Initial genome sequencing and analysis of multiple myeloma

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Abstract

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the dataset. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signaling was suggested by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.

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Most cited references 30

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Genome Remodeling in a Basal-like Breast Cancer Metastasis and Xenograft

Li Ding, Matthew Ellis, Shunqiang Li … (2010)

Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumor progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumor, a brain metastasis, and a xenograft derived from the primary tumor. The metastasis contained two de novo mutations and a large deletion not present in the primary tumor, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumor mutations, and displayed a mutation enrichment pattern that paralleled the metastasis (16 of 20 genes). Two overlapping large deletions, encompassing CTNNA1, were present in all three tumor samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared to the primary tumor suggest that secondary tumors may arise from a minority of cells within the primary.

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The molecular classification of multiple myeloma.

Fenghuang Zhan, Yongsheng Huang, Simona Colla … (2006)

To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.

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DNA sequencing of a cytogenetically normal acute myeloid leukemia genome

Timothy Ley, Elaine R. Mardis, Li Ding … (2008)

Lay Summary Acute myeloid leukemia is a highly malignant hematopoietic tumor that affects about 13,000 adults yearly in the United States. The treatment of this disease has changed little in the past two decades, since most of the genetic events that initiate the disease remain undiscovered. Whole genome sequencing is now possible at a reasonable cost and timeframe to utilize this approach for unbiased discovery of tumor-specific somatic mutations that alter the protein-coding genes. Here we show the results obtained by sequencing a typical acute myeloid leukemia genome and its matched normal counterpart, obtained from the patient’s skin. We discovered 10 genes with acquired mutations; two were previously described mutations thought to contribute to tumor progression, and 8 were novel mutations present in virtually all tumor cells at presentation and relapse, whose function is not yet known. Our study establishes whole genome sequencing as an unbiased method for discovering initiating mutations in cancer genomes, and for identifying novel genes that may respond to targeted therapies. We used massively parallel sequencing technology to sequence the genomic DNA of tumor and normal skin cells obtained from a patient with a typical presentation of FAB M1 Acute Myeloid Leukemia (AML) with normal cytogenetics. 32.7-fold ‘haploid’ coverage (98 billion bases) was obtained for the tumor genome, and 13.9-fold coverage (41.8 billion bases) was obtained for the normal sample. Of 2,647,695 well-supported Single Nucleotide Variants (SNVs) found in the tumor genome, 2,588,486 (97.7%) also were detected in the patient’s skin genome, limiting the number of variants that required further study. For the purposes of this initial study, we restricted our downstream analysis to the coding sequences of annotated genes: we found only eight heterozygous, non-synonymous somatic SNVs in the entire genome. All were novel, including mutations in protocadherin/cadherin family members (CDH24 and PCLKC), G-protein coupled receptors (GPR123 and EBI2), a protein phosphatase (PTPRT), a potential guanine nucleotide exchange factor (KNDC1), a peptide/drug transporter (SLC15A1), and a glutamate receptor gene (GRINL1B). We also detected previously described, recurrent somatic insertions in the FLT3 and NPM1 genes. Based on deep readcount data, we determined that all of these mutations (except FLT3) were present in nearly all tumor cells at presentation, and again at relapse 11 months later, suggesting that the patient had a single dominant clone containing all of the mutations. These results demonstrate the power of whole genome sequencing to discover novel cancer-associated mutations.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 20 January 2013

Publication date (Print): 24 March 2011

Publication date PMC-release: 30 January 2013

Volume: 471

Issue: 7339

Pages: 467-472

Affiliations

[1 ]The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02412, USA

[2 ]Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA

[3 ]On behalf of the Multiple Myeloma Research Consortium, 383 Main Avenue, 5 ^th Floor, Norwalk, Connecticut 06581, USA

[4 ]Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA

[5 ]Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA

[6 ]Multiple Myeloma Research Foundation, 383 Main Avenue, 5 ^th Floor, Norwalk, Connecticut 06581, USA

[7 ]The Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, Arizona 85004, USA

[8 ]Harvard Medical School, Boston, Massachusetts 02115, USA

[9 ]Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

[10 ]Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel

[11 ]The Ohio State University Medical Center, 320 West 10 ^th Avenue, Columbus, Ohio 43210, USA

[12 ]St. Vincent's Comprehensive Cancer Center, 325 West 15 ^th Street, New York, New York 11001, USA

[13 ]University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA

[14 ]City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, California 91010, USA

[15 ]Winship Cancer Institute, Emory University, 1365-C Clifton Road, NE Atlanta, Georgia 30322, USA

[16 ]Mayo Clinic Rochester, 200 1 ^st Street S.W. Rochester, Minnesota, 55905, USA

[17 ]Hackensack University Medical Center, 30 Prospect Avenue, Hackensack, New Jersey 07601, USA

[18 ]Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada

[19 ]Washington University School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA

[20 ]University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA

[21 ]Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA

Author notes

[* ]To whom correspondence should be addressed: Correspondence and requests for materials should be addressed to T.R.G. ( golub@ 123456broadinstitute.org ) or G.G. ( gadgetz@ 123456broadinstitute.org )

Article

Manuscript ID: NIHMS385546

DOI: 10.1038/nature09837

PMC ID: 3560292

PubMed ID: 21430775

SO-VID: 43cb71c3-7512-425e-8a49-cda7c960fb18

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Funding

Funded by: National Cancer Institute : NCI

Award ID: R01 CA133966-03 || CA

Funded by: National Cancer Institute : NCI

Award ID: R01 CA133115-04 || CA

Funded by: National Institute on Aging : NIA

Award ID: R01 AG020686-07 || AG

Funded by: National Cancer Institute : NCI

Award ID: K12 CA133250 || CA

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Initial genome sequencing and analysis of multiple myeloma

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Genome Integrity

Most cited references 30

Genome Remodeling in a Basal-like Breast Cancer Metastasis and Xenograft

The molecular classification of multiple myeloma.

DNA sequencing of a cytogenetically normal acute myeloid leukemia genome

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Cited by 505

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