Knudson, Ryan A.

Abstract Abstract 1567 Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they are believed to promote JAK2-oligomerization and autonomous signalling although the underlying mechanisms remain unclear. Affected entities are candidates for therapy with JAK2 signalling inhibitors. Among 200 peripheral T-cell lymphomas surveyed, we identified only two with JAK2 amplification and none with JAK2 translocations, confirming their rarity in T-cell neoplasias. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in cell lines established at indolent and aggressive phases of a cutaneous T-cell lymphoma. To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 genes most upregulated in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive phase cells, was partially restored by PCM1-JAK2 knockdown. Activation of the tumor suppressor SOCS3 by PCM1-JAK2 may follow structural alteration of JAK2 affecting the ternary complex it forms with SOCS3 and receptor proteins. Treatment with JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive mimicked knockdown results, highlighting JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5 as reported for JAK2V617F or ETV6/TEL-JAK2, thus extending the paradigm of STAT5 activation by JAK2 alterations in hematopoietic malignancies. MAC-1/2A/2B are the first JAK2– translocation cell line models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2803 Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms. Ring sideroblasts (RS) represent abnormal mitochondrial iron accumulation in MDS; with ≥15% RS necessary for the conventional diagnosis of MDS-RS. Somatic spliceosome mutations are recurrent in MDS, with SF3B1 mutations being the most frequent in MDS-RS (∼75%) and SRSF2 in CMML (∼28%). The distribution of these mutations in the presence of both RS and monocytosis is unknown and their prognostic relevance, in the particular setting, undetermined. Methods: Using the Mayo Clinic database for myeloid malignancies (1997–2007), we identified patients who met the 2008 WHO criteria for CMML, and who also displayed at least 1% RS in their bone marrow (BM). All patients underwent BM examination and cytogenetic evaluation at diagnosis and the pathology slides, including iron stains, were centrally re-reviewed to accurately quantify BM RS. DNA was interrogated in the three most frequent spliceosome genes with somatic mutations; SF3B1, SRSF2 and U2AF35. Results: Sixty four patients met the above stipulated criteria for CMML with ≥1% RS; 46 (72%) were males and median age was 71 years (range, 17–90 years). Fifty three (83%) had CMML-1 and the remainder CMML-2. The percentage of patients with ≥15% RS was 41%: 30% had 15–49% RS and 11% had >50% RS. Thirty patients (47%) displayed SRSF2 mutations (mutational frequencies were 58% in the presence of <15% RS, 42% with 15–49% RS and 0% with >50% RS), 9 (14%) SF3B1 mutations (3% with <15% RS, 26% with 15–49% RS and 43% with >50% RS), and 5 (8%) U2AF35 mutations (8% with <15% RS, 11% with 15–49% RS and 0% with >50% RS). Mutational hotspots were P95 for SRSF2 (93%), K700 for SF3B1 (67%) and Q157 for U2AF35 (60%). The three spliceosome mutations were mutually exclusive. At a median follow-up of 26 months, 49 (77%) deaths and 11 (17%) leukemic transformations were documented. In univariate analysis, significant risk factors for survival included increased levels of white blood cell (WBC), absolute neutrophil (ANC), absolute monocyte (AMC), absolute lymphocyte (ALC) counts, the Spanish cytogenetics risk stratification system (Haematologica 2011;96:375), and the presence of circulating blasts. Neither the presence of spliceosome mutations (SF3B1/SRSF2/U2AF35) nor the percentage of RS (considered both as a continuous and a categorical variable), had an impact on either overall or leukemia-free survival. Conclusions: Among spliceosome mutations in CMML, those involving SRSF2 are by far the most frequent, even in the presence of ring sideroblasts. However, in patients with >50% RS, only SF3B1 mutations were seen whereas in those with 15–49% RS, SRSF2 mutations were more common. These observations suggest that SF3B1 mutations play a dominant but not exclusive role in the pathogenesis of RS. Regardless, the current study did not suggest prognostic impact from either the presence of the spliceosome mutations studied or the percentage of RS. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Spliceosome pathway gene mutations are recurrent in myeloid malignancies with the highest frequencies reported for myelodysplastic syndromes associated with ring sideroblasts (MDS-RS; 85%), MDS without RS (44%) and chronic myelomonocytic leukemia (CMML; 55%) (Nature 2011;478:64). SF3B1 mutations were the most frequent (75%) in MDS-RS and SRSF2 mutations in CMML (28%); U2AF1 mutational frequencies were 12% in MDS without RS and 8% in CMML. We have previously described SRSF2 (Blood. 2012;120:4168) and SF3B1 (Leukemia. 2012;26:1135) mutations in 17% and 6.5% of patients with primary myelofibrosis (PMF); prognostic relevance was shown for the former but not the latter. Objectives The objectives of the current study were to i) describe the incidence of U2AF1 mutations in PMF and their correlation with clinical features, karyotype and other mutations and ii) examine the prognostic significance of U2AF1 mutations in PMF, in the context of both conventional prognostic models and other prognostically-relevant mutations. Methods Information on clinical and laboratory parameters and karyotype was available in all study patients, at time of referral, which coincided with time of sample collection for mutation screening. Risk stratification was according to the Dynamic International Prognostic Scoring System (DIPSS)-plus system. U2AF1 and other mutations were analyzed using standard PCR techniques and bidirectional sequencing; for U2AF1, two hot spots that included residues S34 and Q157 were amplified. Results A total of 251 PMF patients (median age 63 years; 160 males) were studied. DIPSS-plus risk distribution was high in 32%, intermediate-2 in 38%, intermediate-1 in 17% and low in 13% of the patients. The frequency of each DIPSS-plus adverse feature was as follows: age >65 years (42%), transfusion need (32%), hemoglobin <10 g/dL (47%), leukocyte count >25 x 10(9)/L, (16%), platelet count <100 x 10(9)/L (22%), ≥1% blasts (57%), constitutional symptoms (35%), and unfavorable karyotype (9%). Karyotype was normal in 156 (63%) patients. At a median follow-up of 48 months, 158 (63%) deaths and 27 (11%) leukemic transformations were recorded. Mutational frequencies Forty-one (16.3%) patients harbored U2AF1 mutations: 16 (39%) Q157P, 10 (24%) Q157R, 8 (20%) S34F, 4 (10%) S34Y and one each for Q157P/E159A, Q157R/S34Y and Q157-Y158insYE. Frequencies for other mutations were 11% for SRSF2, 7.3% for SF3B1, 31% for ASXL1, 5.5% for EZH2, 5% for IDH1/2 and 58% for JAK2V617F. U2AF1 mutations were usually, but not always, exclusive of other spliceosomal mutations: one patient expressed all three spliceosomal mutations. The frequency of any one of the three spliceosomal mutations was 34%. Clinical correlates U2AF1 mutations were significantly associated with older age (p=0.02), JAK2V617F (p=0.002), mutant ASXL1 (p=0.04), transfusion need (p<0.0001), hemoglobin <10 g/dL (p<0.0001), platelets <100 x 10(9)/L (p<0.0001) and normal karyotype (p=0.006). The associations with anemia, thrombocytopenia, JAK2V617F and normal karyotype were inter-independent; the frequency of U2AF1 mutations in the presence of anemia was 29%, transfusion need 36%, thrombocytopenia 35%, JAK2V617F 23% and normal karyotype 21%. Prognostic interactions U2AF1 mutations were associated with inferior overall (p=0.004) but not leukemia-free (p=0.6) survival. However, the survival association was fully accounted for by the above-mentioned clustering of U2AF1 mutations with anemia and thrombocytopenia. Similarly, although multivariable analysis of U2AF1, SRSF2, ASXL1, EZH2 and IDH mutations identified the first three as being independently predictive of poor survival, only ASXL1 and SRSF2 remained significant when either anemia or thrombocytopenia was included as a co-variate. Conclusions U2AF1 mutations are the most frequent spliceosome pathway mutations in PMF, cluster with normal karyotype and JAK2V617F, and are strongly associated with anemia and thrombocytopenia; the latter suggests a pathogenetic contribution to ineffective hematopoiesis in PMF. The current study also suggests that more than one third of patients with PMF carry a spliceosome mutation. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 430 Background: The Dynamic International Prognostic Scoring System (DIPSS-plus) uses eight risk factors to predict overall survival (OS) in primary myelofibrosis (PMF): unfavorable karyotype, peripheral blood (PB) blast count ≥1%, platelet count <100 × 109/L, white blood cell count (WBC) >25 × 109/L, hemoglobin level <10 g/dL, red blood cell transfusion need, constitutional symptoms, and age >65 years (JCO 2011;29:392). Among these risk factors, karyotype holds a dominant role in predicting both overall (OS) and leukemia-free (LFS) survival (Blood 2011;118:4595). More recently, certain PMF-associated somatic mutations (IDH, EZH2, ASXL1, SRSF2) have been reported (in print or at recent meetings) to carry prognostic relevance for OS or LFS in PMF while other mutations (JAK2, MPL, TET2, SF3B1) did not. The purpose of the current study was to examine the individual and combined prognostic relevance of the former in the context of cytogenetic risk stratification and DIPSS-plus. Methods: An updated Mayo Clinic database of 1008 karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify study patients in whom DNA at time of referral was available for mutation analysis. OS and LFS were calculated from the time of referral, which was also the time of study sample collection. Results: In an ongoing project, a total of 397 PMF patients have so far been studied for IDH1/2 (n=367), SRSF2 (n=355), ASXL1 (n=260) and EZH2 (n=43) mutations. The corresponding mutational frequencies were 5.4% (20/367), 14.4% (51/355), 31.2% (81/260) and 7% (3/43). These mutations were not exclusive of either each other or JAK2 or MPL mutations and a significant clustering was noted between SRSF2 and IDH mutations; IDH mutational frequency was 21% (10/48) in SRSF2-mutated versus 3% (9/279) in unmutated cases (P<0.0001). Mutational hotspots were P95 in exon 1 for SRSF2 and exons 1, 2 and 5 for ASXL1. OS and LFS effect have so far been examined for ASXL1, SRSF2 and IDH 1/2 mutations; in univariate analysis, all three mutations significantly affected OS (ASXL1 RR 1.9, 95% CI 1.4–2.7; SRSF2 RR 1.7, 95% CI 1.2–2.5; IDH 1/2 RR 1.8, 95% CI 1.1–3.1) whereas only IDH 1/2 (RR 5.5, 95% CI 2.5–11.8) and SRSF2 (RR 3.5, 95% CI 1.7–7.0) but not ASXL1 (p=0.29) mutations affected LFS. The observed prognostic relevance for OS was sustained during multivariable analysis that included ASXL1 with either SRSF2 or IDH mutations, as co-variates, whereas both IDH and SRSF2 mutations remained significant for LFS. Based on the above observations, study patients were classified into two groups: i) unmutated for ASXL1, SRSF2 and IDH1/2 (all unmutated; n=146) and ii) mutated for at least one of the three mutations (one or more mutated; n=130); the latter group constituted 62%, 52%, 18% and 27% of DIPSS-plus high, intermediate-2, intermediate-1and low risk patients, respectively (p<0.0001). The corresponding rates for patients with favorable and unfavorable karyotype were 47% and 43% (p=0.7) and for normal vs. abnormal karyotype were 53% and 36% (p=0.008). The “all unmutated group”, compared to the “one or more mutated group” enjoyed a significantly superior OS (RR 0.5, 95% CI 0.4–0.7) and LFS (RR 0.3, 95% CI 0.2–0.7) that was DIPSS-plus-independent for OS (p=0.03) and karyotype-independent for LFS (p=0.004). The prognostic value of distinguishing “all unmutated” from “one or more mutated” patient groups was most evident for DIPSS-plus intermediate-2 or lower risk groups (p=0.002) and its added value for high-risk group was limited (p=0.23) (Figure). Conclusions: A concomitant analysis strategy reveals that SRSF2, ASXL1 and IDH mutations carry inter-independent prognostic relevance for overall or leukemia-free survival in PMF. Any one of these three mutations is more likely to occur in patients with normal karyotype and such an event predicts shortened survival that is not accounted for by DIPSS-plus and a higher risk of leukemic transformation that is independent of karyotype. The current study suggests that such information might be useful in treatment decisions involving intermediate-2 or lower risk patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 423 Background: Cytogenetic abnormalities at diagnosis are seen in 20–70% of patients with myelodysplastic syndromes (MDS). The International Prognostic Scoring System -revised (IPSS-R) classifies these cytogenetic abnormalities into five prognostic groups: very good (del(11q), ΠY with overall survival (OS) of 61 months); good (normal, del(20q), del(5q), del(12p) with OS 49 months); intermediate (+8,7q-, i(17q),+19,+21 with OS 26 months); poor (der(3)q21/q26, −7, complex with 3 abnormalities with OS 16 months); and very poor (complex with >3 abnormalities with OS of 6 months) (Schanz J, JCO 2012, Greenberg P, Blood 2012). Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. We have previously shown that MK identifies a prognostically worse subgroup of MDS patients with a complex karyotype (Patnaik M, Leukemia 2010). Objectives: Methods: The Mayo Clinic database for MDS was used to identify patients in whom bone marrow histologic and cytogenetic information was obtained at the time of diagnosis. WHO criteria were used for MDS diagnosis and leukemic transformation. Results: i) Patient characteristics: A total of 1,014 patients met the above-stipulated criteria. Median age of the cohort was 71 years (range: 18–98 years) with 684 (67%) males. 819 patients (81%) had primary MDS with 195 cases (19%) of therapy-related MDS. 759 patients (75%) are dead at a median follow-up of 18 months (range: 0–223 months) with leukemic transformation documented in 125 cases (12%). IPSS-R risk distribution was as follows: very low (n=149, 15%), good (n=261, 26%), intermediate (n=221, 22%), high (n=131, 13%), and very high (n=252, 25%). ii) IPSS-R karyotype (Entire cohort; n=1,014): The five cytogenetic groups by IPSS-R were as follows: very good (n=43, 4%), good (n=577, 57%), intermediate (n=187, 18%), poor (n=83, 8%), and very poor (n=124, 12%). We evaluated the prognostic impact of the above groups by Kaplan Meier and Cox proportional hazards analysis. OS for the five cytogenetic groups was as follows: good (36 months), very good (28 months), intermediate (20 months), poor (13 months), and very poor (6 months) (Figure 1). OS of patients with very good karyotype was significantly better than patients with very poor and poor karyotype (p<0.0001, RR 3.2 and p=0.04, RR 1.6 respectively) but similar to patients with intermediate and good karyotype (p=0.22 and 0.28 respectively). iii) IPSS-R karyotype (Primary MDS; n=819): Cytogenetic risk groups by IPSS-R were as follows: very good (n=38, 5%), good (n=512, 63%), intermediate (n=153, 19%), poor (n=46, 6%), and very poor (n=70, 9%). OS of the five groups was as follows: good (39 months), very good (23 months), intermediate (21.5 months), poor (14.5 months), and very poor (6.5 months). OS of patients with very good karyotype was significantly better than patients with very poor karyotype (p=0.0002, RR 2.5) but similar to patients with poor, intermediate and good karyotype (p=0.23, 0.26 and 0.18 respectively). iv) Monosomal karyotype: MK was identified in 153 (15%) cases of which 4 cases were intermediate, 42 poor, and 107 very poor by IPSS-R. OS of patients with MK was similar to those with very poor karyotype (6 months). In addition, OS of patients with very poor without MK was akin to patients with poor without MK (p=0.21). Furthermore, among primary MDS we identified 83 (8%) cases of MK of which 4 were intermediate, 21 were poor, and 58 very poor by IPSS-R. We confirmed that OS of patients with MK was similar to patients with very poor karyotype (6.5 months). Moreover, survival of patients with very poor without MK was similar to patients with poor without MK (p=0.51). Conclusions: In this independent analysis of 1,014 patients with MDS, IPSS-R cytogenetic risk characterization failed to discriminate between very good, good and intermediate prognostic groups. In addition, patients with very poor without MK have a similar prognosis to patients with poor without MK and should be included in the poor category whereas the presence of MK should warrant inclusion into the very poor risk category. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3790 Background: Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder characterized by: persistent peripheral blood (PB) monocytosis (>1 × 10(9)/L), absence of BCR-ABL1 fusion, absence of rearrangement of the PDGFRA/B genes, <20% bone marrow (BM) & PB blasts, and dysplasia involving one or more myeloid cell lines. It is clinically considered to be an overlapping syndrome with myelodysplastic and myeloproliferative features. The natural history and prognostic features of CMML are not well defined with the MD Anderson prognostic score (MDAPS) and the Spanish risk stratification by cytogenetics being the two major prognostic tools currently being used in clinical practice. Methods: 227 patients with WHO defined CMML were seen at the Mayo Clinic from 1997 through 2007. All patients underwent bone marrow (BM) examination and cytogenetic evaluation at diagnosis. We evaluated the prognostic relevance of several clinical and laboratory parameters including those previously identified by the MDAPS (Blood 2002;99:840) and the Spanish cytogenetic risk stratification (Haematologica 2011;96:375). Results: Among the 227 study patients, 153 (67%) were males and median age was 71 years (range, 17–90 years). There were 192 (85%) patients with CMML-1 & the remainder had CMML-2. At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. Median survivals were 22 months for CMML-1 and 14 months for CMML-2. In univariate analysis, significant risk factors for survival included decreased hemoglobin level, decreased platelet count and increased levels of white blood cells (WBC), absolute neutrophils (ANC), absolute monocytes (AMC), absolute lymphocytes (ALC), PB blasts, BM blasts and presence of circulating immature myeloid cells (IMC; inclusive of PB blasts). However, on multivariable analysis that included the aforementioned Spanish cytogenetic risk stratification, only increased AMC (>10 × 10(9)/L, RR 2.5, 95% CI 1.7–3.8), presence of circulating IMC (RR 2.0, 95% CI 1.4–2.7), decreased hemoglobin (<10 g/dL; RR 1.6, 99% CI 1.2–2.2), and decreased platelet count (<100 × 10(9)/L; RR 1.4, 99% CI 1.0–1.9) retained significance. Using these four independent risk factors, we prepared a new prognostic risk model that performed better than both the MDAPS and the Spanish cytogenetic risk models (Figure). The Mayo risk model was also predictive of leukemic transformation: high risk RR 4.9 (95% CI 1.9–12.8) and intermediate risk RR 2.6 (1.1–5.9). Individual parameters of independent significance for leukemic transformation included PB blast count and AMC >10 × 10(9)/L. Conclusions: Absolute monocyte count is the strongest predictor of survival in CMML. Other independent risk factors include circulating immature myeloid cells, anemia and thrombocytopenia. A risk model based on these four risk factors is effective in predicting both overall and leukemia-free survival and outperforms both the MDAPS and risk stratification by cytogenetics. Disclosures: No relevant conflicts of interest to declare.

AimsThe aims of this study were to review our 5‐year experience with clinical FISH testing for TP63 rearrangements using both TP63 break‐apart (BAP) and TBL1XR1/TP63 dual‐fusion (D‐FISH) probes to evaluate the frequency of TP63 rearrangements and the distribution of TBL1XR1 vs. alternate partner loci, and to assess whether both probe sets are necessary in all cases undergoing FISH testing.Methods and resultsA retrospective review of the Mayo Clinic cytogenetic database identified 470 patients evaluated by FISH testing for TP63 rearrangements in formalin‐fixed paraffin‐embedded (FFPE) tissue using both BAP and D‐FISH probes. Of these, 25 (5.3%) had TP63 rearrangements. All samples were being investigated for anaplastic large‐cell lymphoma or other T cell lymphoma subtypes. A TBL1XR1 partner was identified by D‐FISH in 12 (48%) of 25 cases. All cases positive by TBL1XR1/TP63 D‐FISH were also positive by TP63 BAP FISH.ConclusionThis is the largest series of TP63 rearrangements to date. The frequency of positive results among cases referred to a large reference laboratory for TP63 FISH testing was 5.3%. Approximately half of TP63 rearrangements have a TBL1XR1 partner. TP63 BAP FISH testing is sufficient for up‐front testing of FFPE tissue samples. However, because of the genomic proximity of the TP63 and TBL1XR1 loci, we recommend reflex TBL1XR1/TP63 D‐FISH testing in positive and equivocal cases.

3144 Background: Updated ASCO/CAP Guidelines for HER2 testing in breast cancer have been most impactful on the resolution of certain challenging groups of FISH results. We review the change in assignment of HER2 status in a large series of breast cancers referred to a large national reference laboratory for FISH testing since the introduction of the 2018 updated guidelines. Methods: Patient samples submitted to the Mayo Clinic Cytogenetics Laboratory (N = 2208) were analyzed by FISH. Samples with Group 2, Group 3, or Group 4 FISH results were reflexed to immunohistochemistry (IHC) in our central laboratory; FISH slides for those cases with equivocal 2+ IHC results were re-scored in the regions of invasive cancer showing more intense membranous staining. A subset of 202 samples with Group 4 FISH results were also reflexed to the previously employed reflex FISH assay (HER2/D17S122), and these were also re-analyzed according to the new reflex IHC/FISH process. Results: 382 of 2208 breast cancer samples tested (17.3%) had FISH results categorized as Group 2 (N = 17, 0.8%), Group 3 (N = 34, 1.5%), or Group 4 (N = 331, 15%) and required reflex IHC testing, and of those, 75% were 2+ equivocal and required targeted re-analysis of the FISH slide according to the 2018 updated guidelines. Re-analysis of the FISH slide resulted in switching between Groups 1-5 in 19.4% of cases, but HER2 status was changed by FISH re-scoring in only 7.7% of cases re-scored (1.0% of all samples), generally due to only minor shifts in HER2 copy number and HER2/control ratios between the initial and IHC-guided reflex FISH scores. In the subset of 202 cases tested by both reflex methods, the previously employed HER2/D17S122 reflex probe set was positive in 123 cases (60.9%), whereas reflex IHC/FISH was positive in only 10 cases (7.9%). Including positive reflex IHC (0.4%) and positive reflex FISH results (2.1%), the overall assignment of positive HER2 status on our series of 2208 cases was 11.5%. Conclusions: Overall rates of HER2 positive FISH results have declined under the most recent ASCO/CAP guideline update as a consequence of new recommendations for reflex testing for Groups 2-4. This change is largely due to reassignment of Group 2 and Group 4 results as negative in the absence of positive IHC.

We previously reported an extremely rare case of follicular dendritic cell sarcoma (FDCS) presented as a thyroid mass. Given the rarity of this disease, there are no personalized and molecularly targeted treatment options due to the lack of knowledge in the genomic makeup of the tumor. A 44-year-old white woman was diagnosed with an extranodal FDCS in thyroid. The patient underwent a total thyroidectomy, central compartment dissection, parathyroid re-implantation, and adjuvant radiation therapy. Tumor DNA sequencing of 236 genes by FoundationOne panel found truncating mutations in PTEN and missense mutations in RET and TP53. However, patient-matched germline DNA was not sequenced which is critical for identification of true somatic mutations. Furthermore, the FoundationOne panel doesn't measure genomic rearrangements which have been shown to be abundant in sarcomas and are associated with sarcoma tumorigenesis and progression. In the current study, we carried out comprehensive genomic sequencing of the tumor, adjacent normal tissues, and patient-matched blood, in an effort to understand the genomic makeup of this rare extranodal FDCS and to identify potential therapeutic targets. Eighty-one somatic point mutations were identified in tumor but not in adjacent normal tissues or blood. A clonal truncating mutation in the CLTCL1 gene, which stabilizes the mitotic spindle, was likely a driver mutation of tumorigenesis and could explain the extensive copy number aberrations (CNAs) and genomic rearrangements in the tumor including a chr15/chr17 local chromothripsis resulted in 6 expressed fusion genes. The fusion gene HDGFRP3→SHC4 led to a 200-fold increase in the expression of oncogene SHC4 which is a potential target of the commercial drug Dasatinib. Missense mutations in ATM and splice-site mutation in VEGFR1 were also detected in addition to the TP53 missense mutation reported by FoundationOne.