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Integrated Exome and RNA Sequencing of Dedifferentiated Liposarcoma

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Integrated Exome and RNA Sequencing of Dedifferentiated Liposarcoma Corrected: Publisher correction ARTICLE https://doi.org/10.1038/s41467-019-13286-z OPEN Integrated exome and RNA sequencing of dedifferentiated liposarcoma Makoto Hirata et al.# The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of 1234567890():,; well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management. #A full list of authors and their affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2019)10:5683 | https://doi.org/10.1038/s41467-019-13286-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13286-z edifferentiated liposarcoma (DDLPS) is a rare malignant Dtumor with an incidence of <0.1/million each year1,2 Table 1 Clinical characteristics of patients with DDLPS. that occurs in ~10% of cases of intermediate (locally a aggressive) well-differentiated liposarcoma (WDLPS)3. Surgical Features Total (n = 108) excision is the primary treatment modality used for DDLPS, Male sex, n (%) 75 (69.4) as DDLPS exhibits a low response rate to conventional che- Age at diagnosis ± std (y) 62.7 ± 12.7 motherapeutic reagents4. To date, several analyses have unveiled Primary site, n (%) genomic characteristics common to DDLPS, including the Retroperitoneum or abdomen 79 (73.1) fi Extremity 25 (23.1) ampli cation of 12q13-15, that are also frequently found in Chest wall or back 4 (3.7) 5–10 fi WDLPS . These studies have also identi ed a number of Tumor size, n (%) genes within 12q13-15, including HOXC13, MDM2, HMGA2, 10 cm ≥ 25 (23.6) CDK4,andCPM, as being key to the development of DDLPS and 10 cm < 81 (76.4) WDLPS; a number of additional genomic occurrences, such Unknown 2 (−) as the loss of 11q23 and the gain of 6q23 and 1p32, have Local treatment, n (%) been defined as genomic abnormalities that are specificto Surgery only 97 (89.8) DDLPS6,8,11–17. Recently, the Cancer Genome Atlas (TCGA) Surgery with adjuvant radiation 9 (8.3) Research Network has identified the characteristics of some types Radiation 1 (0.9) fi Heavy ion 1 (0.9) of soft-tissue sarcoma, including DDLPS with ampli cation of Surgical margin, n (%) 12q13-15, through comprehensive genomic analysis and showed fi R0 40 (37.7) that the classi cation of DDLPS tumors based on the status of R1 58 (54.7) their somatic copy-number alterations (SCNA) and DNA R2 3 (2.8) methylation could predict clinical prognosis18. These results, RX 5 (4.9) based on the analysis of 50 DDLPS cases, still require validation. Not applicable 2 (−) In addition, the genomic events associated with the malignant aClinical information from 108 of 115 patients was available for the current study transformation of DDLPS, and with DDLPS tumors without 12q13-15 amplifications that are histologically diagnosed, remain to be identified. We established the Japan Sarcoma Genome Consortium nonsynonymous single nucleotide variants (SNVs) and short (JSGC) in 2014 with the aim of generating a comprehensive map insertions/deletions (INDELs), with a mean of 24.2 (0.274 per of the genomic alterations and abnormalities present in bone and coding megabase) and a range of 0 to 70 mutations (Fig. 1a) per soft-tissue tumors, in order to facilitate the implementation of sample. The frequency distribution of the somatic mutations was precision medicine. Here, we collect tumor and normal tissue almost comparable among the three groups, JSGC-IMSUT, samples from 65 patients with DDLPS and perform whole-exome JSGC-NCC and TCGA (Supplementary Fig. 1a). The mutation and RNA sequencing at two facilities, the Institute of Medical frequency at each chromosome ranged from 0.114 (in chromo- Science at the University of Tokyo (hereinafter, JSGC-IMSUT), some 21) to 0.482 (in chromosome 12) per coding megabase and the National Cancer Center Research Institute, Japan (JSGC- (Fig. 1b; Supplementary Fig. 1b). Base substitution analysis of NCC). In addition, we obtain FASTQ data derived from the synonymous and nonsynonymous SNVs with the adjacent 5′ and whole-exome and RNA sequencing of 50 DDLPS tumors from 3′ flanking nucleotides, in order to better understand the TCGA, in order to conduct genomic meta-analysis on a total of mutational processes involved, showed that nucleotide altera- 115 patients with DDLPS. In addition, eight pairs of well- tions from anyCG to anyTG were the most frequently detected in differentiated (WD) and dedifferentiated (DD) components from DDLPS (Fig. 1c). The nucleotide alterations exhibited similar DDLPS tumors are obtained for the comparison of their genomic trends among the three groups (Supplementary Fig. 1c). Muta- alterations. tion signature analysis, using the COSMIC database, showed that signature 3 contributed the most to these base substitutions, followed by signature 1 (Fig. 1d), indicating that both the failure Results of DNA double-strand break-repair (signature 3) and aging Clinical characteristics of the subjects. A total of 115 patients (signature 1) may contribute to the development of DDLPS. were enrolled in the current study (28 from JSGC-IMSUT, 37 from Recurrently, mutated genes (frequency of more than five sam- JSCG-NCC, and 50 from TCGA), and clinical information was ples) were MUC16, TTN, ATRX, TRHDE, PCLO, ZNF717, TP53, collected from 108 of 115 patients. Of these 108 patients, 75 (69.4%) FLG,andNAV3; however, the mutated loci at each gene were not were male, and the mean age at diagnosis was 62.7 (±12.7) years recurrent (Supplementary Fig. 2). The GISTIC analysis of SCNAs (Table 1). A total of 73.1% of the DDLPS tumors arose from the identified 28 gained regions (357 genes) and 55 lost regions (455 retroperitoneum or abdomen, while the distribution of the primary genes) (Fig. 1e; Supplementary Data 1 and 2). As expected, the tumor sites varied among the three groups; tumors were most fre- gain of 12q15 resulted in the lowest FDR q-value in the GISTIC quently located in an extremity in JSGC-IMSUT patients (66.7%) and analysis. The genome-wide analysis of SCNAs and their corre- in the retroperitoneum or abdomen in JSGC-NCC (78.4%) and in sponding GISTIC values showed that the copy numbers of genes TCGA (86.0%) patients. A total of 76.4% of the patients had tumors in chromosomes 11 and 13, and the short-arm of chromosome 9 that were 10 cm or more in diameter (Table 1; Supplementary were generally decreased, while those of the long-arms of chro- Table 1) and 98.1% of the patients underwent surgery (Table 1; mosomes 9 and 20 and the short-arms of chromosomes 4, 5, 7, Supplementary Table 1). These results indicated that the patients 19, and X were increased. Notably, the copy numbers of the enrolled in this study may be representative of the general population genes located at 12q14.1–15 greatly increased (Supplementary of patients with DDLPS. Fig. 3). Among these genes, SLC35E3, MDM2,andCPM exhib- ited the highest mean GISTIC values with the lowest standard Somatic mutations and copy-number alterations.Basedon deviations (Supplementary Fig. 3, boxed area), indicating exome sequencing for 115 pairs of DDLPS and normal tissue that these three genes are greatly and consistently amplified samples, we identified 2639 somatic mutations, including in DDLPS. 2 NATURE COMMUNICATIONS | (2019)10:5683 | https://doi.org/10.1038/s41467-019-13286-z | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13286-z ARTICLE a (Count) b (Count/Mb) 80 0.5 Nonsynonymous SNVs Nonsynonymous SNVs INDELs INDELs 0.4 60 0.3 40 0.2 0.1 20 0 1 2 3 4 5 6 7 8 9 X 0 10 11 12 13 14 15 16 17 18 19 20 21 22 c C>A C>G C>T T>A T>C T>G 150 100 Count 50 0 T_T T_T T_T T_T T_T T_T A_T T_A A_T T_A A_T T_A A_T T_A A_T T_A A_T T_A C_T T_C C_T T_C C_T T_C C_T T_C C_T T_C C_T T_C A_A A_A A_A A_A A_A A_A A_C C_A G_T T_G A_C C_A G_T T_G A_C C_A G_T T_G A_C C_A G_T T_G A_C C_A G_T T_G A_C C_A G_T T_G C_C C_C C_C C_C C_C C_C A_G G_A A_G G_A A_G G_A A_G G_A A_G G_A A_G G_A C_G G_C C_G G_C C_G G_C C_G G_C C_G G_C C_G G_C G_G G_G G_G G_G G_G G_G de 1p13.3 Signature # 1q24.3 0.00 1q44 1p32.1 2p25.3 1q21.3 2q37.3 1 3p12.3 1q24.3 3q11.2 3q29 4p15.33 1 4q35.2 2 5p15.33 5q35.1 6p25.3 3p12.1 3 6q12 4p16.3 0.25 6q27 7p11.2 4 5p15.33 7p36.3 2 8p23.3 5 5q35.3 8p23.1 6p21.1 8q24.3 6 6q24.2 9p24.3 6q24.3 9p21.2 9q34.11 7 7p15.3 10p15.3 8q22.3 10p12.2 8 0.50 3 10q26.3 9q21.12 11p15.5 9 11q11 11q21 10 11p13 11q24.3 11q13.3 12p13.2 11 Relative contribution Relative 12p13.32 12q24.33 13q32.3 12 12p13.31 4 13q34 14q21.3 13 12q15 14q32.33 6 14 15q11.2 14q32.31 0.75 15q14 15 16p13.3 15q26.3 7 16q24.3 16 17p11.2 16q22.2 17q11.2 10 17 17q21.32 19p13.3 13 15 18q22.1 16 19p12 18 19p13.2 17 19q13.43 19q12 22 20p13 19 24 20p11.22 20q12 29 21q22.3 20 20q13.33 1.00 22q13.31 21 22q13.33 22 Xp21.2 Xp22.33 X Xq21.1 Xq21.2 –10 –6 –4 –2 Xq23 10 10 10 10 0.25 0.25 10–5 10–10 10–40 10–90 10–300 FDR (q value) FDR (q value) Fig.
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