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Melanoma Genome Sequencing Reveals Frequent PREX2 Mutations

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Melanoma Genome Sequencing Reveals Frequent PREX2 Mutations LETTER doi:10.1038/nature11071 Melanoma genome sequencing reveals frequent PREX2 mutations Michael F. Berger1{*, Eran Hodis1*, Timothy P. Heffernan2{*, Yonathan Lissanu Deribe2{*, Michael S. Lawrence1, Alexei Protopopov2{, Elena Ivanova2, Ian R. Watson2{, Elizabeth Nickerson1, Papia Ghosh2, Hailei Zhang2, Rhamy Zeid2, Xiaojia Ren2, Kristian Cibulskis1, Andrey Y. Sivachenko1, Nikhil Wagle2,3, Antje Sucker4, Carrie Sougnez1, Robert Onofrio1, Lauren Ambrogio1, Daniel Auclair1, Timothy Fennell1, Scott L. Carter1, Yotam Drier5, Petar Stojanov1, Meredith A. Singer2{, Douglas Voet1, Rui Jing1, Gordon Saksena1, Jordi Barretina1, Alex H. Ramos1,3, Trevor J. Pugh1,2,3, Nicolas Stransky1, Melissa Parkin1, Wendy Winckler1, Scott Mahan1, Kristin Ardlie1, Jennifer Baldwin1, Jennifer Wargo6, Dirk Schadendorf4, Matthew Meyerson1,2,3,7, Stacey B. Gabriel1, Todd R. Golub1,7,8,9, Stephan N. Wagner10, Eric S. Lander1,11*, Gad Getz1*, Lynda Chin1,2,3{* & Levi A. Garraway1,2,3,7* Melanoma is notable for its metastatic propensity, lethality in the comparable to other solid tumour types (3 and 14 mutations per advanced setting and association with ultraviolet exposure early in Mb)5,6, whereas melanomas from the trunk harboured substantially life1. To obtain a comprehensive genomic view of melanoma in more mutations, in agreement with previous studies3,7,8. In particular, humans, we sequenced the genomes of 25 metastatic melanomas sample ME009 exhibited a striking rate of 111 somatic mutations per and matched germline DNA. A wide range of point mutation rates Mb, consistent with a history of chronic sun exposure. was observed: lowest in melanomas whose primaries arose on non- In tumours with elevated mutation rates, most nucleotide substitu- ultraviolet-exposed hairless skin of the extremities (3 and 14 per tions were C R TorGR A transitions consistent with ultraviolet megabase (Mb) of genome), intermediate in those originating from irradiation9. The variations in mutation rate correlated with differ- hair-bearing skin of the trunk (5–55 per Mb), and highest in a ences in the ultraviolet mutational signature. For example, 93% of patient with a documented history of chronic sun exposure (111 substitutions in ME009 but only 36% in acral melanoma ME015 were per Mb). Analysis of whole-genome sequence data identified C R T transitions (Fig. 1); these tumours contained the highest and PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac lowest base mutation rates, respectively (111 and 3 mutations per Mb). exchange factor 2)—a PTEN-interacting protein and negative regu- Interestingly, the acral tumour ME032 also showed a discernible lator of PTEN in breast cancer2—as a significantly mutated gene enrichment of ultraviolet-associated mutations (Fig. 1). Thus, genome with a mutation frequency of approximately 14% in an independent sequencing readily confirmed the contribution of sun exposure in extension cohort of 107 human melanomas. PREX2 mutations melanoma aetiology. are biologically relevant, as ectopic expression of mutant PREX2 In agreement with prior studies7,9, we detected an overall enrich- accelerated tumour formation of immortalized human melanocytes ment for dipyrimidines at C R T transitions. Analysis of intragenic in vivo. Thus, whole-genome sequencing of human melanoma C R T mutations yielded a significant bias against such mutations on tumours revealed genomic evidence of ultraviolet pathogenesis the transcribed strand for most melanomas, consistent with transcrip- and discovered a new recurrently mutated gene in melanoma. tion-coupled repair (Supplementary Fig. 1)3,7,10. Most commonly, To gain a comprehensive view of the genomic landscape in human C R T mutations occurred at the 39 base of a pyrimidine dinucleotide melanoma tumours, we sequenced the genomes of 25 metastatic (CpC or TpC; Supplementary Fig. 2). In contrast, the C R T mutations melanomas and peripheral blood obtained from the same patients in sample ME009 (with hypermutation and chronic sun exposure (Supplementary Table 1). Two tumours (ME015 and ME032) were history) more often occurred at the 59 base of a pyrimidine dinucleotide. metastases from cutaneous melanomas arising on glabrous (that is, As expected, the acral tumour ME015 exhibited mutation patterns hairless) skin of the extremities, representing the acral subtype. The observed in non-ultraviolet-associated tumour types11,suchasan other tumours were primarily metastases from melanomas originating increased mutation rate at CpG dinucleotides relative to their overall on hair-bearing skin of the trunk (the most common clinical subtype). genome-wide frequency (Supplementary Fig. 2). These different muta- Further, ME009 represented a metastasis from a primary melanoma of tional signatures suggest a complex mechanism of ultraviolet mutagenesis a patient with a clinical history of chronic ultraviolet exposure. across the clinical spectrum of melanoma, probably reflecting distinct We obtained 59-fold mean haploid genome coverage for tumour histories of environmental exposures and cutaneous biology. DNA and 32-fold for normal DNA (Supplementary Table 2). On We detected 9,653 missense, nonsense or splice site mutations in average, 78,775 somatic base substitutions per tumour were identified, 5,712 genes (out of a total of 14,680 coding mutations; Supplementary consistent with prior reports3,4 (Supplementary Table 3). This corre- Tables 4 and 5), with an estimated specificity of 95% (Supplementary sponded to an average mutation rate of 30 per Mb. However, the Methods). A mutation of BRAF, BRAFV600E, was present in 16 of 25 mutation rate varied by nearly two orders of magnitude across the tumours (64%), including the acral melanoma ME015. NRAS was 25 tumours (Fig. 1). The acral melanomas showed mutation rates mutated in 9 of 25 tumours (36%) in a mutually exclusive fashion with 1The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. 3Harvard Medical School, Boston, Massachusetts 02115, USA. 4Department of Dermatology, University Hospital Essen, D-45122 Essen, Germany. 5Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel. 6Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. 7Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. 8Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. 9Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. 10Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna and CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. 11Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. {Present address: Department of Pathology, Memorial Sloan- Kettering Cancer Center, New York, New York 10065, USA (M.F.B.); Department of Genomic Medicine, Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA (T.P.H., Y.L.D., A.P., I.R.W., M.A.S., L.C.). *These authors contributed equally to this work. 502 | NATURE | VOL 485 | 24 MAY 2012 ©2012 Macmillan Publishers Limited. All rights reserved LETTER RESEARCH 100 111 80 60 40 20 No. of mutations per Mb 0 64% BRAF NRAS 36% 100 15 10 5 0 No. of mutations 80 Percentage Indels and other muts 60 Transversions A→G 40 (A/C/G)pC→(A/C/G)pT TpC→TpT 20 0 ME009 ME044 ME049 ME043 ME002 ME024 ME029 ME020 ME050 ME018 ME041 ME011 ME016 ME037 ME001 ME030 ME035 ME048 ME045 ME012 ME032 ME021 ME007 ME015 ME100L Figure 1 | Elevated mutation rates and spectra indicative of ultraviolet number of mutations in each oncogene as well as percent frequency. Bottom radiation damage. Top bar plot shows somatic mutation rate of 25 sequenced plot displays each tumour’s somatic mutation spectrum as a percentage of all melanoma genomes, in decreasing order. Middle matrix indicates BRAF and mutations (right axis). Tumour sample names are indicated at the bottom of the NRAS somatic mutation status, with left-adjacent bar plot indicating total figure, with acral melanomas in red. BRAF, with the exception of one non-canonical substitution PCR followed by massively parallel sequencing to successfully validate (NRAST50I) in the hypermutated sample ME009. We also identified 6 177 of 182 events tested in this sample, confirming its high rate of insertions and 34 deletions in protein coding exons (Supplementary rearrangement. The elevated frequency of genomic rearrangements in Table 6), including a 21-base-pair (bp) in-frame deletioninvolving exon acral melanomas has been reported previously20. In comparison, 11 of the KIT oncogene in the acral tumour ME032 (Supplementary ME032 exhibited one of the lowest base-pair mutation rates of the Fig. 3). KIT mutations occur in 15% of acral and mucosal melanomas12, melanomas examined (22nd out of 25 samples), suggesting that dif- and melanoma patients with activating KIT mutations in exon 11 have ferent tumours might preferentially enact alternative mechanisms of demonstrated marked responses to imatinib treatment13. genomic alteration to drive tumorigenesis. We identified an average of 97 structural rearrangements per As noted above, many rearrangements in ME032 involved multiple melanoma genome (range: 6–420) (Supplementary Table 7). In addi- breakpoints within
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