InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma

Orlow, Irene; Sadeghi, Keimya; Edmiston, Sharon N.; Kenney, Jessica; Lezcano, Cecilia; Wilmott, James S.; Cust, Anne E.; Scolyer, Richard A.; Mann, Graham J.; Lee, Tim K.; Burke, Hazel; Jakrot, Valerie; Shang, Peng; Ferguson, Peter M.; Boyce, Tawny; Funchain, Pauline; Ko, Jennifer S.; Ngo, Peter; Rees, Judy R.; OʼConnell, Kelli; Hao, Honglin; Parrish, Eloise; Conway, Kathleen; Ollila, David W.; Moschos, Stergios J.; Hernando, Eva; Hanniford, Douglas; Argibay, Diana; Amos, Christopher I.; Lee, Jeffrey E.; Osman, Iman; Luo, Li; Kuan, Pei‐Fen; Aurora, Arshi; Rothberg, Bonnie E. Gould; Bosenberg, Marcus W.; Gerstenblith, Meg R.; Thompson, Cheryl L.; Bogner, Paul N.; Gorlov, Ivan P.; Holmen, Sheri L.; Brunsgaard, Elise K.; Saenger, Yvonne M.; Shen, Ronglai; Seshan, Venkatraman; Nagore, Eduardo; Ernstoff, Marc S.; Busam, Klaus J.; Begg, Colin B.; Thomas, Nancy E.; Berwick, Marianne

doi:10.1101/2022.05.21.22275329

Cited by 2 publications

(3 citation statements)

References 18 publications

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“…Hemoxylin and eosin‐stained slides were then sent back to the pathologists for thorough pathological review, evaluating cellularity a second time. Quality control and other technical details are discussed in Orlow et al ( 2022 ).…”

Section: Methodsmentioning

confidence: 99%

“…We were not especially concerned about mis‐diagnosing important germ‐line variants as somatic, such as CDKN2A germ‐line mutations, since germ‐line mutations in this gene are so infrequent, occurring in only about 1% of melanoma cases in the general population (Aoude et al, 2015 ; Berwick et al, 2006 ). Quality control was applied at every step: eligibility, nucleic acid extraction, sequencing, and post‐sequencing, as well as analysis (Orlow et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

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Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study

Luo

Shen

Arora

et al. 2022

Pigment Cell Melanoma Res

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It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi‐omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early‐stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub‐types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub‐type. The InterMEL study will provide the most extensive multi‐omic profiling of early‐stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early‐stage tumors.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study

Luo

Shen

Arora

et al. 2022

Pigment Cell Melanoma Res

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“…We apply the method to the InterMEL consortium dataset of early-stage melanoma tumors 23, 24 , and then explore, via simulations, the properties of the method.…”

Section: Resultsmentioning

confidence: 99%

Adaptation of a Mutual Exclusivity Framework to Identify Driver Mutations within Biological Pathways

Wang,

Kostrzewa,

Reiner

et al. 2023

Preprint

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Distinguishing genomic alterations in cancer genes that have functional impact on tumor growth and disease progression from the ones that are passengers and confer no fitness advantage has important clinical implications. Evidence-based methods for nominating drivers are limited by existing knowledge on the oncogenic effects and therapeutic benefits of specific variants from clinical trials or experimental settings. As clinical sequencing becomes a mainstay of patient care, applying computational methods to mine the rapidly growing clinical genomic data holds promise in uncovering novel functional candidates beyond the existing knowledge-base and expanding the patient population that could potentially benefit from genetically targeted therapies. We propose a statistical and computational method (MAGPIE) that builds on a likelihood approach leveraging the mutual exclusivity pattern within an oncogenic pathway for identifying probabilistically both the specific genes within a pathway and the individual mutations within such genes that are truly the drivers. Alterations in a cancer gene are assumed to be a mixture of driver and passenger mutations with the passenger rates modeled in relationship to tumor mutational burden. A limited memory BFGS algorithm is used to facilitate large scale optimization. We use simulations to study the operating characteristics of the method and assess false positive and false negative rates in driver nomination. When applied to a large study of primary melanomas the method accurately identified the known driver genes within the RTK-RAS pathway and nominated a number of rare variants with previously unknown biological and clinical relevance as prime candidates for functional validation.

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InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma

Cited by 2 publications

References 18 publications

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study

Adaptation of a Mutual Exclusivity Framework to Identify Driver Mutations within Biological Pathways

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