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Whole-Genome Sequencing of Acral Melanoma Reveals Genomic Complexity and Diversity ✉ Felicity Newell 1 , James S

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Whole-Genome Sequencing of Acral Melanoma Reveals Genomic Complexity and Diversity ✉ Felicity Newell 1 , James S ARTICLE https://doi.org/10.1038/s41467-020-18988-3 OPEN Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity ✉ Felicity Newell 1 , James S. Wilmott2, Peter A. Johansson1, Katia Nones1, Venkateswar Addala 1,3, Pamela Mukhopadhyay1, Natasa Broit 1,3, Carol M. Amato 4, Robert Van Gulick4, Stephen H. Kazakoff 1, Ann-Marie Patch 1, Lambros T. Koufariotis1, Vanessa Lakis1, Conrad Leonard 1, Scott Wood 1, Oliver Holmes1, Qinying Xu1, Karl Lewis4, Theresa Medina4, Rene Gonzalez4, Robyn P. M. Saw 2,5,6, Andrew J. Spillane 2,5,7, Jonathan R. Stretch2,5,6, Robert V. Rawson2,5,6,8, Peter M. Ferguson2,5,6,8, Tristan J. Dodds2, John F. Thompson 2,5,6, Georgina V. Long 2,5,7, Mitchell P. Levesque9, 4 1 2,10,11 2,5,6,8 1234567890():,; William A. Robinson , John V. Pearson , Graham J. Mann , Richard A. Scolyer , Nicola Waddell 1,3,12 & Nicholas K. Hayward 1,12 To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultra- violet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential ther- apeutic options. 1 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. 2 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. 3 School of Medicine, The University of Queensland, Brisbane, QLD, Australia. 4 Center for Rare Melanomas, University of Colorado Cancer Center, Aurora, Colorado, USA. 5 Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. 6 Royal Prince Alfred Hospital, Sydney, NSW, Australia. 7 Royal North Shore Hospital, Sydney, NSW, Australia. 8 New South Wales Health Pathology, Sydney, NSW, Australia. 9 Dermatology Clinic, University Hospital Zürich, University of Zurich, Zurich, Switzerland. 10 John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia. 11 Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, Sydney, NSW, Australia. 12These authors ✉ contributed equally: Nicola Waddell, Nicholas K. Hayward. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:5259 | https://doi.org/10.1038/s41467-020-18988-3 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-18988-3 cral melanoma (AM) is a rare subtype of melanoma that tumors had a higher TMB of ≥6 mutations/Mb (3 times the occurs on non-hair-bearing glabrous skin on the palms, median of the cohort) in comparison with other tumors, with A fi soles and nail apparatus (subungual). In European-derived four having a TMB of >20 mutations/Mb. There was a signi cant populations 2–3% of melanoma cases are acral, however AM is the difference in mutation burden based on site of the primary lesion most common subtype in Asian and African populations1,2.Com- (all tumors, n = 87: Kruskal–Wallis test, p = 8.5 × 10−6, Fig. 1c). pared with cutaneous melanoma (CM), AM has a poorer prognosis, Subungual tumors from the fingernail/thumbnail had the highest potentially due to diagnosis at a more advanced clinical stage, or due mutation burden and tumors arising on the foot had the lowest to biological differences favouring tumor aggression1,3–6. mutation burden. Tumors that had undergone WGD had a Next generation sequencing analyses of AM have either significantly higher number of mutations (Mann–Whitney U-test, involved targeted or exome sequencing7–9, or whole-genome p = 0.0045, Fig. 1d). Higher rearrangement count was observed in sequencing (WGS) of small numbers (35 or fewer) of tumors10–13. tumors where the primary tumor was thicker (Mann–Whitney U- These studies have shown that AM is distinctive, with a lower test, p = 0.0007, Fig. 1e) and therefore those with higher T number of SNV/indel mutations and higher numbers of structural classification (Mann–Whitney U-test, p = 0.0042, Fig. 1f). rearrangement variants (SVs) and focal copy number events than in CM. The high mutation burden in CM is attributed to the effect The UVR mutational signature is present in higher TMB of ultraviolet radiation (UVR) and while not considered a major tumors. To investigate the variability in TMB, mutational sig- driver in AM we13,14 and others7,9 have shown that small num- nature analysis of single base substitutions (SBS), doublet based bers of tumors do exhibit effects of UVR. Mutations in BRAF and substitutions (DBS) and indels (ID) was performed (Fig. 2a). NRAS occur in AM, but at lower rates than in CM15,16. Mutations UVR related signatures (SBS7a, SBS7b, SBS7c, SBS7d, DBS1 and in NF1 and KIT, as well as oncogenic amplification of genes ID13) were identified in a subset of tumors, with 11 tumors including CCND1, PAK1, GAB2, CDK4 and TERT, are more having a greater than 50% contribution of the SBS UVR sig- common events in AM than in CM7,8,13. natures (Fig. 2b). For tumors with a subungual primary site, 6/7 In this work, as the whole-genome landscape of AM is not fingernail/thumbnail tumors and 5/15 toenail tumors had evi- completely understood, we extend our previous analysis of AM13 dence of a UVR signature. UVR signature was significantly to fully define the key genomic aberrations, and the mutational − associated with higher TMB (Kruskal–Wallis test, p = 3.5 × 10 5, processes driving this rare melanoma subtype. Fig. 2c). Other SBS signatures were identified in single tumors with a higher TMB (Fig. 2a, b), including one tumor Results (MELA_0271) with a mismatch repair signature (SBS21/SBS26 The study involved WGS of 87 fresh-frozen tumor specimens and and ID2) due to a somatic homozygous deletion (copy number 0) matched germline DNA (Supplementary Data 1 and 2). Tumor affecting MLH1, and another tumor (MELA_0015) with a > 30% samples were sequenced to a median coverage of 59X (range contribution of signature 17a/b, a signature we have also pre- 35–118) and germline blood samples to a median coverage of 35X viously identified in mucosal melanoma (MM)19. Another tumor (range 21–124). Sixty-three tumors underwent RNA sequencing. with a higher TMB within the cohort (MELA_0870) had evidence Patients had a mean age of 68 and 52% were female. Fifty-nine of SBS32, a signature found in cutaneous squamous cell carci- tumors were from the sole of the foot, six were from the palm of noma in association with prior treatment with azathioprine to the hand and there were twenty-two subungual tumors (15 toe- induce immunosuppression20,21, however, this patient had no nail, 7 thumbnail/fingernail). Thirty-six tumors were from pri- history of azathioprine treatment. mary sites and the rest were recurrent (3) or metastatic tumors Signatures 1, 5, and 40, which are associated with aging and (48), including a cell line derived from a metastasis. For most found in most cancer types20, were present in the majority of patients (75%, 65), there was no treatment listed (either before or tumors. Other signatures were also present in tumors with a lower after sample collection) in the available clinical data. Males had a TMB. SBS38, postulated to be the result of indirect UVR20,was lower age at diagnosis of the primary tumor (Supplementary present with a > 25% contribution in 9 tumors and these tumors Fig. 1a). More tumors with a higher T classification (T3 or T4) had no contribution of a UVR signature. The etiology of SBS38 had ulceration (T3 or T4, 64% and T1 or T2 19%, Fisher’s exact may be associated with oxidative stress as the signature was test, p = 0.0017, Supplementary Data 1). As expected, higher N reported to cluster with other oxidation damage repair related classification (Supplementary Fig. 1b), and locoregional and dis- signatures when using the simple probabilistic model DNA Repair tant metastasis status of the patient (Supplementary Fig. 1c) were FootPrint (RePrint) to represent each signature22. APOBEC associated with poorer melanoma-specific survival. (SBS2, SBS13) signatures were present at low levels (≤30% contribution) in 51 tumors, and these had a higher number of rearrangements (Fig. 2d). One tumor (MELA_0872) had cisplatin Mutational and rearrangement burden in acral melanoma. signatures SBS31 and DBS5 and was a subcutaneous metastasis Overall, the SNV/indel mutation burden (tumor mutational collected after the patient had undergone cisplatin chemotherapy. burden, TMB) was low, with a median burden of 2.1 mutations Indel signatures for non-UVR tumors were ID1, ID2 and ID8, per megabase (range of 0.68–34.9) (Fig. 1a). Rearrangements which correlate with age of diagnosis, and ID9, which has no (SVs) were frequent, with a median of 283 rearrangements per proposed etiology but is found in many cancer types20. tumor (range = 32–1251), and the percentage of the genome affected by copy number variation such as amplification with copy number (CN) ≥ 6, copy-neutral LOH, copy number loss Rearrangement and copy number signatures. Rearrangement (CN1) and deletion (CN0), was variable (Fig. 1a), with a median signatures (RS) and copy number signatures (CNS) were of 26% of the genome affected (range 7–45%). Whole-genome extracted to further understand the associations of rearrange- duplication (WGD) was present in 71% (62/87) of tumors ments and copy number events with WGD, aneuploidy and (Fig.
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