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So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)., Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.

Male factors account for roughly half of infertility cases, with most male infertility diagnosed as idiopathic. Researchers predicting intrauterine insemination success rates have identified multiple prognostic factors, including semen parameters and seminal fluid composition. Seminal plasma contains extracellular exosomes, which contain RNAs and proteins involved in spermatogenesis. The contents of seminal plasma exosomes may be an indicator of overall sperm quality or fertility potential; therefore, analysis of exosomes may provide a measure for sperm viability and fertilization potential. In our study, exosomes were isolated and purified from seminal plasma obtained from IUI treatments with known pregnancy outcomes. We used a unique method to isolate the exosomes which made use of the hydrophobic interaction chromatography method. RNASeq was performed on RNAs from the purified exosomes. This analysis revealed holistic trends, including increased expression associated with RNA originating from chromosomes 1, 10, 12, 16 and 21. Overall, total RNA was significantly decreased and rRNA was significantly increased in successful IUI attempts. Furthermore, we found specific mRNAs and lincRNAs associated with positive versus negative pregnancy outcomes. Our study isolated and purified seminal plasma exosomes without ultracentrifugation, and it provides further evidence for differences in seminal plasma exosome molecular contents associated with pregnancy status.

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we performed a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identified a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identified a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N=1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology by identifying putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Canadian Institutes of Health Research, Grant/ Award Number: 81274; Huntsman Cancer Institute Pilot Funds; Leukemia Lymphoma Society, Grant/Award Number: 6067-09; the National Institute of Health/National Cancer Institute, Grant/Award Numbers: P30 CA016672, P30 CA042014, P30 CA13148, P50 CA186781, R01 CA107476, R01 CA134674, R01 CA168762, R01 CA186646, R01 CA235026, R21 CA155951, R25 CA092049, R25 CA47888, U54 CA118948; Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah; VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council, Grant/Award Numbers: 1074383, 209057, 396414; Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database; Mayo Clinic Cancer Center; University of Pisa and DKFZ, The authors thank all site investigators that contributed to the studies within the Multiple Myeloma Working Group (Interlymph Consortium), staff involved at each site and, most importantly, the study participants for their contributions that made our study possible. This work was partially supported by intramural funds of University of Pisa and DKFZ. This work was supported in part by the National Institute of Health/National Cancer Institute (R25 CA092049, P30 CA016672, R01 CA134674, P30 CA042014, R01 CA186646, R21 CA155951, U54 CA118948, P30 CA13148, R25 CA47888, R01 CA235026, R01 CA107476, R01 CA168762, P50 CA186781 and the NCI Intramural Research Program), Leukemia Lymphoma Society (6067-09), Huntsman Cancer Institute Pilot Funds, Utah PopulationDatabase, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah StateDepartment of Health, University of Utah, Canadian Institutes of Health Research (Grant number 81274), VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council (Grants 209057, 396414, 1074383), Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database and the Mayo Clinic Cancer Center.Open Access funding enabled and organized by ProjektDEAL., The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions., Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10(-7) either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients., Canadian Institutes of Health Research (CIHR) 81274, Huntsman Cancer Institute Pilot Funds, Leukemia and Lymphoma Society 6067-09, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) P30 CA016672 P30 CA042014 P30 CA13148 P50 CA186781 R01 CA107476 R01 CA134674 R01 CA168762 R01 CA186646 R01 CA235026 R21 CA155951 R25 CA092049 R25 CA47888 U54 CA118948, Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah, VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council 1074383 209057 396414, Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database, Mayo Clinic Cancer Center, University of Pisa, Helmholtz Association

Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10−6), EOMES (P = 6.0 × 10−6) and BTNL2 (P = 2.1 × 10−3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.

Key Points Pre-HCT mosaicism is related to increased relapse risk and lower survival after unrelated HCT, independent of cytogenetics at diagnosis. Pre-HCT mosaicism could be a useful clinical tool to guide risk stratification in acute lymphoblastic leukemia patients.

Although survival outcomes have significantly improved, up to 40% of patients die within 1 year of HLA-matched unrelated-donor blood and marrow transplantation (BMT). To identify non-HLA genetic contributors to mortality after BMT, we performed the first exome-wide association study in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip. This study includes 2473 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome and 2221 10/10 HLA-matched donors treated from 2000 to 2011. Single-variant and gene-level analyses were performed on overall survival (OS), transplantation-related mortality (TRM), and disease-related mortality (DRM). Genotype mismatches between recipients and donors in a rare nonsynonymous variant of testis-expressed gene TEX38 significantly increased risk of TRM, which was more dramatic when either the recipient or donor was female. Using the SKAT-O test to evaluate gene-level effects, variant genotypes of OR51D1 in recipients were significantly associated with OS and TRM. In donors, 4 (ALPP, EMID1, SLC44A5, LRP1), 1 (HHAT), and 2 genes (LYZL4, NT5E) were significantly associated with OS, TRM, and DRM, respectively. Inspection of NT5E crystal structures showed 4 of the associated variants affected the enzyme structure and likely decreased the catalytic efficiency of the enzyme. Further confirmation of these findings and additional functional studies may provide individualized risk prediction and prognosis, as well as alternative donor selection strategies.

Background Identification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT. Methods We performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000–2011. Findings Using meta-analyses of both cohorts, genome-wide significant associations (p

Clonal mosaicism, detectable in peripheral blood, can be an important predictor of developing a hematological malignancy. We sought to determine if mosaic events, in addition to clinical and demographic variables, contributed independent information about acute lymphoblastic leukemia (ALL) patient survival and risk of relapse after allogeneic hematopoietic cell transplant (HCT). HumanOmniExpress-12v1_A BeadChip SNP array data were used to detect mosaicisms >=2Mb based on the log2 relative probe intensity ratio (LRR) and B allele frequency (BAF) for each SNP measured in 773 ALL patients from DISCOVeRY-BMT cohorts. DNA was extracted from recipient peripheral blood samples taken immediately prior to start of conditioning before allogeneic HCT for ALL (2000-2011). Mosaic events include copy-number gain (LRR >0), loss (LRR The impact of mosaicism on overall survival (OS) probability and cumulative incidence of relapse at 1-year post-HCT were calculated using the Kaplan-Meier estimator and cumulative incidence functions, respectively. The association of clonal mosaicism with OS was evaluated with multivariable Cox proportional hazard models. For disease relapse, competing risk models were used with transplant related mortality (TRM) treated as a competing event. Stratified survival analyses were performed by cytogenetic status at diagnosis. Statistical analyses were conducted using R 3.6.1. Thirty-four patients (4.4%) had 1 or more mosaicisms (82 total detected) with almost half having advanced disease (Table 1). The median proportion of affected cells was 61% (interquartile range = 39 - 93%). Copy-number losses on chromosomes 7 (13.4%) and 9 (8.54%) and 17 (6.10%) were the most frequently detected events (Figure 1). OS at 1-year post HCT in patients with and without a mosaic event was 26.5% and 60.1%, respectively, (P=8.2×10-8, Figure 2A) and normal cytogenetic patients with mosaicism had significantly lower survival compared to all other patients (OSnormal/mosaic+= 8.3% vs. OS= 60.6%, P=3.0×10-10, Figure 2B-C). ALL patients with a mosaic event also had an increased risk of disease relapse overall (Relapsemosaic+= 50% vs. Relapsemosaic-=26%, P=0.00067) and when stratified by cytogenetic abnormalities (P=0.015) and normal cytogenetics (P=0.041) (Figure 2D-F). Multivariable models of OS and relapse included age, race/ethnicity, complete remission or advanced disease status (Figure 3). Patients with a mosaic event had ~2.5 fold increase risk of death (P=2.5×10-5), independent from cytogenetics (P=8.6×10-5, Figure 3). OS associations are likely driven by the 2.8 fold increase risk of relapse (P= 5.9×10-5) which remains highly significant when stratified by cytogenetics (Figure 3). Almost half of the copy-number losses included well-known regions on chromosomes 7, 9 and 17 (Figure 1). Deletions of 7p have been shown to correlate with lower event-free survival in ALL pediatric patients. Our findings suggest mosaic loss of 7p might be an important indicator of poor OS across the lifespan, with 5/6 patients with 7p losses aged >18 years. Higher mortality was also associated with the loss of the chr9p21.3 locus, seen in all patients (N=5) with chromosome 9p losses. This region harbors tumor suppressor CDKN2A; inactivation of CDKN2A can lead to poor survival in both children and adults with ALL. Lastly, we found that all patients (N=4) with copy-number loss of 17p13.1, which contains tumor suppressor TP53 died within 1-year post-HCT. We identified detectable mosaicism prior to transplant in 4.4% of patients and showed that mosaicism was associated with lower survival and higher disease relapse at 1-year post-HCT. While mosaicism is more common in patients with advanced disease stage, mosaic events are an independent contributor to lower survival and higher relapse in the first year after transplant. This is the first study to show that mosaic events detectable in pre-transplant peripheral blood from ALL patients are correlated with poor survival. Future studies replicating these associations in different ethnicities and age groups and evaluating specific chromosomal regions could be informative in classifying patient risk post-HCT attributable to mosaic events. Disclosures McCarthy: Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. Lee:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Kadmon: Research Funding; Incyte: Consultancy, Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding.

The first three authors contributed equally. The last three authors share senior authorship. Background: Although there has been an increased recognition of the contribution of germline variants to development of myeloid neoplasms, only two large-scale case-control genome-wide association studies (GWASs) have been conducted to identify variants that predispose to AML. Importantly, these studies were dedicated to AML predisposition in general, without investigation of molecularly distinct AML subtypes. Thus, we performed the first dedicated meta-analysis combining the two GWASs to investigate predisposing variants to cytogenetic AML subsets characterized by recurrent translocations and inversions. Methods: Two sets of adult de novo AML patients treated on Alliance for Clinical Trials in Oncology (Alliance) protocols, and two sets of adult de novo AML patients reported to CIBMTR (2000-11) from DISCOVeRY-BMT cohorts were compared with four sets of population-matched non-leukemic individuals of European ancestry. Illumina Infinium arrays were used for genotyping. The haplotype reference consortium was used for imputation and comparisons were performed using SNPtest and METAL with fixed-effects, for CBF-AML (n=251, including t(8;21), n=115; inv(16), n=136) and AML with 11q23/KMT2A translocations (n=177). Blood or bone marrow samples from subsets of these patients and additional AML patients with other cytogenetic abnormalities were used for total transcriptome RNA sequencing with Illumina instruments. Results: Two risk loci reached genome-wide significance in AML patients with 11q23/KMT2A translocations (Fig 1A). The most significant single nucleotide polymorphism (SNP) in the 4q21.3 risk locus, rs17668899[A] (P = 2.32 x 10-8, odds ratio [OR] = 3.92 [2.43-6.32]) is in intron 6 of the AFF1 gene (also called AF4) (Fig 1B), within an enhancer that interacts with the AFF1 transcription start site (Fig 1C, left). KMT2A-translocated AML patients with the risk allele had higher blast expression of AFF1 compared to those homozygous for the non-risk allele, although the trend did not reach significance (Fig 1D). Notably, AFF1 encodes a subunit of the super-elongation-complex (SEC) that acts as Pol II-associated master regulator of global transcription elongation. AFF1 is a common translocation partner of KMT2A in patients with acute lymphoblastic leukemia with t(4;11)(q21;q23), and is required for KMT2A-mediated leukemogenesis. We observed significantly higher AFF1 expression in both KMT2A-translocated AML and cytogenetically normal (CN) AML compared to CBF-AML (Fig 1E). The suggested role of AFF1/SEC is consistent with recent studies showing an important role for DOT1L, H3K79 methylation, and transcriptional elongation in NPM1-mutant AML (the most common subtype of CN-AML). Outcome analysis showed higher expression of AFF1 associated with shorter disease-free (DFS) in patients < 60 years treated on Alliance studies (hazard ratio [HR] = 1.36, P=0.04; Fig 1F). The second KMT2A-translocated AML risk locus was located at 22q13.31, and the most significant SNP was rs62231468[A] (P = 4.95 x 10-9, OR = 3.25). rs62231468 is immediately 5' of the LDOC1L gene (a retrotransposon GAG-related gene, also called RTL6), and analysis of expression quantitative trait loci (eQTL) showed association of rs62231468[A] with higher LDOC1L expression, consistent with its location in an active enhancer (Fig 1C, right). The association between rs62231468[A] and higher LDOC1L expression was validated in leukemic blast expression from a set of 449 AML patients of any cytogenetic subset (Fig 1G). Notably, higher LDOC1L expression was associated with shorter DFS and overall survival (OS) in Alliance patients < 60 years (DFS, HR = 1.25, P=0.03; OS, HR = 1.46, P Analysis of patients with CBF-AML identified rs71568004[C] as more common in CBF-AML patients compared to controls (P = 3.84 x 10-8 , OR = 3.05 [2.05-4.53]). This SNP is ~50kb 5' of the MARCKS gene located at 6q21, but genomic context analysis did not reveal any clear associations with MARCKS expression. Conclusions: Our first assessment of risk alleles for cytogenetic subsets of AML identified two novel independent risk loci associated with 11q23/KMT2A-translocated AML, and one risk locus associated with CBF-AML. These data suggest an important, subtype-specific role for transcriptional elongation in AML and that functional studies of retro transposition elements should be undertaken in leukemogenesis. Figure Disclosures Walker: Karyopharm: Current Employment, Current equity holder in publicly-traded company; Vigeo Therapeutics: Consultancy. Powell:Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Genentech: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Kolitz:Pfizer: Membership on an entity's Board of Directors or advisory committees; Magellan: Membership on an entity's Board of Directors or advisory committees. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding. McCarthy:Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding. Stone:AbbVie: Consultancy, Research Funding; Actinium: Consultancy; Agios: Consultancy, Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Arog: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Biolinerx: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Takeda: Consultancy; Daiichi-Sankyo: Consultancy; Elevate: Consultancy; Gemoab: Consultancy; Janssen: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy; Stemline: Consultancy; Syndax: Consultancy; Syntrix: Consultancy; Syros: Consultancy. Byrd:Trillium: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Syndax: Research Funding; Vincera: Research Funding; Acerta Pharma: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau. Eisfeld:Karyopharm: Current Employment, Current equity holder in publicly-traded company; Vigeo Therapeutics: Consultancy.

Introduction Genetic abnormalities can predispose patients to develop acute myeloid leukemia (AML), aplastic anemia (AA) and myelodysplastic syndrome (MDS). These mutations are more often seen in pediatric patients so genetic screening is more routinely performed in that population. Recent algorithms propose screening in adolescent and young adults (AYAs) with AML/AA/MDS. However, this is not routine practice in community hospitals where most AYAs are treated. Discovery of familial genetic abnormalities can impact donor choice in patients undergoing allogeneic stem cell transplant and treatment/screening in family members. Objectives The goal of this study is to determine the rate of genetic screening in AYAs with AML/AA/MDS based on recently proposed screening algorithms in a community hospital setting. Methods Patients with AML/AA/MDS aged ≤50 years treated at Prisma Health Upstate (2015 to 2019) were included in this retrospective study. While the AYA population is typically defined as ages 18-39, we included patients up to age 50 given screening recommendations from some centers. Charts were reviewed to determine rates of genetic screening based on published algorithms from M.D. Anderson Cancer Center. We compared rates of screening in pediatric and AYA patients and documentation of pertinent family history. Results Thirty-nine patients (12 pediatric, median age: 9 years; 27 AYA, median age: 33 years) diagnosed with AML (n=19)/MDS (n=6)/AA (n=14) were included in the study. Genetic screening was performed in 8/12 (67%) pediatric patients and 8/27 (30%) in AYAs (P Conclusions Screening for hereditary predispositions to hematologic malignancies in AYAs is underperformed despite recent evidence suggesting otherwise. We report low rates of screening in our community hospital where transplant is a treatment option for AYAs with MDS/AA/AML. In addition to donor considerations, predisposition syndromes can affect treatment toxicities, conditioning regimens, and screening of family members. Our results, despite the small sample size, indicate a high detection rate of genetic abnormalities and need for improving focused family history documentation. Based on our findings, we will implement an institution wide genetic screening protocol for AYAs with MDS/AA/AML.

We and others have shown increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (MM). Whether familial risk of MGUS differs by the MM proband's age at onset, tumor or clinical characteristics is unknown. MM and smoldering MM (SMM) cases (N = 430) were recruited from the Mayo Clinic in Rochester, Minnesota between 2005-2015. First-degree relatives over age 40 provided serum samples for evaluation of MGUS (N = 1179). Age and sex specific rates of MGUS among first-degree relatives were compared to a population-based sample. Cytogenetic subtypes were classified by Fluorescence in situ hybridization. MGUS was detected in 75 first-degree relatives for an age- and sex- adjusted prevalence of 5.8% (95% CI: 4.5-7.2). Prevalence of MGUS in first-degree relatives was 2.4 fold (95% CI: 1.9-2.9) greater than expected rates. Familial risk did not differ by proband's age at diagnosis, gender, isotype, IgH translocation, or trisomy. This study confirms first-degree relatives of MM cases have a significantly higher risk of MGUS compared to the general population, regardless of age, gender, or tumor characteristics. In selected situations, such as multiple affected first-degree relatives, screening of first-degree relatives of MM cases could be considered for follow-up and prevention strategies.

Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN.Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versusgrade 3 in CALGB 40101 assuming a fixed effects model.The percentage of ≥grade 3 TIPN in 1269 European Americans and 139 African Americans in S0221, was 11.6 and 22.3%, respectively. CALGB 40101 ≥grade 3 TOPN was 7.2%. The most significant association with ≥grade 3 TIPN was the G allele of rs1858826 in GNGT1 (Pmeta=1.1×10), which showed a decrease in risk of ≥grade 3 TIPN (odds ratio=0.29, 95% confidence interval: 0.18-0.46).The genetic variants associated with ≥grade 3 TIPN are hypothesized to have biochemical functions and reside in and near genes involved in diabetes and diabetic neuropathy. This finding is consistent with results from CALGB 40101 pathway analyses. Larger homogeneous trials with similar dosing and criteria for defining neuropathy are needed to properly assess the relationship of genomics with the neuropathy spectrum.

Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at P < .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at P < .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at P < .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes.

The incidence and mortality rates of B-cell acute lymphoblastic leukemia (B-ALL) differ by age and sex. To determine if inherited genetic susceptibility contributes to these differences we performed 2 genome-wide association studies (GWAS) by age, sex, and subtype and subsequent meta-analyses. The GWAS included 446 B-ALL cases, and 3027 healthy unrelated blood and marrow transplant (BMT) donors as controls from the Determining the Influence of Susceptibility Conveying Variants Related to One-Year Mortality after BMT (DISCOVeRY-BMT) study. We identified 1 novel variant, rs189434316, significantly associated with odds of normal cytogenetic B-ALL (odds ratio from meta-analysis [ORmeta] = 3.7; 95% confidence interval [CI], 2.5, 6.2; P value from meta-analysis [Pmeta] = 6.0 × 10-9). The previously reported pediatric B-ALL GWAS variant, rs11980379 (IKZF1), replicated in B-ALL pediatric patients (ORmeta = 2.3; 95% CI, 1.5, 3.7; Pmeta = 1.0 × 10-9), with evidence of heterogeneity (P = .02) between males and females. Sex differences in single-nucleotide polymorphism effect were seen in those >15 years (OR = 1.7; 95% CI, 1.4, 2.2, PMales = 6.38 × 10-6/OR = 1.1; 95% CI, 0.8, 1.5; PFemales = .6) but not ≤15 years (OR = 2.3; 95% CI, 1.4, 3.8; PMales = .0007/OR = 1.9; 95% CI, 1.2, 3.2; PFemales = .007). The latter association replicated in independent pediatric B-ALL cohorts. A previously identified adolescent and young-adult onset ALL-associated variant in GATA3 is associated with B-ALL risk in those >40 years. Our findings provide more evidence of the influence of genetics on B-ALL age of onset and we have shown the first evidence that IKZF1 associations with B-ALL may be sex and age specific.

Background: Multiple myeloma (MM) treatment has advanced considerably with proteasome inhibitors, immunomodulatory drugs (IMiDs), and, most recently, monoclonal antibodies. However, treatment response is quite heterogeneous, and many patients still progress even with novel combination therapies. Thus, understanding the factors that underlie response to treatment is a priority. Several somatic genomic aberrations and mutations predict poor response to therapy. However, germline variation has not previously been investigated as a predictor of treatment response in MM. We used genome-wide association and transcriptome-wide association approaches to identify germline genetic predictors of treatment response in MM. Methods: We included 510 MM patients from Mayo Clinic and 324 MM patients from UCSF diagnosed from 1999-2015. Basic demographics, laboratory values and pathology at diagnosis, type of initial therapy, duration of therapy, and follow-up were ascertained by chart review. Patients were grouped into categories of treatment based on their first line therapy: proteasome inhibitor-based regimen, IMiD based regimen, combination proteasome and IMiD based regimen, or other. Response was assessed using International Myeloma Working Group (IMWG) response criteria after 4-6 cycles of induction. As such, response was categorized into progressive disease (PD), minimal response (MR), partial response (PR), very good partial response (VGPR), or complete response (CR). Germline samples were genotyped using Illumina or Affymetrix arrays and were imputed based on the Haplotype Reference Consortium (HRC). For the genome-wide association study (GWAS), we included all SNPs with minor allele frequency >0.01 and imputation r2 of >0.5. We tested each SNP for association with treatment response using a linear regression model that adjusted for age, gender, and genetic ancestry (from principal components analysis (PCA)). To perform the transcriptome-wide association study (TWAS), we calculated predicted gene expression data using PREDIXCAN software on a reference cohort of 922 individuals with genotype and RNA expression data from peripheral blood. We then tested the association between predicted gene expression and response to therapy using linear regression models. Both the GWAS and TWAS were performed on subgroups of patients who received either proteasome inhibitors or IMiD therapies. The analyses of patients on proteasome inhibitors were adjusted for IMiD use as a covariate and analyses of patients on IMiDs were adjusted for proteasome inhibitor use. The threshold for genome-wide significance loci was set at P = 5 x 10-8 and the threshold for suggestive loci was set at P = 10-6. The threshold for significance for TWAS was set at P = 4 x 10-6 by using a Bonferroni correction for the number of genes for which genetic models of expression could be developed by PREDIXCAN. Results: Overall, 42.7% (59 of 138) of patients on proteasome inhibitors alone, 32.5% (66 of 203) of patients on IMiDs alone, and 58.1% (50 of 86) of patients on combination achieved at least a VGPR. There were no significant differences in response across centers in analyses that adjusted for age, sex and types of therapy. There were no genome wide significant loci to predict for response. We identified 8 suggestive SNPs associated with proteasome inhibitor response and 4 suggestive SNPs associated with IMiD response. TWAS identified ZNF622 as a candidate genetic modifier of proteasome inhibitor effect that was significant after correction for multiple hypothesis testing (P = 1.6 x 10-6). Higher genetically predicted expression was associated with improved response to proteasome inhibitor therapy. Among patients above the median of predicted expression of ZNF622 on proteasome inhibitors, 62.6% achieved at least VGPR; among patients at or below the median of expression, only 37.6% achieved at least VGPR. Conclusions: We identified an association between predicted expression of ZNF622 and clinical response to proteasome inhibitor therapy among MM patients. ZNF622 is a zinc finger binding protein which is known to be co-activator of B Myb activity and to affect apoptosis in response to oxidative stress. Our work highlights the potential importance of pharmacogenetic modifiers of treatment response in MM. Disclosures Shah: Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; University of California, San Francisco: Employment; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wong:Celgene: Research Funding; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.

Background Genome-wide association studies (GWAS) conducted in populations of European ancestry (EA) have identified and confirmed 23 germline susceptibility loci for multiple myeloma (MM). The effect sizes of single nucleotide polymorphisms (SNPs) at these loci are small, therefore combining them into a single summary measure, known as a polygenic risk score (PRS), may provide a more meaningful risk factor. We have previously shown a PRS comprised of the 23 SNPs for MM contributes to increased risk of MM, with a 2.7-fold increase for highest vs. lowest PRS quintiles. Whether the MM-PRS is also associated with overall survival (OS) in MM cases has not been evaluated. We examined the association between MM-PRS and OS in two EA studies. Methods The first study consisted of 2,179 EA MM cases from ten studies included in the Multiple Myeloma Working Group within the International Lymphoma Consortium (InterLymph). Cases were diagnosed between 1970 and 2015 and genotyped using multiple platforms (Oncoarray, Affymetrix, Human660W-quad Beadchip, and Illumina arrays); 885 cases also had stage [based on International Staging System (ISS)] available. Each of the GWAS was subjected to rigorous standard quality control independently (prior to imputation via the Michigan imputation server based on the Haplotype Reference Consortium (HRC). The second study consisted of 515 newly diagnosed EA MM cases from CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile), diagnosed from 2011-2013, who had whole genome sequencing (WGS) performed on germline DNA. The WGS data was used to call common germline genetic variants through the Mayo Clinic bioinformatics pipeline. Briefly, genetic variants were detected with GenomeGPS, aligned to the hg19 reference genome, called using the GATK (V3.6) Haplotype Caller, and merged for multiple-sample joint calling. To reduce the false positive variants, variant quality score recalibration (VQSR) was applied for both SNPs and INDELs. After quality control, 458 EA samples remained. Follow-up was available for both studies and consisted of time from MM diagnosis date until death or date of last known follow-up. The PRS was constructed from the 23 MM SNPs using the published per allele odds ratio associated with MM risk. The published log odds ratios for each SNP were multiplied by the number of risk alleles (0, 1, 2) for the corresponding SNP, and summed, resulting in a unique score per person. Kaplan-Meier curves and Cox proportional hazard models were used to assess the association between PRS with MM OS considering two models: 1) adjusted for age, sex, study and 2) additional adjustment by stage (ISS). Hazard ratios (OR) and 95% confidence intervals (CI) were estimated. The PRS was evaluated both as a continuous variable, per standard deviation (SD), and as a categorical variable (quintiles). Results MM cases (N=2,179) in the InterLymph study were 59% male and 41% female and the median age was 61.0 years (26-90 years). Median follow-up time was 57.2 months (1.0-509.0 months) with 868 reported deaths. MM cases with stage information available consisted of 20% stage I (n=178), 53% stage II (n=466), and 27% stage III (n=241). No association was observed between PRS and OS in MM patients regardless of adjustment for stage (continuous PRS (HR: 1.03, 95% CI: 0.83-1.28, P=0.80) or by quintile PRS (p>0.05)) (Table). The CoMMpass EA MM cases (n=458) had similar distributions for sex (61% male and 39% females) but were slightly older 65 years (27-93 years) and had shorter follow-up time (median=39.75 months (0.13-77.2)) with 117 deaths. Stage was available for 96% of CoMMpass cases including 36% stage I (n=159), 33% stage II (n=146), and 31% stage III (n=134). We also observed no association of PRS and OS in the CoMMpass study (HR=1.02, 95% CI: 0.72 -1.46, P= 0.89), adjusted for age, sex, and stage (Table). Discussion A PRS score for MM risk is not associated with OS for MM cases in two EA populations. Given that prior studies have shown association of genetic variation with MM survival, efforts to identify additional loci associated with OS or MM specific survival are warranted. Future studies should also consider germline variants impact on molecular subtypes, specific therapies, and outcomes. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Genome-wide association studies (GWAS) conducted among populations of European ancestry (EA) have identified 23 common single nucleotide polymorphisms (SNPs) associated with multiple myeloma (MM) risk. We hypothesize that the combination of these SNPs in a polygenic risk score (PRS) is likely to be a strong risk factor for MM. However, it is unclear whether the genetic variation associated with MM susceptibility also predisposes to monoclonal gammopathy of undetermined significance (MGUS). Thus, we calculated a PRS and evaluated the association with risk of MM and its precursor, MGUS. We pooled genotype data for 2434 MM and 3446 controls from ten MM GWAS of individuals of EA within the Interlymph Consortium, for 23 MM risk SNPs identified by prior GWAS. An additional 754 MGUS cases were ascertained from Mayo Clinic and MD Anderson clinical practices. To calculate the PRS, we used the risk estimates corresponding to the 23 SNP associations from the largest published MM GWAS. The log of the odds ratio (OR) for each SNP was multiplied by the respective number of risk alleles and summed to generate a PRS for each individual. The PRS was examined continuously, per one standard deviation (SD), and as quintiles, based on the PRS distribution in the controls. Associations of PRS with MM and MGUS risk were examined separately, using multivariable logistic regression assuming an additive model to assess ORs and 95% confidence intervals adjusted for age, sex, and site. We also evaluated age and sex stratified models. The distribution of sex within MM cases, MGUS cases and controls were each ~60% male and ~40% female. The median age was 61, 66, and 66 years for MM cases, MGUS cases and controls, respectively. PRS ranged from 1.52-4.91, with a median PRS of 3.21 for MM cases, 3.19 for MGUS cases, and 3.05 for controls. PRS was significantly associated with MM risk when assessed continuously (OR=1.19 per SD, p=2.2x10-16) and categorically; compared with the middle quintile (Q3), individuals in the highest quintile (Q5) had a 66% increased MM risk (OR=1.66, p=2.3x10-9) and those in the lowest quintile (Q1) had a 38% decreased MM risk (OR=0.62, p=1.3x10-6). PRS was also significantly associated with MGUS risk (OR=1.19 per SD, p=1.7x10-11); individuals with the highest PRS (Q5) had a 77% increased risk (OR=1.77, p=4.0x10-4) and those with lowest PRS (Q1) had 30% decreased risk (OR=0.70, p=0.04), compared with Q3. When stratified by age and sex, similar associations and trends were found. Using an independent sample of MM / MGUS cases and controls, we showed that a PRS constructed from 23 common genetic variants for MM risk is associated with risk of both MM and MGUS, regardless of age or sex. A future direction of this work is testing associations with PRS and clinical characteristics of the MM cases, as well as differences between MGUS cases that progress and those that do not. Our results suggest that common genetic variation may predispose to MGUS as the precursor to MM. Citation Format: Alyssa I. Clay-Gilmour, Michelle A. Hildebrandt, Nicola J. Camp, Elad Ziv, Elizabeth E. Brown, Jonathan N. Hofmann, John J. Spinelli, Graham G. Giles, Parveen Bhatti, Wendy Cozen, Xifeng Wu, Dennis P. Robinson, Aaron D. Norman, Jason P. Sinnwell, Shaji K. Kumar, S Vincent Rajkumar, Susan L. Slager, Celine M. Vachon. Associations between a polygenic risk score and risk of multiple myeloma and its precursor [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 2686.

Introduction Multiple myeloma (MM) is a result of a malignant transformation of plasma cells that is preceded by the presence of an asymptomatic clonal plasma cell expansion, a condition referred to as monoclonal gammopathy of undetermined significance (MGUS). We and others have shown familial aggregation of MM and MGUS. Evidence from epidemiologic, family and genome-wide association studies (GWAS) suggests a genetic component underlying MM etiology. GWAS have successfully established 17 common genetic risk loci for MM to date and recently, rare inherited susceptibility variants in the LSD1 / KDM1A and USP45 genes were identified in familial MM / MGUS kindreds. Family-based approaches may be used to elucidate genetic variation contributing to familial MM. Genetic linkage analysis has historically been used to detect the chromosomal location of disease genes. The objective of this study was to conduct a linkage analysis of MM / MGUS families to identify genomic regions for MM / MGUS. Methods Linkage analysis was performed on whole exome sequencing (WES) data generated from germline DNA extracted from peripheral blood from MM / MGUS families ascertained at four sites, of which 79 were selected with 2 or more affected members with any combination of MM or MGUS. Whole exome capture was performed using Agilent SureSelect 38 Mb paired end sequencing and ran on Illumina HiSeq 2000s/2500s; standard analyses for alignment (GRCh37) and quality control were conducted. The Genome Analysis Toolkit's (GATK) HaplotypeCaller in per-sample mode was used to jointly call all the samples together. Quality control included removing variants that had Results Among the 79 families, 28 consisted of two or more MM, 41 had two or more MM and MGUS cases and 10 had two or more MGUS. Analyses of the 79 MM / MGUS families identified chromosome 6 at 123420001-149070000 BP region, with evidence for linkage by the non-parametric model (LOD score=3.3) and supportive evidence for linkage by the dominant parametric model (LOD=2.5) (Figure). The chromosome 6 region, which is outside the HLA-region, contains a total of 72 genes. Using gene-level association tests, we identified four genes within the region (MOXD1, TRDN, ADAT2, LTV1) that were associated within MM / MGUS in the family cases (p Discussion We found evidence for a locus on chromosome 6 linked to MM / MGUS. Four genes in this region may be associated with MM / MGUS in these families. Follow-up of these genes/variants in high-risk individuals (early-onset / age Disclosures Dumontet: Roche: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

CLL is a highly heritable cancer with first degree relatives of CLL cases having a 7.5-fold increased CLL risk. Genome-wide association studies (GWAS) and linkage studies have been performed to study inherited predisposition; however a larger proportion of heritability to CLL remains unexplained. Rare coding variants might account for the missing heritability information. Inherited loss of function variants in shelterin complex genes (POT1, ACD, TERF1, TINF2, TERF2, TERF2IP- involved in telomere regulation), CDK1 (critical for cell division) and ATM (tumor suppressor gene) have been found to co-segregate in CLL families and be enriched in CLL cases using exome-wide sequencing data. Our study evaluates rare germline variants from these suspect genes segregating in CLL families who are followed at the Mayo Clinic. Using whole exome sequencing (WES), we sequenced 93 CLL families with at least 2 reported CLL cases consisting of 443 individuals: 160 with CLL, 73 with monoclonal B-cell lymphocytosis (MBL), and 210 relatives. DNA was extracted from buccal cells, coding exons were selectively captured using Agilent 50Mb and SureSelect Human All Exon V4 capture kits; sequencing was performed using Illumina HiSeq 2000. Mayo Clinic's DNASeq pipeline uses Novoalign (initial read alignment), Picard (marking duplicate reads), and the Genome Analysis Toolkit (GATK) for local realignment, recalibration, and variant calling. The variant discovery step leverages GATK's HaplotypeCaller in per sample mode and all of the samples across the cohort are jointly genotyped together. All called variants are evaluated with GATK's Variant Quality Score Recalibration tool and annotated for biological relevance (BIOR). Quality control included removing variants that had We identified three novel rare missense variants, defined as functionally deleterious, which each co-segregated within a CLL family. Specifically, these variants from shelterin complex genes; POT1 (rs116916706), TERF2IP (rs138458227), and TERF2 (rs749171225), met the criteria. This study further highlights telomere dysregulation as a key process in CLL development. Investigating rare variants within CLL pedigrees with WES can help identify germline variants impacting predisposition to familial CLL. Citation Format: Alyssa I. Clay-Gilmour, Daniel R. O'Brien, Sara J. Achenbach, Celine M. Vachon, Kari G. Chaffee, Timothy G. Call, Jose F. Leis, Aaron D. Norman, Brian F. Kabat, Sameer A. Parikh, Neil E. Kay, Esteban Braggio, James R. Cerhan, Susan L. Slager. Rare germline variants segregating in chronic lymphocytic leukemia (CLL) families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1226.