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Supplementary Table 5 shows the results of NSD2-MASPEC in KMS11 cells.

Supplementary Table 2 shows 26 SE-associated genes commonly acquired in both t(4:14)-positive HMCLs and patient-derived MM sample.

Supplementary Table 1 shows the list of 4C primers applied in the Circular Chromosome Conformation Capture assay.

Supplementary Materials and Methods shows detailed descriptions of methodology or materials and methods used in this manuscript.

Supplementary Figures, including Figures S1-6, and each figure legends.

Supplementary Table 4 shows the sequences of SE fragments inserted into pGL3 vector

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma.Significance:A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets.

Supplementary Table 3 Uni- and multivariate Cox survival analysis using HJURP and NSD2 expression in myeloma dataset

Multiple myeloma is an incurable malignancy with marked clinical and genetic heterogeneity. The cytogenetic abnormality t(4;14) (p16.3;q32.3) confers aggressive behavior in multiple myeloma. Recently, essential oncogenic drivers in a wide range of cancers have been shown to be controlled by super-enhancers (SE). We used chromatin immunoprecipitation sequencing of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs in t(4;14)-translocated multiple myeloma. The histone chaperone HJURP was aberrantly overexpressed in t(4;14)-positive multiple myeloma due to transcriptional activation by a distal SE induced by the histone lysine methyltransferase NSD2. Silencing of HJURP with short hairpin RNA or CRISPR interference of SE function impaired cell viability and led to apoptosis. Conversely, HJURP overexpression promoted cell proliferation and abrogated apoptosis. Mechanistically, the NSD2/BRD4 complex positively coregulated HJURP transcription by binding the promoter and active elements of its SE. In summary, this study introduces SE profiling as an efficient approach to identify new targets and understand molecular pathogenesis in specific subtypes of cancer. Moreover, HJURP could be a valuable therapeutic target in patients with t(4;14)-positive myeloma. SIGNIFICANCE: A super-enhancer screen in t(4;14) multiple myeloma serves to identify genes that promote growth and survival of myeloma cells, which may be evaluated in future studies as therapeutic targets. Published version The work was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative (to W.J. Chng), the NMRC Clinician Scientist Investigator award (to W.J. Chng), the RNA Biology Center at CSI Singapore, NUS, from funding by the Singapore Ministry of Education’s Tier 3 grants, grant number MOE2014-T3–1-006 (to W.J. Chng), the National Natural Science Foundation of China (grant no. 82000212 to Y. Jia), Natural Science Foundation of Zhejiang Province (grant no. LQ21H160022 to Y. Jia), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (grant no. 2021RC003 to Y. Jia). Y. Jia also thanks the China Scholarship Council (grant no. 201706320167) for financial support to visit National University of Singapore.

Breast cancer remains the first cause of death in women worldwide even if the average 10-year survival rate is 83%. It remains difficult to accurately evaluate the risk of recurrence, and consequently the need of chemotherapy, in estrogen receptor (ER)-positive, HER2-negative early breast cancers, at the individual level, leading to overtreatment for some patients. In that context, multigene prognostic scores are proposed in combination with clinicopathological parameters, to guide adjuvant treatment decisions. In our study, patients diagnosed with ER-positive, Her2-negative breast cancer, analyzed with the 12-gene EndoPredictTM test are prospectively included in the national SiMosein registry. The decision for Endopredict testing is determined by an oncological tumor board in expert breast cancer centers. The test is locally performed (10 national laboratories, evaluated by a national quality control exchange program). Clinicopathological parameters are recorded and the treatment decision before and after the genomic test is requested. The aim of the study is to prospectively evaluate the real-life use of the EndopredictTM test and the impact of the recurrence risk on the adjuvant treatment decision. A total of 3153 patients were included between May 2016 and December 2018. Patients are 75.6% post-menopausal (median age: 57.55y) and are mostly diagnosed as invasive ductal carcinoma not otherwise specified (81.2%) with SBR grade 2 (74.02%) and positive Ki67 staining (>14%, 66.4%). Tumor sizes are pT1ab, pT1c or pT2 in respectively 12.1%, 54.7% and 31.4% of the cases. Lymph node involvement is negative (pN0) in 70.5% of the cases. However, 29.5% of cases are pN1-3 with 5.2% of pN1mi. All cases are ER-positive, HER2-negative early breast cancers and 74.8% are progesterone receptor (PR)-positive (PR>10%) and 76.43% of the cases are of luminal B-like subtype. The population evaluated in this prospective study is in accordance to the intermediate prognostic subpopulation of luminal breast cancers where genomic signatures could contribute to guide the adjuvant treatment decision. The risk of relapse at 10 years, as reflected by the EPclin score, is of 13.16% on average, with 55.18% of high risk (positive threshold 10%). Treatment decisions before and after the test were recorded for 599 patients. The decision remains unmodified after the test in 54.59% of the cases. Conversely, change in adjuvant treatment decision was made from hormone therapy (HT) to adjunction of chemotherapy (HT+CT) in 18.20% of the cases and from (HT+CT) to (HT) leading to chemotherapy withdrawn in 27.21%. Finally, the national SiMosein registry, evaluated the utility of the test. The use of EndopredictTM is mostly restricted to the intermediate prognostic subgroup of the early luminal breast subtype as requested by the French health authority (HAS). The test is routinely used in France and clinicians need mainly the test for treatment decision. The EPclin score leads to 45.41% of modification of treatment with a majority of avoidance of chemotherapy (59.93%). Citation Format: Jacqueline Lehmann-Che, Jennifer Wong, Lucie Tixier, Ludovic Lacroix, Magali Triki-Lacroix, Pierre-Jean Lamy, Agnes Garnier, Véronique Quillien, Florence Godey, Isabelle Soubeyran, Gaëtan MacGrogan, Laurent Arnould, Juliette Haudebourg, Anne Tallet, Linda Dainese, Caroline Hugonin, Frédérique Penault-Llorca. Simosein registry, the French national real-life prospective evaluation of the impact of Endopredict® (EPclin) on treatment decision in ER-positive, HER2-negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-25.

Introduction Breast-conserving surgery (BCS) with radiation therapy is the procedure of choice for early-stage breast cancer. Survival and locoregional recurrence is non-inferior to mastectomy, with superior cosmetic and psycho-social outcomes. Differing health systems have demonstrated a wide variation in the rate of BCS. Little is known about the rate of BCS and factors influencing its practice in middle resource countries. This study aims to examine the BCS rates in Malaysia and to identify factors influencing its uptake. Methodology This is a multi-centre, cross-sectional study involving the University of Malaya Medical Centre (UMMC), Queen Elizabeth II Hospital (QEH), and Tengku Ampuan Rahimah Hospital (TARH). Patients diagnosed with invasive breast cancer from January 2014 to December 2015 were included, excluding stromal cancers and lymphomas. Univariate and multivariate analyses identified factors influencing BCS. Results A total of 1005 patients were diagnosed with breast cancer in the allocated time frame. Excluding incomplete records and those who did not have surgery, 730 patients were analysed. Overall BCS rate was 32.9%. The BCS rate was highest at QEH (54.1%), followed by UMMC (29.5%), and TARH (17.4%). 16.9% had BCS after neoadjuvant therapy. Factors influencing BCS uptake included age, ethnic group, breast-surgeon led services, AJCC Stage, tumour size, HER-2 expression, and tumour grade. Conclusions The rate of BCS in Malaysia is low. A wide variation of rate exists among the studied hospitals. Younger age, earlier AJCC stage, and the presence of a Breast sub-specialist surgeon, would make it more likely that the patient has her breast conserved.