higher use of genetic counseling for BRCA 1/2 mutations in women with a family history of breast or ovarian cancer. The association can not be explained by differences in education, cancer risk, age or race. A possible hypothesis for this association is that internet use exposes women to more information about genetic testing, BRCA testing opportunities and the experiences of other women who have utilized BRCA counseling services. No significant financial relationships to disclose.

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Germline mutations in Brazilian pancreatic carcinoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16749 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16749-e16749

Author(s):

Livia Munhoz Rodrigues ◽

Simone Maistro ◽

Maria Lucia Hirata Katayama ◽

Luiz A.Senna Leite ◽

Joao Glasberg ◽

...

Keyword(s):

Pancreatic Cancer ◽

Genetic Testing ◽

Family History ◽

Pancreatic Carcinoma ◽

Germline Mutations ◽

Family History Of Cancer ◽

First Degree Relatives ◽

Pathogenic Variants ◽

History Of ◽

History Of Cancer

e16749 Background: Pancreatic cancer has the prospect of becoming the second leading cause of cancer death by 2030. The NCCN Guidelines recommend genetic testing for all patients with pancreatic cancer, however, the spectrum of germline mutations has not been extensively evaluated because recent studies with genetic testing have explored only a limited number of genes and have focused predominantly on Caucasian populations. Therefore, our objective is to evaluate the frequency and spectrum of germline mutations in unselected patients with pancreatic cancer in a multiethnic population. Methods: Patients from Instituto do Câncer do Estado de São Paulo (Brazil) with histopathological diagnosis of non-endocrine pancreatic carcinoma were included, regardless of the family history of cancer. These patients answered a life habits and family history of cancer questionnaire and supplied blood for the Next Generation Sequencing (MiSeq platform) with the TruSight Hereditary Cancer panel (Illumina), which includes 115 cancer predisposing genes. Variant analysis was performed with the VarStation, a Brazilian tool that offers post-sequencing computational support and aid for clinical interpretation. Results: To the present moment, 77 patients were evaluated. The mean age of the patients was 62 years (27-83), among whom, 13% with young age (≤50 years) and 47 women (61%). Thirty-eight patients (49%) reported cases of cancer in first-degree relatives. Regarding risk factors, 41 patients (53%) reported smoking, 19 (25%) alcohol ingestion and 20 (26%) had obesity. Seven out of 77 patients presented pathogenic variants in ATM (n = 2) , CHEK2, FANCM (n = 2) or PALB2 (n = 2) genes. Two of these patients ( CHEK2 and FANCM) had early onset pancreatic cancer (≤45 years), both denied smoking habit and family history of cancer in 1st degree relatives. Two patients, who were ATM mutation carriers, reported 1st or 2nd degree relatives with cancer and are alive after 4 and 8 years of diagnosis. Conclusions: In this unselected group of pancreatic cancer patients, 15% were young, almost half reported first-degree relatives with cancer and 9% were carriers of pathogenic variants in genes related with the homologous recombination DNA repair.

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Elucidating the phenotypic variability associated with the polyT tract and TG repeats in CFTR

10.1101/2020.12.02.20242719 ◽

2020 ◽

Author(s):

Keith Nykamp ◽

Rebecca Truty ◽

Darlene Riethmaier ◽

Julia Wilkinson ◽

Sara L. Bristow ◽

...

Keyword(s):

Genetic Counseling ◽

Family History ◽

Hereditary Cancer ◽

Phenotypic Variability ◽

Clinical Information ◽

History Of ◽

Disease Risks ◽

Reduced Penetrance ◽

The Individual ◽

Single Organ

ABSTRACTPurposeTo evaluate the risk and spectrum of phenotypes associated in individuals with one or two of the CFTR T5 haplotype variants (TG11T5, TG12T5 and TG13T5) in the absence of the R117H variant.MethodsIndividuals who received testing with CFTR NGS results between 2014 and 2019 through Invitae at ordering provider discretion were included. TG-T repeats were detected using a custom-developed haplotype caller. Frequencies of the TG-T5 variants (biallelic or in combination with another CF-causing variant [CFvar]) were calculated. Clinical information reported by the ordering provider (via requisition form) or the individual (during genetic counseling appointments) was examined.ResultsAmong 548,300 individuals, the minor allele frequency of the T5 allele was 4.2% (TG repeat distribution: TG11=68.1%, TG12=29.5%, TG13=2.4%). When present with a CFvar, each of the TG[11-13]T5 variants were significantly enriched in individuals with a “high suspicion” of CF/CFTR-RD (personal/family history of CF/CFTR-RD) compared to those with very “low suspicion” for CF or CFTR-RD (hereditary cancer testing, CFTR not requisitioned). Compared to CFvar/CFvar individuals, TG[11-13]T5/CFvar individuals generally had single organ involvement, milder symptoms, variable expressivity, and reduced penetrance.DiscussionData from this study provides a better understanding of disease risks associated with inheriting TG[11-13]T5 variants and has important implications for reproductive genetic counseling.

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Haemophilia A in a Female Patient with Turner Syndrome

Haematology Journal of Bangladesh ◽

10.37545/haematoljbd20178 ◽

2019 ◽

Vol 1 (01) ◽

pp. 26-27

Author(s):

Salma Afrose

Keyword(s):

Family History ◽

Turner Syndrome ◽

Haemophilia A ◽

Bleeding Tendency ◽

Factor Viii Activity ◽

Sexual Character ◽

Negative Family History ◽

Primary Amenorrhoea ◽

First Case ◽

History Of

A 28-year-old female presented with occasional swelling of knees and prolonged bleeding after trauma. She also complained of gum bleeding in few occasions. She also gave history of primary amenorrhoea and failure of development of secondary sexual character. There was negative family history of bleeding tendency in both maternal and paternal family. Her investigation profile showed prolonged Partial Thromboplastin Time and reduced factor VIII activity (2.5%). Karyotyping showed (45 XO) Turner syndrome. This is the reported first case of association of Turner syndrome with moderate Haemophilia A in Bangladesh.

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Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing

10.1101/497917 ◽

2018 ◽

Author(s):

Brooke N. Wolford ◽

Whitney E. Hornsby

Keyword(s):

Family History ◽

Aortic Dissection ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Family Members ◽

Aortic Disease ◽

Thoracic Aortic Dissection ◽

Pathogenic Variants ◽

Whole Exome ◽

History Of

ABSTRACTBackgroundThoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members.MethodsWe performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.ResultsTwenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed significant risk factors associated with pathogenic variants are age <50 [odds ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7).ConclusionsClinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset of aortic dissection <50 years old, family history of aortic disease, and no history of hypertension.

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A high proportion of novel ACAN mutations and their prevalence in a large cohort of Chinese short stature children

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab088 ◽

2021 ◽

Author(s):

Li Lin ◽

Mengting Li ◽

Jingsi Luo ◽

Pin Li ◽

Shasha Zhou ◽

...

Keyword(s):

Growth Hormone ◽

Family History ◽

Short Stature ◽

Bone Age ◽

Hormone Treatment ◽

Pathogenic Variants ◽

Common Causes ◽

History Of ◽

The Common ◽

Next Generation Sequencing Ngs

Abstract Context Aggrecan, encoded by ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated. Objective We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone (GH) therapies. Patients and Methods Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by Next-generation sequencing (NGS)-based test. Result We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort, it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, five out of eleven ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SDS improvement. Conclusion Our data suggested that ACAN mutation is one of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.

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ATM Germline Variant Increases the Risk of MPN Progression

Blood ◽

10.1182/blood-2019-125362 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 835-835

Author(s):

Theodoros Karantanos ◽

Shruti Chaturvedi ◽

Christopher D Gocke ◽

Donna Marie Williams ◽

Alison R. Moliterno ◽

...

Keyword(s):

Family History ◽

Somatic Mutations ◽

Chromosomal Abnormalities ◽

Positive Family History ◽

Driver Mutation ◽

Free Survival ◽

Germline Variants ◽

Germline Variant ◽

Kaplan Meier ◽

History Of

Introduction: Chronic myeloproliferative neoplasms (MPN) share the same driver mutations but their disease course and prognosis varies significantly. Deficiency of DNA damage repair (DDR) due to germline mutation is known to predispose to certain cancer types and has been implicated in the biology of MPN. The aim of our study was to evaluate the impact of germline variants in DDR genes in the natural history and outcomes of MPN patients. Patients and Methods: 76 individuals who were diagnosed with MPN (essential thrombocytosis (ET), polycythemia vera (PV) and primary myelofibrosis (PMF)) at Johns Hopkins University Hospital were included in this study. Targeted sequencing of 63 genes implicated in myeloid malignancies was performed as part of a standard clinical evaluation. Germline variants were determined by a variant allele frequency between 40-60% in blood samples and presence in the dbSNP database. Only rare variants (minor allele frequency < 0.01) were included in this analysis. Regression analysis was used to determine the association of the presence of germline variants with disease phenotype, driver mutation, number of somatic mutations, age and sex. Cox regression and Kaplan-Meier were used to assess the implication of germline variants in the progression to MF. Results: Median time from diagnosis to enrollment and follow up were 6 and 11 years respectively. 22 patients (28.9%) had at least one variant in a DDR gene, with ATM the most frequent (11/76 patients, 14.5%). Other recurrently mutated DDR genes included RECQL4 (6/76 patients, 7.9%), ATRX and RAD50 (Figure 1A). Patients with an ATM germline variant had higher incidence of a second malignancy (OR 4.37, 95% CI 1.16 - 16.46, P=0.029), a non-significant trend toward positive family history of malignancy (OR 3.75, 95% CI 0.91 - 15.46, P=0.067) and higher incidence of both second malignancy and positive family history of cancer (OR 4.58, 95% CI 1.17 - 17.94, P=0.029) (Figure 1B). The presence of an ATM germline variant was associated with MF or AML as opposed to ET or PV at the time of sequencing (RRR 5.84, 95% CI 1.12 - 30.34, P=0.036) independently of driver mutation, number of additional somatic mutations, age and male sex (Figure 1C). We did not find a significant difference in the number of somatic mutations between patients with and without ATM variant, however there was a trend toward increased chromosomal abnormalities among patients with ATM variant (Figure 1D). Finally, the presence of ATM variant was associated with higher risk of MF transformation (HR 3.43, 95% CI 1.02 - 11.6, P=0.047) independently of driver mutation (JAK2 Ref, CALR - HR 0.79, 95% CI 0.21 - 2.94, P=0.73) and male sex (HR 1.4, 95% CI 0.52 - 3.76, P=0.68). Kaplan-Meier analysis confirmed that progression to MF-free survival was shorter in patients harboring an ATM variant (P=0.01) (Figure 1E). Conclusion: The presence of a DDR gene germline variant, particularly ATM, is relatively common among patients with MPN. Patients with ATM variants had higher incidence of additional cancers and family history of malignancy, as well as an association with MF/AML phenotype and early transformation to MF. These data suggest involvement of ATM signaling in the progression of MPN, potentially via accumulation of DNA damage and genomic instability. Figure 1. A. Frequency of germline variants in MPN patients. The graph includes the gene variants identified in at least 2 distinct patients. Of known DDR related genes (in red) ATM is the most frequent (11/76 patients, 14.5%), followed by RECQL4 (6/76 patients, 7.9%) and ATRX and RAD50. B. Personal and family history of cancer among patients with and without ATM variant. Patients with ATM germline variant have higher incidence of additional malignancy (OR 4.37, 95% CI 1.16 - 16.46, P=0.029), higher incidence of family history of malignancy (OR 3.75, 95% CI 0.91 - 15.46, P=0.067) and higher incidence of concurrent personal history of malignancy and family history of malignancy (OR 4.58, 95% CI 1.17 - 17.94, P=0.029). C. MPN subtype per ATM variant status. Patients with an ATM germline variant were more likely to have MF or AML at the time of sequencing independent of driver mutation, number of somatic mutations, age and sex. D. Patients with an ATM variant had higher number of chromosomal abnormalities. E. Kaplan-Meier analysis of progression to MF free survival(P=0.01). Disclosures Chaturvedi: Shire/Takeda: Research Funding; Alexion: Consultancy; Sanofi: Consultancy.

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