The mutational burden of acral melanoma revealed by whole‐genome sequencing and comparative analysis

Furney, Simon J.; Turajlic, Samra; Stamp, Gordon; Thomas, Janet; Hayes, Andrew; Strauß, D.; Gavrielides, Mike; Wei, Xing; Gore, Martin; Larkin, James; Marais, Richard

doi:10.1111/pcmr.12279

Cited by 114 publications

(116 citation statements)

References 20 publications

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“…It confirmed the main mutational subgroups of BRAF, NRAS, NF1, and triple wild type, as well as highlighting the distinct heterogeneity and high mutational burden of melanoma (Cancer Genome Atlas, 2015). Subtypes not included in the TCGA but published elsewhere were uveal (Van Raamsdonk et al, 2010), acral cutaneous (Furney et al, 2014), and mucosal melanoma (Sheng et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

et al. 2017

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Summary Therapy of advanced melanoma has been changing dramatically. Following mutational and biological sub-classification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays, and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.

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Section: Introductionmentioning

confidence: 99%

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

et al. 2017

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“…27 There have been recent conflicting reports on UVR signatures in sequenced acral melanomas. Some studies report no dominant UVR signature within acral melanomas 10,15,26 while other studies report a dominant UVR signature in cases of acral melanoma: one case report of whole-genome sequencing; 28 two of six cases of melanoma cell lines examined; 29 and one of two cases of whole-genome sequencing. 27 In our view, these findings probably relate to the case selection; some cases designated as arising from acral sites may have involved the non-acral surfaces of the hands or feet.…”

Section: Acral and Subungual Melanomas With A Dominant Uvr Signaturementioning

confidence: 99%

“…In previous exome and whole-genome sequencing studies, mutations per Mb in acral melanomas have been reported to range from 1.02 to 3.68 (5 cases), 15 1.95, 28 and 2.79 to 14 (two cases). 27 In contrast, the mean mutation rate of The Cancer Genome Atlas Network study, 20 which consisted entirely of cutaneous melanomas, was 16.8 mutations/Mb.…”

Section: Acral and Subungual Melanomas With A Dominant Uvr Signaturementioning

confidence: 99%

“…This is typically reflected in low mutation burden, which is offset by numerous focused gene amplifications and deletions or structural abnormalities. 2,13,15 They also have characteristic histological features, including a predominantly lentiginous growth pattern. 8,16 We recently performed the first high coverage wholegenome sequencing study of a large cohort of cutaneous, acral, and mucosal melanomas, which enable a highresolution assessment of mutation signatures in melanomas arising in these different anatomical sites (currently submitted for review).…”

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confidence: 99%

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Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas

Rawson

Johansson

Hayward

et al. 2017

Laboratory Investigation

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Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Wholegenome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35 = 8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140 = 2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.

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“…40 Cutaneous melanoma has a mutation rate of ~15 mutations/Mb, 41,42 while the somatic mutation rate in acral and mucosal melanomas is 5-10-fold lower. 43,44 Uveal melanomas have the lowest mutational burden of any melanoma subtype. 45 Thus, mutational burden also generally parallels the reported ORRs for melanoma subtypes, though perhaps not as closely as PD-L1 expression.…”

Section: Discussionmentioning

confidence: 99%

781 Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Kaunitz¹,

Cottrell²,

Lilo³

et al. 2017

Journal of Investigative Dermatology

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PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n = 16), mucosal (n = 36), uveal (n = 103), and chronic sun-damaged (CSD) (n = 45) melanomas (24 lentigo maligna, 13Correspondence: Dr JM Taube, MD, Division of Dermatopathology, Johns Hopkins Hospital, Blalock 907, 600N. Wolfe Street, Baltimore, MD 21287, USA. jtaube1@jhmi.edu. CONFLICT OF INTEREST:The remaining authors declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P = 0.0002) and higher in CSD (P = 0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P = 0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.Increased objective response rates (ORRs) to anti-PD-1/PD-L1 monotherapy as well as improved progression-free survival and overall survival have been linked to PD-L1 expression in the tumor microenvironment (TME) in some studies. [1][2][3][4] Studies from our group and others indicate that the major mechanism driving melanoma tumor cell PD-L1 expression is an association with tumor-infiltrating lymphocytes (TIL), consistent with an endogenous antitumor immune response that may be unleashed with anti-PD-1/PD-L1 therapies. 5 Such adaptive PD-L1 expression by melanoma is...

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The mutational burden of acral melanoma revealed by whole‐genome sequencing and comparative analysis

Cited by 114 publications

References 20 publications

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas

781 Melanoma subtypes demonstrate distinct PD-L1 expression profiles

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