Gain Of Chromosome Research Articles

The yin and yang of chromosomal instability in prostate cancer.

Metastatic prostate cancer remains an incurable lethal disease. Studies indicate that prostate cancer accumulates genomic changes during disease progression and displays the highest levels of chromosomal instability (CIN) across all types of metastatic tumours. CIN, which refers to ongoing chromosomal DNA gain or loss during mitosis, and derived aneuploidy, are known to be associated with increased tumour heterogeneity, metastasis and therapy resistance in many tumour types. Paradoxically, high CIN levels are also proposed to be detrimental to tumour cell survival, suggesting that cancer cells must develop adaptive mechanisms to ensure their survival. In the context of prostate cancer, studies indicate that CIN has a key role in disease progression and might also offer a therapeutic vulnerability that can be pharmacologically targeted. Thus, a comprehensive evaluation of the causes and consequences of CIN in prostate cancer, its contribution to aggressive advanced disease and a better understanding of the acquired CIN tolerance mechanisms can translate into new tumour classifications, biomarker development and therapeutic strategies.

Genetic characterization of intramuscular myxomas.

Introduction: Intramuscular myxomas are benign tumors that are challenging to diagnose, especially on core needle biopsies. Acquired chromosomal aberrations and pathogenic variants in codon 201 or codon 227 in GNAS complex locus gene (GNAS) have been reported in these tumors. Here we present our genetic findings in a series of 22 intramuscular myxomas. Materials and methods: The tumors were investigated for the presence of acquired chromosomal aberrations using G-banding and karyotyping. Pathogenic variants in codon 201 or codon 227 of GNAS were assessed using direct cycle Sanger sequencing and Ion AmpliSeq Cancer Hotspot Panel v2 methodologies. Results: Eleven tumors carried chromosomal abnormalities. Six tumors had numerical, four had structural, and one had both numerical and structural chromosomal aberrations. Gains of chromosomes 7 and 8 were the most common abnormalities being found in five and four tumors respectively. Pathogenic variants in GNAS were detected in 19 myxomas (86%) with both methodologies. The detected pathogenic variants were p.R201H in nine cases (seven with abnormal and two with normal karyotypes), p.R201C in five cases, all with normal karyotypes, p.R201S in three cases (two with abnormal and one with normal karyotype), p.R201G in one case with a normal karyotype, and p.Q227E in one case with a normal karyotype. Conclusion: Firstly, our data indicate a possible association between chromosomal abnormalities and GNAS pathogenic variants in intramuscular myxomas. Secondly, the presence of the rare pathogenic variants R201S, p.R201G and p.Q227E in 26% (5 out of 19) of myxomas with GNAS pathogenic variants shows that methodologies designed to detect only the common "hotspot" of p.R201C and p.R201H will give false negative results. Finally, a comparison between Ion AmpliSeq Cancer Hotspot Panel v2 and direct cycle Sanger sequencing showed that direct cycle Sanger sequencing provides a quick, reliable, and relatively cheap method to detect GNAS pathogenic variants, matching even the most cutting-edge sequencing methods.

Clinicopathological and Molecular Characteristics of IDH-Wildtype Glioblastoma with FGFR3::TACC3 Fusion.

The World Health Organization Classification of Tumors of the Central Nervous System recently incorporated histological features, immunophenotypes, and molecular characteristics to improve the accuracy of glioblastoma (GBM) diagnosis. FGFR3::TACC3 (F3T3) fusion has been identified as an oncogenic driver in IDH-wildtype GBMs. Recent studies have demonstrated the potential of using FGFR inhibitors in clinical trials and TACC3-targeting agents in preclinical models for GBM treatment. However, there is limited information on the clinicopathological and genetic features of IDH-wildtype GBMs with F3T3 fusion. The aim of this study was to comprehensively investigate the clinical manifestations, histological features, and mutational profiles of F3T3-positive GBMs. Between September 2017 and February 2023, 25 consecutive cases (5.0%) of F3T3-positive GBM were extracted from 504 cases of IDH-wildtype GBM. Clinicopathological information and targeted sequencing results obtained from 25 primary and 4 recurrent F3T3-positive GBMs were evaluated and compared with those from F3T3-negative GBMs. The provisional grades determined by histology only were distributed as follows: 4 (26/29; 89.7%), 3 (2/29; 6.9%), and 2 (1/29; 3.4%). Grade 2-3 tumors were ultimately diagnosed as grade 4 GBMs based on the identification of the TERT promoter mutation and the combined gain of chromosome 7 and loss of chromosome 10 (7+/10-). F3T3-positive GBMs predominantly affected women (2.6 females per male). The mean age of patients with an F3T3-positive GBM at initial diagnosis was 62 years. F3T3-positive GBMs occurred more frequently in the cortical locations compared to F3T3-negative GBMs. Imaging studies revealed that more than one-third (12/29; 41.4%) of F3T3-positive GBMs displayed a circumscribed tumor border. Seven of the seventeen patients (41.2%) whose follow-up periods exceeded 20 months died of the disease. Histologically, F3T3-positive GBMs more frequently showed curvilinear capillary proliferation, palisading nuclei, and calcification compared to F3T3-negative GBMs. Molecularly, the most common alterations observed in F3T3-positive GBMs were TERT promoter mutations and 7+/10-, whereas amplifications of EGFR, PDGFRA, and KIT were not detected at all. Other genetic alterations included CDKN2A/B deletion, PTEN mutation, TP53 mutation, CDK4 amplification, and MDM2 amplification. Our observations suggest that F3T3-positive GBM is a distinct molecular subgroup of the IDH-wildtype GBM. Both clinicians and pathologists should consider this rare entity in the differential diagnosis of diffuse astrocytic glioma to make an accurate diagnosis and to ensure appropriate therapeutic management.

Spatiotemporal regulation of CENP-E-guided chromosomes using a fast-relaxing arylazopyrazole photoswitch.

We developed a centromere-associated protein E (CENP-E) inhibitor employing trans to cis photoisomerization with 405 nm visible light illumination and fast thermal relaxation. This photoswitching characteristic of the inhibitor enabled selective blockage or release of the motion of particular chromosomes within a single mitotic cell. Using this technique, we successfully demonstrated targeted chromosome gain and loss in daughter cells by introducing asymmetric chromosome segregation.

Targeted treatment options for paediatric B-cell precursor acute lymphoblastic leukaemia patients with constitutional or somatic chromosome 21 alterations

BackgroundChromosome 21 is affected in ∼60% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients and includes somatic and constitutional gains, intrachromosomal amplification of chromosome 21 (iAMP21), and the translocation t(12;21) resulting in the ETV6::RUNX1 gene fusion. MethodsSince these numeric and structural chromosome 21 alterations are not targetable, we studied the type and frequency of yet-proven targetable events co-occurring with chromosome 21 alterations. ResultsAmong 307 primary paediatric BCP-ALL cases, JAK/STAT pathway lesions were most frequent in patients with constitutional gain of chromosome 21 (Down syndrome ALL; 35/71, 49%) and iAMP21 (9/22, 41%). RAS pathway lesions were most frequent in high hyperdiploidy (62/108, 57%) and FLT3 lesions were most frequent in iAMP21 (7/22, 32%). Virtually all cases expressed CD19 and CD22 at the cell surface. Positivity for CD20 surface expression ranged from 67% in iAMP21 (8/12) to 20% in ETV6::RUNX1 (26/129). ConclusionActivated JAK/STAT, RAS or FLT3 signalling, and CD marker surface expression may provide targetable treatment options for the majority of chromosome 21-altered BCP-ALL cases.

Case report: Pediatric acute lymphoblastic leukemia with trisomy 5 as sole cytogenetic abnormality

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood and represents about 75 -80% of ALL in pediatric age group. ALL is characterised by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors and replacing the bone marrow elements and other lymphoid organs by leukemic cells (ALL blasts). The 5 year survival rate for childhood ALL is about 90% overall, children in lower risk groups have a better prognosis than those in higher risk group. Risk assessment is mainly based on cytogenetic and molecular factors in addition, clinical symptoms and signs, White blood cell count at diagnosis are all recognized for stratification. In present case the cytogenetic analysis showed the presence of trisomy 5 as a sole numerical abnormality. Trisomy 5 accounts for aneuploidy change in the cytogenetic analysis. The gain or loss of whole chromosome, ie aneuploidy is a major genomic insult in human cancers. Aneuploidy is observed in ~90% of solid tumors and~60% of hematological maignancies. The increased gene expression in trisomy 5 causes chromosomal instability (CIN), microsatellite instability (MIN) and genomic instabilty which inturn causes the cancer genome to undergo evolution, adaptation and favors tumor progression in patients with B cell acute lymphoblastic leukemia.

Neuro-oncology Treatment Strategies for Primary Glial Tumors.

Primary brain tumors underwent reclassification in the 2021 World Health Organization update, relying on molecular findings (especially isocitrate dehydrogenase mutations and chromosomal changes in 1p, 19q, gain of chromosome 7 and loss of chromosome 10). Newer entities have also been described including histone 3 mutant midline gliomas. These updated pathologic classifications improve prognostication and reliable diagnosis, but may confuse interpretation of prior clinical trials and require reclassification of patients diagnosed in the past. For patients over seventy, multiple studies have now confirmed the utility of shorter courses of radiation, and the risk of post-operative delirium. Ongoing studies are comparing proton to photon radiation. Long term follow up of prior clinical trials have confirmed the roles and length of chemotherapy (mainly temozolomide) in different tumors, as well as the wearable novottf device. New oral isocitrate dehydrogenase inhibitors have also shown efficacy in clinical trials.

Primary Central Nervous System ALK-negative Anaplastic Large Cell Lymphoma, with TP53 Deletion

Abstract Introduction/Objective ALK-negative anaplastic large cell lymphoma (ALCL) primary to the central nervous system (CNS), is a sporadic and rare lymphoma, characterized by neoplastic T-cells which are CD30 positive and ALK negative. It has a male predominance, mostly affects old adults and usually displays supratentorial, single or multiple lesions. Methods/Case Report We report the case of a 57-year-old woman with medical history of breast cancer, S/P lumpectomy and radiation therapy, who came to our institution with confusion, partial aphasia and headache. MRI showed a thick-walled, irregular, ring enhancing mass in the periventricular white matter of the occipital and temporal horns of the lateral ventricle with surrounding vasogenic edema and mass effect. It was isointense to cortex on T1- and heterogeneously hyperintense on T2-weighted images with mild diffusion restriction in the enhancing portion. A left parieto-occipital decompressive craniotomy was performed and tissue was procured for diagnosis. The biopsy showed an infiltrating, angiocentric neoplasm, composed of large anaplastic cells, including hallmark cells with "horseshoe" nuclei, abundant eosinophilic cytoplasm and occasional perinuclear clearing. Large areas of necrosis and pericellular reticulin deposits of the vascular walls were also noted. On immunohistochemistry, the neoplastic cells diffusely expressed CD45, CD2, CD3, CD25, CD43, MUM1, and CD30, and were negative for ALK, CD20, CD79a, PAX-5, CD15, CD5, BCL-6, BCL-2, Granzyme B, GFAP, Pancytokeratin. In situ hybridization for EBER was negative. The proliferative index (Ki-67), while variable, was as high as 80%. TP53 deletion was detected by FISH in 100% of the cells analyzed. No rearrangements in the ALK or MYC genes was noted by FISH. Additional studies revealed a complex karyotype including loss of chromosomes 9 and 10, gain of chromosome 17 and a marker chromosome, and structural rearrangements involving chromosomes 4, 10, and 13. Previously reported rearrangements involving DUSP22 (6p25) and TP63 (3q28) were not identified. TCR gene rearrangement was also identified by PCR. High dose Cytarabine/Methotrexate, and radiation were not successful in controlling disease progression and home hospice was recommended. Results (if a Case Study enter NA) N/A Conclusion This is an infrequent type of primary CNS lymphoma with a poor prognosis and, while TP53 has been reported in sporadic, and cutaneous ALCL, to our knowledge, this is the first report of primary CNS ALK-negative anaplastic large cell lymphoma with TP53 deletion.

A novel GLCC1::BRAF fusion with independent MYCN and MYC amplifications in primary tumor and metastasis in pediatric pancreatic acinar carcinoma

Abstract Introduction/Objective Pediatric pancreatic acinar cell carcinoma (PACC) is a rare malignancy, comprising 5-15% of pediatric pancreatic tumors. BRAF rearrangement is found in 20-30% of PACC cases, most commonly an inversion in chromosome 7. We report a case of PACC with GLCC1::BRAF fusion. Methods/Case Report A 10-year-old male presented with six months of weight loss, back pain, and loose stools. Imaging demonstrated concentric soft tissue thickening around the celiac axis and superior mesenteric artery, clinically interpreted as vasculitis. Follow-up imaging showed extension of the soft tissue thickening, prompting biopsy of a periaortic lymph node showing metastatic PACC. Pancreaticduodenectomy revealed a 3.8 cm pancreatic neck mass with perineural invasion and metastatic deposits in multiple lymph nodes and retroperitoneal soft tissue. Fluorescence in situ hybridization of both specimens demonstrated BRAF gene rearrangement, with the partner identified as GLCC1 by next generation sequencing and fusion assays. Microarray on the lymph node demonstrated amplification of MYC on chromosome 8, but not in the resection specimen, which showed gain of chromosome 2 and amplification of MYCN. Results (if a Case Study enter NA) NA Conclusion The GLCC1::BRAF fusion has previously been reported once in a case of pheochromocytoma with peritoneal seeding. The MYC gene family members, c-MYC and MYCN, are involved many cancer types; amplifications are often associated with unfavorable prognosis in tumors such as neuroblastoma. However, the amplification of both genes in the same tumor at different loci has not been reported. The combination of the primary GLCC1::BRAF fusion with secondary amplification of MYC and MYCN is likely to drive the aggressive behavior and metastasis in this case of PACC. Treatment for PACC includes chemoradiation and BRAF inhibition. However, BRAF rearrangements without the V600E mutation show variable response to BRAF inhibitors. Potential alternatives include inhibitors to other targets within the BRAF signaling pathway. Further investigation is needed to determine the clinicopathologic impact of these novel genetic aberrancies.

Molecular and Cytogenetic Evaluation in Systemic Mastocytosis

Systemic mastocytosis (SM) is a rare hematological neoplasm characterized by pleomorphic symptoms, related to mediators release from pathological mast cells. Tissue infiltration of liver, spleen, gastro-intestinal (GI) tract and osteolysis are present in aggressive disease. As KIT D816V mutation can be found in approximately 80% of patients, several additional somatic mutations of prognostic significance have been detected in a subset of patients. We report on clinical, cytogenetic and molecular characteristic of 160 patients with SM diagnosed in the last 15 years at our center. Fourteen (8.9%) patients had cutaneous mastocytosis, 85 (53.5%) had indolent SM (ISM), 12 (7.5%) had smoldering SM (SSM), 27 (17%) had aggressive SM (ASM), 17 (10.5%) had SM with an associated hematological neoplasm (AHN-SM) and 1 (0.6%) had mast cell leukemia. Symptoms were mostly related to mediators release: itching and blistering (69, 43%), anaphylaxis (49, 30%), diarrhea/bloating (19, 12%), osteoporosis/bone fracture (10, 6%), constitutional symptoms (8, 5%), bone pain and myalgia (16, 10%), anaphylaxis from Hymenoptera venom (24, 15%). While SM patients were mostly treated with antihistamines and membrane stabilizers, 29 patients needed a disease modifying therapy. Four patients with ISM were treated with Interferon (IFN) for bone lytic alterations, while 1 patient with ISM started midostaurin for uncontrolled symptoms. Other 11 patients with ASM were treated with midostaurin: 4 responded, while 7 needed multiple lines of therapy including allogeneic transplant in 4 cases. Eleven patients with ASM were treated with tyrosin kinase inhibitors (TKI) before midostaurin became available, while 2 elderly patients were treated with low dose cytarabine and TKI for concomitant acute leukemia. KIT D816V mutation was found in 111 of 131 (85%) evaluable patients with SM. Cytogenetics was normal in all but 2 patients with AHN-SM in which a chromosomal gain was reported. Among 6 patients with ISM, KIT mutation was found in only 2 cases. One patient had isolated KIT mutation and was treated with IFN for skin symptoms and bone fracture, and another patient had a DNMT3A associated mutation and was treated with imatinib. Moreover, 1 patient presented both DNMT3A and TET2 mutations and was treated with IFN for bone fracture. Among 12 ASM patients, 1 was negative for significant mutations: no disease control was achieved after target therapy, and bone marrow function slowly recovered after allogeneic transplant. The most frequently recorded mutations were SRSF2 and TET2: they were present in 4 patients each and recorded together in 3 cases. Two patients with SRSF2 and TET2 mutations died after multiple lines of therapy: 1 patient for infection and graft versus host disease after allogeneic transplant and 1 for progressive disease. Moreover, the latter had additional RUNX1 mutation. Two patients with concomitant SRSF2 and IDH1 mutations and TET2 mutation respectively responded to midostaurin, while 1 with DNMT3A mutation received multiple lines of therapy and died for pneumonia. One patient with ASXL1 mutation responded to chemotherapy after 2 previous lines of treatment. Among 4 patients with isolated KIT mutation, 2 responded to midostaurin, 1 obtained a partial control of symptoms after 4 lines of treatment and 1 suddenly died after achieving stable disease after 2 lines of therapy. Among 3 patients with SM associated to myelodyplastic syndrome, 1 was negative for KIT but positive for TP53 mutations and died for natural event after symptoms directed therapy and continuing recombinant erythropoietin. The other 2 KIT positive patients presented multiple concomitant mutations. Additional TET2 and SRSF2 mutations were recorded in a patient who died few weeks after diagnosis, while additional TET2, SRSF2, RUNX1 and KRAS mutations were recorded in a patient treated with midostaurine and 2CDA before successful allogeneic transplant. Molecular characterization of SM has uncovered a complex landscape of somatic mutations other than KIT D816V. Although the prognostic significance of some recurrent mutations has been reported, prospective correlation with clinical response may highlighted their role in the pathogenesis of disease and possibly elucidate mechanism of resistance to treatment. On the other hand, cytogenetics might no be considered mandatory except for AHN-SM

Revealing Novel Mechanisms Underlying Inactivation of Tumor Suppressor Genes on Duplicated Chromosomes in Multiple Myeloma

INTRODUCTION: Multiple myeloma (MM) evolution is complex and heterogeneous. Hyperdiploidy (HRD) and translocations affecting the immunoglobulin heavy chain (IGH) locus are historically considered initiating genomic events of MM. The potential impact of genomic events acquired before known MM initiating events has never been addressed. METHODS: To investigate whether genomic deletions are acquired before and after known MM initiating events we interrogated whole-genome sequencing (WGS) data from patients with newly diagnosed MM (NDMM, n=319) and relapsed MM (RRMM, n=59). Our newly developed analytical and chronological workflow integrating single nucleotide variants (SNV), structural variants (SV), and copy number variants (CNV) comprises two main steps. First, we estimated the molecular time (i.e. corrected ratio between duplicated and non-duplicated clonal SNV) of large clonal chromosomal duplications and identified the earliest set of chromosomal gains in each patient. Second, within each early large chromosomal gain we identified clonal SV mediating CNV loss. A deletion on a gain can generate three possible scenarios: 1) one of the duplicated alleles is lost after the gain (i.e. post-gain) causing a CNV jump from 3:1 to 2:1 (total alleles : minor alleles); 2) there is a deletion before the duplication (i.e., pre-gain) causing a CNV jump from 3:1 to 1:0. 3) the deletion occurs on the minor, non-duplicated allele, causing a CNV jump from 3:1 to 2:0. Timing the deletion in relation with the chromosomal duplication is impossible in this scenario. RESULTS: Molecular time data were successfully generated for 249/319 (78%) NDMM and 51/59 (86%) RRMM patients. Restricting our analysis to NDMM with HRD without canonical IGH translocations, 16/170 (9%) of patients acquired deletions before the earliest multi-chromosomal gains, suggesting MM precursors can acquire deletions before HRD. Investigating the entire series, post-gain deletions were observed in 126/417 (30%) samples considering both early and late time windows. Leveraging a background model, we demonstrated that pre-gain events involved more tumor-suppressor genes (TSG) than expected by chance, including TCF3, ATM and TRAF3. In contrast, oncogenes were involved less than expected. In post-gain deletions, both oncogenes and TSG were involved more than expected by chance . To validate and assess the impact of deletions on driver gene expression we investigated WGS and RNAsequencing data from the MMRF CoMMpass study (n=752 NDMM). Because of the low coverage not allowing for molecular time estimation, we limited our analysis to HRD without IGH translocations. Pre-gain and post-gain deletions were observed in 47/431 (11%) and 225/431 (52%) of patients, respectively. We defined loss and gain of function events based on whether the expression level of a gene affected by the deletion was in the first or fourth quartile, respectively. Pre-gain deletions were mostly associated with downregulation of TSG expression [n=31 events in 13/431 (3%) patients]. In contrast,post-gain deletions had a more heterogenous impact with loss- and gain-of-function events. Gain-of-function events were driven by two main mechanisms: 1) the deletion joined an oncogene with a distal regulatory region inducing its overexpression [n=44 events in 6/431 (1.3%) patients]; 2) the deletion caused a new and expressed fusion [n=231 events in 109/431 (25%) patients], resulting in either loss- or gain-of-function. Surprisingly, post-gain deletions had also a major impact on TSG expression. In 60 patients (14%), we observed 146 post-gain deletions where the affected tumor suppressor gene (TSG) expression was downregulated to the level of cases with monoallelic and biallelic deletions, even though two alleles were retained. Finally, to validate these findings, we investigated 16 RRMM patients with available WGS, scATAC-seq and scRNA-seq and observed additional evidence of TSG downregulation after both pre- and post-gain deletions. CONCLUSION: Leveraging a large cohort of NDMM we show that somatic deletions can be acquired before HRD trisomies that are assumed to be initiating events. Furthermore, post-gain deletions emerged as a new mechanism inducing TSG down-regulation, despite an apparently diploid gene status.

Real-World Utilization of Daratumumab in Front-Line Treatment of Newly Diagnosed Multiple Myeloma: A Retrospective Observational Study

Introduction: Daratumumab (DARA), a CD38 monoclonal antibody, has demonstrated remarkable efficacy among newly diagnosed (ND) and relapsed/refractory multiple myeloma (MM) patients. The introduction of a quadruplet therapy with an addition of DARA per the GRIFFIN trial has improved the treatment paradigm. However, the real-world data on treatment patterns and utilization of DARA in front-line treatment are limited. This study aimed to evaluate the real-world utilization of DARA in front-line treatment and examine factors that may impact the utilization of DARA-based regimen in NDMM. Methods: We conducted a retrospective observational study of all patients, age ≥ 18, with clinical MM who were newly diagnosed and treated within the Yale New Haven Health (YNHH) system between August 1, 2020 and August 31, 2022. We manually reviewed clinical presentation, age at diagnosis, gender, race, ethnicity, Revised International Staging System (R-ISS) stage, Eastern Cooperative Oncology Group (ECOG) performance status (PS), insurance type, practice setting, immunoglobulin (Ig) isotype, hemoglobin (Hb), creatinine (Cr), and calcium (Ca) at diagnosis, presence of bone lesion, bone marrow plasma cell (BMPC) %, cytogenetic abnormalities, transplant eligibility, and treatment response based on the International Myeloma Working Group (IMWG) criteria at 3 months after front-line therapy. Descriptive statistics were performed with Pearson's χ²-test using GraphPad PRISM version 9.0.0. Results: We identified 241 patients with NDMM during the study period within the YNHH system. Overall median age at diagnosis was 69 years (interquartile range: 61-78). 60.2% (n=145) were male, 68% (n=164) identified themselves as white and 90% (n=217) as non-Hispanic. 51.9% (n=125) had R-ISS stage II and 65.6% (n=158) had ECOG PS of 0-1. 63.1% (n=152) were treated at a community practice setting and 53.9% (n=130) had commercial insurance. 55.6% (n=134) had IgG isotype and 41.1% (n=99) had unfavorable risk cytogenetics which was defined as a 17p deletion, t(4;14), t(14;16), t(14;20), gain or amplification of 1q, 1p deletion, and chromosome 1 translocations. 28.2% (n=68) received front-line quadruplet therapy: DARA+lenalidomide (LEN)+bortezomib (BORTE)+dexamethasone (DEX) (n=54), DARA+cyclophosphamide+BORTE+DEX (n=10), or DARA+LEN+carfilzomib (CARFIL)+DEX (n=4). 58.5% (n=141) received triplet therapy, 8.3% (n=20) received doublet therapy, 0.83% (n=2) received monotherapy, and 4.1% (n=10) opted for hospice care. 41.5% (n=100) received DARA in front-line treatment: quadruplet as above (n=68), triplet of DARA+LEN+DEX, DARA+BORTE+DEX, or DARA+CARFIL+DEX (n=31), and doublet of DARA+DEX (n=1). Factors including gender (male vs. female, p=0.018), practice setting (academic vs community, p=0.014), R-ISS stage (I vs II vs III vs unknown, p=0.003), Ig isotype (IgG vs IgA vs light chain vs other, p=0.006), cytogenetic abnormalities (standard risk vs unfavorable risk, p=0.02), and transplant eligibility (transplant eligible vs transplant ineligible, p=0.001) were associated with the adoption of DARA in front-line treatment. While 51.7% (n=46) of the patients treated at an academic practice setting received DARA in front-line treatment, only 35.5% (n=54) of the patients treated at a community practice setting received such treatment. 69% (n=69) of those who received DARA-based regimen in front-line treatment achieved at least a very good partial response (VGPR) at 3 months compared to 54.6% (n=77) of those who received non-DARA-based regimen. There were no significant differences in age, race, ethnicity, ECOG PS, insurance type, laboratory data (Hb, Cr, and Ca) at diagnosis, presence of bone lesion, and BMPC % between the group treated with DARA-based regimen and the group treated with non-DARA-based regimen. Conclusion: This analysis of real-world data from patients with NDMM highlighted underutilization of DARA in front-line treatment, especially at a community practice setting. Gender, practice setting, R-ISS stage, Ig isotype, cytogenetic abnormalities, and transplant eligibility were significantly associated with the adoption of DARA in front-line treatment. Additionally, utilization of DARA in front-line treatment was associated with a better treatment response at 3 months, suggesting that interventions to promote the utilization of DARA will help improve outcomes of NDMM patients.

Proposal ofmyeloid Neoplasms with MYC-Positive Double Minutes As a Distinct Entity

Background: As reported in our preliminary work (Blood (2022) 140 (Supplement 1): 9142-9143) myeloid neoplasms (MN) with MYC-positive double minutes (dmin) are mostly AML and often show a cytomorphological proximity to APL. We here now present detailed genotypical and phenotypical characteristics to address the question if MN with MYC dmin might represent a distinct hematologic entity. Aim: In-depth characterization of cytomorphological, mutational, transcriptional and clinical features of 76 MN with MYC dmin and analysis of the amplified chromosomal region and its effect on gene expression (GE). Methods: We analyzed 60 bone marrow (BM) and 16 peripheral blood (PB) samples of 76 pts with MN and MYC dmin (36 female, 40 male; median age 75 yrs, range 44-89 yrs). The diagnosis was established following WHO guidelines. Dmin and MYC amplification were assessed by chromosome banding analysis and FISH. Cytomorphologic examination included assessment of APL-like features, i.e. high number of atypical hypergranulated promyelocytes, high number of Auer rods, faggot(-like) cells and pseudo Chediak-Higashi (PCH) granules. Molecular genetic analyses comprised a targeted NGS panel (all pts, median coverage 1500x), WGS (16 pts, median coverage 100x) and WTS (40 pts, 50 Mio reads). Mut frequencies and GE levels were compared to AML cases without MYC dmin (“non dmin” AML). Survival data were available for 41 pts (median follow-up: 12 months). Results: According to WHO 2022 most of the 76 cases were AML-MR (myelodysplasia-related) (55/76, 72 %, 9 of these post MDS or post MDS/MPN). Three (4 %) cases each were classified as AML with maturation or without maturation, while one case with AML was not further classifiable due to insufficient material quality and lack of defining markers. Other diagnoses comprised MDS with biallelic TP53 inactivation (4/76, 5 %), MDS-IB1 (1/76, 1 %), CMML-2 (4/76, 5 %), CMML-1 (1/76, 1 %), MDS/MPN (3/76, 4 %) and MPN in blast phase (1/76, 1 %). BM blast count was ≥10 % in 52/60 (87 %) pts, likely underestimated in the remaining 8 samples due to lack of particles, and all 16 pts where only PB was available showed >2 % blasts. Out of 50 pts with fully assessable cytomorphology 48 (96 %) presented with a highly dysplastic granulopoiesis, often including severe dysplasia in other myeloid lineages, independent of myelodysplasia-related genetic markers. Twenty-nine of 50 (58 %) pts were APL-like (≥2 APL-like features), but with a higher degree of maturation than APL. A complex karyotype (ck, ≥3 aberrations in addition to MYC dmin) was present in 25/76 pts (33 %), whereas 21/76 (28 %) pts presented with MYC dmin as the only cytogenetic aberration. TET2 mut, which represented the most frequent mut in MYC dmin pts (55/76, 72 %), often were biallelic events (36/55 pts, 65 %). TET2 mut were strikingly overrepresentated compared to “non dmin” AML (19 %) (p<0.001) (Figure A) and often accompanied by trisomy 4, representing the most frequent chromosomal gain (12/76, 16 %). TP53 mut (24/75, 32 %) and U2AF1 mut (20/75, 27 %) were almost always mutually exclusive (except for 2 pts). While TP53 mut were strongly associated with ck (84 % vs. 6 % in non ck, p<0.001), U2AF1 mut were associated with APL-like cytomorphology (48 % vs. 5 % (1 case) in non APL-like cases, p=0.001). Both mut were highly overrepresented in MYC dmin pts compared to “non dmin” AML ( TP53: 32 % vs. 11 %, p<0.001; U2AF1: 27 % vs. 4 %, p<0.001) (Figure A). WGS analysis revealed an amplified chromosomal region with a size varying from 4.3 - 5.6 Mb and a commonly amplified region of 4.3 Mb (Chr 8:126,422,001-130,697,000). This region encompasses 6 protein coding genes ASAP1, CYRIB, GSMDC, LRATD2, POU5F1B and MYC as well as several non-coding RNAs including the long non-coding RNA PVT1. An effect of the amplified region on GE was confirmed by overexpression of MYC (p<0.001) and PVT1 (p<0.001) compared to “non dmin” AML (Figure B). The median overall survival of 41 evaluable pts was 16 months. Only TP53 mut was independently associated with inferior survival (HR: 11.0, p=0.001). Conclusion: MN with MYC dmin are often AML-MR according to WHO 2022 definition, but even if not, show consistent features of severe dysplasia. They exhibit characteristic mutational patterns and distinct GE profiles, which are affected by a commonly amplified chromosomal region. Thus, we suggest MN with MYC dmin as a distinct genetically defined entity.

PATH-15. GLIOBLASTOMA, IDH-WILDTYPE WITHOUT KEY MOLECULAR FEATURES.

Abstract Molecular alterations that predict aggressive behavior of astrocytic tumors include EGFR amplification, TERT promoter (pTERT) mutations, gain of chromosome 7 and loss of chromosome 10. During January 2020 and February 2023, we encountered 21 cases of pathologically diagnosed glioblastoma, IDH-wildtype without the above-mentioned molecular characteristics. In this study, we tried to characterize these tumors. For all cases, genomic DNA was extracted from fresh frozen tissue. Using extracted DNA, to analyze the status of IDH mutation, 1p/19q codeletion, pTERT mutation, EGFR gene amplification, combined gain of entire chromosome 7, and loss of entire chromosome 10 (+7/− 10), whole exome sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) was performed. In addition, gene panel testing was performed for suspected familial cases. Among 21 cases, 2 harbored histone G34 mutation and was diagnosed as diffuse hemispheric gliomas, H3 G34-mutant. Among the rest 19 patients, CDKN2A/B homozygous deletions were detected in 7. Three of the rest 12 patients were diagnosed as patients with Li Fraumeni syndrome. Glioblastoma IDH-wildtype CNS WHO grade 4 typically presents necrosis and/or microvascular proliferation. Molecular alterations including EGFR amplification, pTERT mutations, gain of chromosome 7 and loss of chromosome 10 are key features that characterize GBM IDH-wildtype. However, some of the pathologically diagnosed GBM, do not carry these gene alterations. Among those, there existed cases harboring CDKN2A/B homozygous deletions or H3 G34 mutations, and cases suffering Li Fraumeni syndrome.

Pediatric Sertoli-Leydig Cell Tumors of the Ovary: An Integrated Study of Clinicopathological Features, Pan-cancer-Targeted Next-generation Sequencing and Chromosomal Microarray Analysis From a Single Institution.

Sertoli-Leydig cell tumors (SLCTs) are currently classified into 3 molecular subtypes: DICER1 -mutant (younger patient age), FOXL2 -mutant, and DICER1/FOXL2 -wildtype. However, it is not clear whether all pediatric SLCTs are DICER1 -mutant molecular subtypes and whether other molecular genetic aberrations besides DICER1 are involved in the pathogenesis and prognosis of these tumors. We studied comprehensive data for 8 cases of pediatric SLCTs, including clinicopathological features, pan-cancer-targeted next-generation sequencing/OncoKids panel, and chromosomal microarray analysis, to further analyze the correlation among clinicopathological features, molecular genetic aberrations, and prognosis. The ages of the patients ranged from 4 to 16 years (median, 14y). Seven cases were moderately differentiated, and one was poorly differentiated with heterologous mesenchymal elements. Two cases had heterologous epithelium or retiform elements. Follow-up was available for all 8 patients (median, 49.5mo). Seven patients were alive without evidence of recurrence or metastasis, and only case 5 developed metastases (synchronous bilateral pulmonary tumors with rhabdomyosarcomatous differentiation). All 8 tumors were found to harbor somatic hotspot DICER1 mutations, and 5 patients carried germline DICER1 mutations (2 of them had the phenotype of DICER1 syndrome). Together with recent studies, the DICER1 mutation frequency is 100% in pediatric SLCTs (n=27, age≤16y). Copy number alterations were detected in 3 tumors; the only recurrent copy number alterations was the gain of whole chromosome 6 in case 5 and case 8. This is the first report describing clinicopathological features and molecular alterations in pediatric SLCTs. Our results demonstrate that all pediatric SLCTs belong to the DICER1 -mutant molecular subtype, highlighting that somatic hotspot DICER1 mutation detection has high sensitivity (100%) for the auxiliary diagnosis of pediatric SLCTs (age ≤16y). Some pediatric SLCTs harbor molecular genetic aberrations other than DICER1 mutation, and their significance needs further study.

PATH-18. MORE UNUSUAL FEATURES IN H3 K27M-MUTANT GLIOMAS

Abstract Diffuse midline glioma, H3 K27M-altered, WHO grade 4 is an infiltrating midline glioma; however, H3 K27M mutation can also be seen in midline circumscribed, non-infiltrating gliomas and rarely in non-midline tumors. We report 2 unusual examples. A 37-year-old female developed a right posterior frontal infiltrating glioma; resection showed infiltrative tumor with brisk mitotic activity, elevated MIB-1 (20%), negative p53 expression, ATRX retention, but no necrosis or microvascular proliferation. Molecular workup showed neither IDH1/2/TERT promoter mutations or co-deletion 1p, 19q; further testing showed gain of whole chromosome 7 + loss of whole chromosome 10, meeting molecular criteria for glioblastoma. Recurrent tumor 2 years later in the same area prompted re-resection again of infiltrating tumor devoid of necrosis or microvascular proliferation; molecular testing now revealed a H3F3A (p.K28M) mutation. Both tumors showed protein expression by H3 K27M IHC+. She succumbed post-therapy at 3 ½ years. A 30-year-old woman developed a circumscribed, non-enhancing third ventricular mass; resection demonstrated circumscribed, non-infiltrating glioneuronal tumor with monotonous rounded tumor nuclei, synaptophysin IHC+, negative GFAP, H3 K27M IHC+, and low MIB-1. Molecular testing identified alterations in H3F3A p. K28M and FGFR1 p.N546K. She was treated, but lost to follow-up, until she re-presented 5 years later with hemorrhagic left frontal lobe tumor contiguous with the midline, with dorsal midbrain and 4th ventricular involvement. After resection, tumor now showed infiltrative features, necrosis and microvascular proliferation, diffuse GFAP IHC+, retention of nuclear ATRX, p53 (20%), MIB-1 (22%), and H3 K27M IHC+. New tumor had no FGFR1 alteration or PDGFRA amplification to suggest radiation-induced tumor, instead manifesting PTPRZ1-MET fusion. She survives at 5 years. These cases offer new insights into survival of a non-midline example and transformation of a circumscribed, non-infiltrating tumor to secondary infiltrating H3 K27-altered tumor with new molecular alterations, possibly representing second independent tumor development.

BIOM-17. WHOLE GAIN OF CHROMOSOME 19, NOT CO-GAIN OF CHROMOSOMES 19 AND 20, IS A FAVORABLE PROGNOSTIC BIOMARKER IN IDH-WILDTYPE GLIOBLASTOMA

Abstract BACKGROUND IDH-wildtype glioblastoma carries an abysmal prognosis, but long-term survivors exist. Previous studies have suggested that co-gain of chromosomes 19 and 20 (+19/+20) is a favorable prognostic marker. We sought to validate this claim and investigate whether gain of chromosome 19 (+19) is a superior prognostic indicator. METHODS We collected somatic copy number alteration data for primary glioblastoma tumors from TCGA (N = 356) and paired primary (N = 169) and recurrent (N = 167) glioblastoma tumors from GLASS. We assessed the frequency of these events and conducted survival analyses with univariate and multivariate Cox proportional hazard models to examine the association between +19/+20 and +19 and patient outcomes. RESULTS Among primary glioblastomas, the frequency of +19/+20 (20.8% vs. 23.7%) and +19 (34.6% vs. 36.7%) did not differ between TCGA and GLASS. However, the presence of +19/+20 was significantly reduced in GLASS recurrent tumors compared to primary tumors (14.3%, p = 0.04), while +19 without +19/+20 was unchanged (13.8%), indicating that +19/+20 is selected against in recurrent glioblastoma. Tumors harboring +19/+20 did not exhibit improved overall survival (OS) or progression-free survival (PFS) in TCGA (p = 0.21 and p = 0.14, respectively), nor did they demonstrate improved OS in GLASS (p = 0.32). Conversely, tumors with +19 showed significantly better OS and PFS in TCGA (HR = 1.4, p< 0.01; HR = 1.5, p< 0.01, respectively) and improved OS in GLASS (HR = 1.6, p< 0.01). In multivariate survival analyses, +19 remained a prognostic factor independent of +19/+20, patient sex, age, MGMT promoter methylation status, and KPS in TCGA (p< 0.05) and +19/+20 and age in GLASS (p = 0.01). CONCLUSION Although previous studies have suggested that +19/+20 is a positive prognostic biomarker in glioblastoma, our findings indicate that this assertion should be reevaluated. Our results demonstrate that +19 is associated with favorable outcomes in the TCGA and GLASS datasets, whereas +19/+20, while possibly selected against in recurrent glioblastomas, is not.

Lessons of Nature in Trisomy-8 MDS and AML: Determinants of Clonal Drive

The clinical consequences of trisomy 8 (+8) are reflected by its categorization as an intermediate risk cytogenetic abnormality in AML while in MDS it has a more favorable impact. Gain of chromosome (chr.) 8 is a frequent event in other hematologic disorders and its prognostic role seems to be dependent on disease context. Some molecular lesions ( RUNX1, ASXL1) are distinctive of +8 AML and important in delineating its clinical phenotype and prognosis. However, the intrinsic molecular drivers contributing to clonal pathogenesis of myeloid neoplasia (MN) as repercussion of gain of chr.8 remain unclear. We stipulated that the study of clinical, genomic, and transcriptomic features of +8 MN will provide important clues to the pathogenesis of +8 and help refine its clinical implications in a specific clinical context. NGS and clinical data from a cohort of 3971 MDS and 3973 AML patients were reviewed, including normal karyotype MDS/AML (NK MDS or AML), isolated +8 (iso +8 MDS/AML), and non-isolated +8 (non-iso +8 MDS/AML). In addition, RNASeq data were available in a subcohort of patients (82: +8; 617 NK MDS). Expression of chr.8 genes was studied to unmask culprit genes in +8 MN. Compared to NK-AML, iso +8 AML patients were older (76% aged >60 years, P= .0005) and had more dysplastic than hyperproliferative phenotype as they presented with lower WBC (median: 9.5 vs 15.2x10 9/L, P= .008) and platelet counts (median: 49 vs 64 x10 9/L, P= .0002). Iso +8 AML had higher percentages of secondary AML (sAML, 17 vs 11%, P= .001) arising from antecedent MDS (14 vs 9%, P= .002) vs NK AML. As expected, survival analysis showed iso +8-AML to have worse median overall survival (mOS) vs NK AML (20 vs 32 months, P= .0001). Yet, when sub-classifying AML based on disease ontogeny (primary vs secondary), a significant mOS difference was only seen in primary AML (21.5 vs 34.5 months, P= .0002; in sAML, 14.7 vs 24.3 months, P= .3). As for molecular associations, a variety of mutations were more frequent in iso +8 AML vs NK AML, including: lineage transcriptional factors ( RUNX1, 33 vs 17%, P< .0001), chromatin modifiers ( ASXL1 37 vs 13%, P< .0001; EZH2 10 vs 3.4%, P< .0001), splicing factors ( SRSF2 30 vs 13%, P< .0001; U2AF1, 12 vs 3%, P< .0001) and cohesin genes ( STAG2, 13 vs 7%, P= .02). In contrast, mutations in FLT3 (33 vs 42%, = .01), DNMT3A (24 vs 35%, P=.002), NPM1 (14 vs 44%, P<.0001) and CEBPA (7 vs 12%, P= .02) were more frequent in NK AML. We then focused on the iso +8 MDS vs NK MDS groups, and interestingly, found that ASXL1 (52 vs 19%, P< .0001), EZH2 (25 vs 4, P< .0001), RUNX1 (29 vs 12%, P= .0009), and STAG2 (27 vs 6%, P< .0001) were more frequently found in the +8 MDS compared to NK-MDS (similar patten to AML), whereas SRSF2 (19 vs 18%, P= .9) and U2AF1 (9 vs 6%, P=.7) were similar in both. The comparison of AML and MDS then showed that iso +8 AML was more commonly associated with mutations in FLT3 (33 vs 3%, P< .0001), IDH1 (17 vs 5%, P= .03), and IDH2 (25 vs 3%, P< .0001), while iso +8-MDS had higher odds of SF3B1 (19 vs 4%, P= .001) ( Fig1A). We then investigated whether specific transcriptomic features may play a role in +8 MN pathogenesis by targeting the transcriptome of 412 chr.8 genes ( Fig1B). After adjusting for zygosity, we identified 186 genes correlating the change in expression levels with clonality. We further interrogated genes possibly eliciting oncogenic potential with log2 fold change (log2FC) ratio of at least 1.25 to reflect an extra chr.8 copy. We found higher mRNA expression levels of 13 putative culprit genes of known oncogenic potential in iso +8 MDS vs NK MDS including the anti-apoptotic protein BAG4 (LogFC 7.1 vs 5.4, P< .0001), possibly conferring growth advantage, toll-like receptor LY96 (LogFC 3.3 vs 2.0, P< .0001),the tyrosine protein kinase LYN (LogFC 8.4 vs 6.7, P< .0001), human oncogene WHSC1L1/NSD3 (LogFC 8.1 vs 6.5, P< .0001)and long non-coding RNA, PVT1 derived from an 8q24 intergenic region (LogFC 4.0 vs 2.2, P< .0001). In summary, iso +8 MN represents a distinct entity defined by older age and dysplastic phenotype, likely due to genotypic enrichment in RUNX1 mutations, while inversely associated with proliferation genes ( e.g., FLT3 and NPM1 in NK). The key culprit oncogenes implicated in +8 MN may be located on the extra chr.8 itself. Indeed, we found transcriptomic changes pertinent to +8 MDS whose role in driving leukemogenesis and interaction with specific myeloid drivers needs to be confirmed by future experimentations on cellular and murine models.

The Temporal Evolution of Chromosome 1q Gain and Hyperdiploidy and Its Impact on Clinical Outcomes in Multiple Myeloma

INTRODUCTION: Multiple myeloma (MM) evolution is shaped by the acquisition and selection of distinct genomic events over time. While various temporal patterns have been identified, the precise chronological order in which key clonal genomic defining events are acquired, and their specific impact on clinical outcomes remain to be fully elucidated. METHODS: To decipher the genomic life history of MM and its impact on clinical outcomes, we interrogated the high coverage (80X) whole genome sequencing (WGS) of 378 MM patients. Overall, 319 and 59 WGS were generated from samples collected at diagnosis and at relapse, respectively. Newly diagnosed MM (NDMM) patients were treated upfront with proteosome inhibitors, lenalidomide, dexamethasone, +/- monoclonal antibodies. To estimate the relative and absolute temporal relationship among clonal events, we leveraged the molecular time approach, based on the corrected ratio between duplicated and non-duplicated single nucleotide variants (SNV). RESULTS: Overall, 300/378 (79%) patients had at least one large chromosomal gain defined as >1Mb with >50 clonal SNV eligible for molecular time analysis, for a total of 1493 events tested. Consistent with recent findings, using clock-like mutational signatures SBS1-SBS5, we estimated that the first gain in MM is typically acquired around the second or third decade of life, with a median time lag of approximately 33 years between acquisition and diagnosis. In 158/178 (89%) of hyperdiploid (HRD) patients, all trisomies of odd-numbered chromosomes were acquired simultaneously. Among patients with canonical IGH translocations and HRD, the molecular time when trisomies were acquired was usually late compared to HRD without canonical IGH translocations (p<0.0001). Next, we examined the temporal relationship between IGH canonical translocations and gains linked to the same IGH canonical translocation in 29 patients. We consistently observed that when IGH canonical translocations co-occurred with HRD (n=7), and/or 1q gain (n=8) in the same patient, the canonical IGH translocation was always found to be the initiating event, occurring earlier than the chromosomal gains. Interestingly, in 104/178 (58.4%) HRD patients, the earliest multi-gain event was not always restricted to odd chromosomes, but in involved other non-HRD chromosomes such as: 6p (n=43) and 1q (n=32), demonstrating that gain 1q, which is assumed to occur at progression, can also be acquired very early in disease life history. A total of 92 and 21 patients with 1q gain and 1q amp (>3 copies) were identified, respectively. In 14/21 (66%) with 1q amp, the first and second 1q extra copies were acquired in two distinct and independent time windows. Interestingly, patients with early 1q gain showed the same clinical outcomes as 1q amp, and inferior progression free survival outcomes compared to late 1q gain (p=0.01; Figure 1). In 18/21 1q amp the first 1q duplication was acquired early, suggesting that the adverse prognostic effect of 1q gain/amp in NDMM may be more dependent on the timing of its acquisition rather than the number of extra copies gained. To investigate late temporal patterns and differentiate selection versus acquisition of large gains at relapse after autologous stem cell transplant (ASCT), we interrogated 25/59 (42%) RRMM patients exposed to melphalan with detectable SBS-MM1. To establish the temporal order of events, we employed the melphalan mutational signature, SBS-MM1, as a unique temporal barcode (Diamond et al. Blood 2023). Overall, we observed that 21% of all loss of heterozygosity (LOH) events and 15% of all gains were acquired after ASCT (i.e., SBS-MM1 mutations were only detectable in the pre-gain/duplicated SNV). Notably, among these events, 1q gain was acquired after ASCT in 3/4 patients, indicating that the acquisition of 1q gain can occur even after administration of first-line therapy. CONCLUSIONS: In our study, we have uncovered distinct temporal patterns in the acquisition of early genomic drivers in MM. These patterns contribute to the reconstruction and better understanding of the life history of MM and may hold potential clinical and prognostic implications.

11q Gain with t(11;14) or Alone Were Associated with Poor Prognosis in Newly-Diagnosed Multiple Myeloma Patients By SNP-Array Analysis and FISH

t(11;14) is currently classified as a standard-risk genetic marker for newly diagnosed multiple myeloma (NDMM) patients. But some recent studies have suggested that t(11;14) may be an intermediate-risk marker in multiple myleoma (MM). The clinical significance of t(11;14) in MM is still controversial. Here, using high-resolution single nucleotide polymorphism-based mapping array (SNP-array) analysis and fluorescence in situ hybridization (FISH), the most common gained region of chromosome 11 was identified in 96/611 (15.7%) NDMM patients which located at 11q13.3-q25 (65.7Mb in size and contains 622 genes including CCND1). It demonstrated a statistically significant coexisting with t (11;14) (p<0.001), complex karyotypes (involves at least 6 chromosomes) (p<0.001), high plasma cell ratio in bone marrow (p=0.001) and poor response to VRD (bortezomib, lenalidomide, dexamethasone) treatment (p<0.001), but mutually exclusive with monosome 13, del(13q14), dup1q21 and t (4;14). When exploring the correlation of t(11;14) with genomic copy number variations (CNAs), it was also indicated that t(11;14) was most closely related to 11q gain (39%), while negatively correlated with others including gain of 1q and chromosome 3, 5, 6, 7, 9, 11, 15, 19, loss of 1p, 12p, 14q and chromosome 13 and 22. With a median follow up time of 22 months, survival analysis of 40 t(11;14) patients, 123 hyperdiploid (HRD) patients showed that 11q gain could have an adverse impact on the progression-free survival (PFS) in both groups. In t(11;14) subgroup, the median PFS (mPFS) were not reached, but PFS at 40 months were 60.9% vs 81.7% with 11q gain vs non-11q gain patients. In HRD subgroup, the mPFS were 23 months vs 49 months with 11q gain vs non-11q gain groups. Autologous hematopoietic stem cell transplantation (ASCT) can significantly improve the PFS of patients with t(11;14) and 11q gain (mPFS for transplant-eligible (TE) vs transplant-ineligible (TIE) patients were not reached vs 9 months, P=0.0067), but not helpful to 11q gain patients without t(11;14) (mPFS for TE vs TIE: 23 months vs 22 months, p=0.2137). Multivariate analysis confirmed that 11q gain was an independent adverse factor to PFS of MM with t(11;14) (Hazard ratio: 11.621, 95% CI: 1.027-131.507; p=0.048; n=37). Conclusions: Gain of 11q13.3-q25 is a reproducible chromosomal copy number abnormality in NDMM characterized by coexisting with t (11;14), complex karyotypes, higher plasma cell ratio in bone marrow and poor treatment response to VRD. t(11;14) patients with 11q gain had a poorer PFS compared to patients with t(11;14) only, mPFS was only 9 months for TIE patients. t(11;14) with 11q gain NDMM patients needs to be considered as high risk and ASCT could improve patients' survival.