Alterations in key signaling pathways in sinonasal tract melanoma. A molecular genetics and immunohistochemical study of 90 cases and comprehensive review of the literature.

Male Female Humans Aged Proto-Oncogene Proteins B-raf / genetics In Situ Hybridization, Fluorescence Melanoma / genetics Paranasal Sinus Neoplasms / genetics Mutation Signal Transduction Paranasal Sinuses / pathology Class I Phosphatidylinositol 3-Kinases / genetics TOR Serine-Threonine Kinases / genetics RNA Molecular Biology DNA Mutational Analysis

Journal

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

ISSN: 1530-0285

Titre abrégé: Mod Pathol

Pays: United States

ID NLM: 8806605

Informations de publication

Date de publication:
11 2022

Historique:

received: 15 05 2021

accepted: 01 06 2022

revised: 01 06 2022

pubmed: 18 8 2022

medline: 28 10 2022

entrez: 17 8 2022

Statut: ppublish

Résumé

Sinonasal mucosal melanoma is a rare tumor arising within the nasal cavity, paranasal sinuses, or nasopharynx (sinonasal tract). This study evaluated 90 cases diagnosed in 29 males and 61 females with median age 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. Spectrum of research techniques used in this analysis includes targeted-DNA and -RNA next-generation sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry. Sinonasal melanomas were commonly driven by RAS (38/90, 42%), especially NRAS (n = 36) mutations and rarely (4/90, 4%) displayed BRAF pathogenic variants. BRAF/RAS mutants were more frequent among paranasal sinuses (10/14, 71%) than nasal (26/64, 41%) tumors. BRAF/RAS-wild type tumors occasionally harbored alterations of the key components and regulators of Ras-MAPK signaling pathway: NF1 mutations (1/17, 6%) or NF1 locus deletions (1/25, 4%), SPRED1 (3/25, 12%), PIK3CA (3/50, 6%), PTEN (4/50, 8%) and mTOR (1/50, 2%) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors some of which were NRAS mutants, TP53 was deleted (6/48, 13%) and/or mutated (5/90, 6%). Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression was seen in >50% of cases. Furthermore, sinonasal melanomas (n = 7) including RAS/BRAF-wild type tumors (n = 5) harbored alterations of the key components and regulators of canonical WNT-pathway: APC (4/90, 4%), CTNNB1 (3/90, 3%) and AMER1 (1/90, 1%). Both, TERT promoter mutations (5/53, 9%) and fusions (2/40, 5%) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors including 7 BRAF/RAS-wild type cases expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of Ras-MAPK signaling pathway such as SPRED1 in a majority of sinonasal melanomas.

Identifiants

DOI: 10.1038/s41379-022-01122-7 PMID: 35978013

pubmed: 35978013

doi: 10.1038/s41379-022-01122-7

pii: S0893-3952(22)00227-7

doi:

Substances chimiques

Proto-Oncogene Proteins B-raf EC 2.7.11.1

Class I Phosphatidylinositol 3-Kinases EC 2.7.1.137

TOR Serine-Threonine Kinases EC 2.7.11.1

RNA 63231-63-0

Types de publication

Review Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1609-1617

Informations de copyright

Références

Lucke A. Die melanotischen Geschwulste. Die Lehre von de Geschwulsten in anatomischet und lkinische Beziehung. In: Itha F, Billroth T, eds. Handbuch Der Allgemeinen und Speziellen Chirurgie, Erlangen, Band 2, Abteil 1, Seite 244 (1869)

Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol 27, 594-611(2003)

Marcus DM, Marcus RP, Prabhu RS, Owonikoko TK, Lawson DH, Switchenko J, et al. Rising incidence of mucosal melanoma of the head and neck in the United States. J Skin Cancer 2012, 231693 (2012)

Amit M, Na’ara S, Hanna EY. Contemporary Treatment Approaches to Sinonasal Mucosal Melanoma. Curr Oncol Rep 20, 10 (2018)

Chraybi M, Abd Alsamad I, Copie-Bergman C, Baia M, André J, Dumaz N, et al. Oncogene abnormalities in a series of primary melanomas of the sinonasal tract: NRAS mutations and cyclin D1 amplification are more frequent than KIT or BRAF mutations. Hum Pathol 44, 1902-1911 (2013)

Öztürk Sari Ş, Yilmaz İ, Taşkin OÇ, Narli G, Şen F, Çomoğlu Ş, et al. BRAF, NRAS, KIT, TERT, GNAQ/GNA11 mutation profile analysis of head and neck mucosal melanomas: a study of 42 cases. Pathology 49, 55-61 (2017)

Toscano de Mendonça UB, Cernea CR, Matos LL, Monteiro de Araujo Lima RR. Analysis of KIT gene mutations in patients with melanoma of the head and neck mucosa: a retrospective clinical report. Oncotarget 9, 22886-22894 (2018)

Turri-Zanoni M, Medicina D, Lombardi D, Ungari M, Balzarini P, Rossini C, et al. Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases. Head Neck 35, 1066-1077 (2013)

Wroblewska JP, Mull J, Wu CL, Fujimoto M, Ogawa T, Marszalek A, et al. SF3B1, NRAS, KIT, and BRAF Mutation; CD117 and cMYC Expression; and Tumoral Pigmentation in Sinonasal Melanomas: An Analysis With Newly Found Molecular Alterations and Some Population-Based Molecular Differences. Am J Surg Pathol 43, 168-177 (2019)

Zebary A, Jangard M, Omholt K, Ragnarsson-Olding B, Hansson J. KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases. Br J Cancer 109, 559-564 (2013)

Colombino M, Paliogiannis P, Cossu A, De Re V, Miolo G, Botti G, et al. BRAF Mutations and Dysregulation of the MAP Kinase Pathway Associated to Sinonasal Mucosal Melanomas. J Clin Med 8, 1577 (2019)

Ablain J, Xu M, Rothschild H, Jordan RC, Mito JK, Daniels BH, et al. Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma. Science 362, 1055-1060 (2018)

Amit M, Tam S, Abdelmeguid AS, Roberts DB, Takahashi Y, Raza SM, et al. Mutation status among patients with sinonasal mucosal melanoma and its impact on survival. Br J Cancer 116, 1564-1571 (2017)

Freiberger SN, Morand GB, Turko P, Wager U, Dummer R, Hüllner M, et al. Morpho-Molecular Assessment Indicates New Prognostic Aspects and Personalized Therapeutic Options in Sinonasal Melanoma. Cancers (Basel) 11, 1329 (2019)

Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome landscapes of major melanoma subtypes. Nature 545, 175-180 (2017)

Hintzsche JD, Gorden NT, Amato CM, Kim J, Wuensch KE, Robinson SE, et al. Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma. Melanoma Res 27, 189-199 (2017)

Newell F, Kong Y, Wilmott JS, Johansson PA, Ferguson PM, Cui C, et al. Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets. Nat Commun 10, 3163 (2019)

Stout LA, Kassem N, Hunter C, Philips S, Radovich M, Schneider BP. Identification of germline cancer predisposition variants during clinical ctDNA testing. Sci Rep 11, 13624 (2021)

Chang MH, Kuo YJ, Ho CY, Kuan EC, Lan MY. Metastatic Tumors of the Sinonasal Cavity: A 15-Year Review of 17 Cases. J Clin Med 8, 539 (2019)

Röhrich M, Koelsche C, Schrimpf D, Capper D, Sahm F, Kratz A, et al. Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol 131, 877-887 (2016)

Argani P, Aulmann S, Illei PB, Netto GJ, Ro J, Cho HY, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol 34, 1395-1406 (2010)

Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signaling pathway and tumorigenesis. Exp Ther Med 19, 1997-2007 (2020)

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 417, 949-954 (2002)

The Cancer Genome Atlas Network. Genomic Classification of Cutaneous Melanoma. Cell 161, 1681-1696 (2015)

Omholt K, Grafström E, Kanter-Lewensohn L, Hansson J, Ragnarsson-Olding BK. KIT pathway alterations in mucosal melanomas of the vulva and other sites. Clin Cancer Res 17, 3933-3942 (2011)

Maldonado-Mendoza J, Ramírez-Amador V, Anaya-Saavedra G, Ruíz-García E, Maldonado-Martínez H, Fernández Figueroa E, et al. CD117 immunoexpression in oral and sinonasal mucosal melanoma does not correlate with somatic driver mutations in the MAPK pathway. J Oral Pathol Med 48, 382-388 (2019)

Quek C, Rawson RV, Ferguson PM, Shang P, Silva I, Saw RPM, et al. Recurrent hotspot SF3B1 mutations at codon 625 in vulvovaginal mucosal melanoma identified in a study of 27 Australian mucosal melanomas. Oncotarget 10, 930-941 (2019)

Mikkelsen LH, Maag E, Andersen MK, Kruhøffer M, Larsen AC, Melchior LC, et al. The molecular profile of mucosal melanoma. Melanoma Res 30, 533-542 (2020)

Cosgarea I, Ugurel S, Sucker A, Livingstone E, Zimmer L, Ziemer M, et al. Targeted next generation sequencing of mucosal melanomas identifies frequent NF1 and RAS mutations. Oncotarget 8, 40683-40692 (2017)

Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet. 2015;47:996-1002.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2, 401-404 (2012)

Cirenajwis H, Lauss M, Ekedahl H, Törngren T, Kvist A, Saal LH, et al. NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics. Mol Oncol 11, 438-451 (2017)

Lorenzo C, McCormick F. SPRED proteins and their roles in signal transduction, development, and malignancy. Genes Dev 34, 1410-1421 (2020)

Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24, 4340-4346 (2006)

Beadling C, Jacobson-Dunlop E, Hodi FS, Le C, Warrick A, Patterson J, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 14, 6821-6828 (2008)

Satzger I, Schaefer T, Kuettler U, Broecker V, Voelker B, Ostertag H, et al. Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas. Br J Cancer 99, 2065-2069 (2008)

Torres-Cabala CA, Wang WL, Trent J, Yang D, Chen S, Galbincea J, et al. Correlation between KIT expression and KIT mutation in melanoma: a study of 173 cases with emphasis on the acral-lentiginous/mucosal type. Mod Pathol 22,1446-1456 (2009)

Handolias D, Hamilton AL, Salemi R, Tan A, Moodie K, Kerr L, et al. Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT. Br J Cancer 102, 1219-1223 (2010)

Abysheva SN, Iyevleva AG, Efimova NV, Mokhina YB, Sabirova FA, Ivantsov AO, et al. KIT mutations in Russian patients with mucosal melanoma. Melanoma Res 21, 555-559 (2011)

Kong Y, Si L, Zhu Y, Xu X, Corless CL, Flaherty KT, et al. Large-scale analysis of KIT aberrations in Chinese patients with melanoma. Clin Cancer Res17, 1684-1691 (2011)

Furney SJ, Turajlic S, Stamp G, Nohadani M, Carlisle A, Thomas JM, et al. Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma. J Pathol 230, 261-269 (2013)

Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 31, 3182-3190 (2013)

Aulmann S, Sinn HP, Penzel R, Gilks CB, Schott S, Hassel JC, et al. Comparison of molecular abnormalities in vulvar and vaginal melanomas. Mod Pathol 27, 1386-1393 (2014)

Lyu J, Song Z, Chen J, Shepard MJ, Song H, Ren G, et al. Whole-exome sequencing of oral mucosal melanoma reveals mutational profile and therapeutic targets. J Pathol 244, 358-366 (2018)

Ma X, Wu Y, Zhang T, Song H, Jv H, Guo W, et al. The clinical significance of c-Kit mutations in metastatic oral mucosal melanoma in China. Oncotarget 8, 82661-82673 (2017)

Heppt MV, Roesch A, Weide B, Gutzmer R, Meier F, Loquai C, et al. Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma. Eur J Cancer 81, 36-44 (2017)

Iida Y, Salomon MP, Hata K, Tran K, Ohe S, Griffiths CF, et al. Predominance of triple wild-type and IGF2R mutations in mucosal melanomas. BMC Cancer 18,1054 (2018)

Parish AJ, Nguyen V, Goodman AM, Murugesan K, Frampton GM, Kurzrock R. GNAS, GNAQ, and GNA11 alterations in patients with diverse cancers. Cancer 124, 4080-4089 (2018)

Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 363, 2191-2199 (2010)

Stahl JM, Cheung M, Sharma A, Trivedi NR, Shanmugam S, Robertson GP. Loss of PTEN promotes tumor development in malignant melanoma. Cancer Res 63, 2881-2890 (2003)

Shull AY, Latham-Schwark A, Ramasamy P, Leskoske K, Oroian D, Birtwistle MR, et al. Novel somatic mutations to PI3K pathway genes in metastatic melanoma. PLoS One 7, e43369 (2012)

Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2, a001008 (2010)

Hocker T, Tsao H. Ultraviolet radiation and melanoma: a systemic review and analysis of reported sequence variants. Hum Mutat 28, 588 (2007)

Shangary S, Wang S. Targeting the MDM2-p53 interaction for cancer therapy. Clin Cancer Res 14, 5318-5324 (2008)

Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell 149, 1192-1205 (2012)

Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol 4, a008052 (2012)

Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T, et al. Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. Int J Cancer 100, 549-556 (2002)

Kim G, Kurnit KC, Djordjevic B, Singh C, Munsell MF, Wang WL et al. Nuclear β-catenin localization and mutation of the CTNNB1 gene: a context-dependent association. Mod Pathol 31, 1553-1559 (2018)

Gao C, Wang Y, Broaddus R, Sun L, Xue F, Zhang W. Exon 3 mutations of CTNNB1 drive tumorigenesis: a review. Oncotarget 9, 5492-5508 (2017)

Lasota J, Kowalik A, Felisiak-Golabek A, Zięba S, Waloszczyk P, Masiuk M, et al. Primary malignant melanoma of esophagus: clinicopathologic characterization of 20 cases including molecular genetic profiling of 15 tumors. Mod Pathol 32, 957-966 (2019)

Harbour JW, Roberson ED, Anbunathan H, et al. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet 45, 133-135 (2013)

Kong Y, Krauthammer M, Halaban R. Rare SF3B1 R625 mutations in cutaneous melanoma. Melanoma Res 24, 332-334 (2014)

Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 4, 505-518 (2004)

Liu S, Meric-Bernstam F, Parinyanitikul N, Wang B, Eterovic AK, Zheng X, et al. Functional consequence of the MET-T1010I polymorphism in breast cancer. Oncotarget 6, 2604-2614 (2015)

Lawrence RE, Salgia R. MET molecular mechanisms and therapies in lung cancer. Cell Adh Migr 4, 146-152 (2010)

Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, et al. Pathogenic Germline Variants in 10,389 Adult Cancers. Cell 173, 355-370 (2018)

Yuan X, Larsson C, Xu D. Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players. Oncogene 38, 6172-6183 (2019)

Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun 5, 4846 (2014)

Delespaul L, Lesluyes T, Pérot G, Brulard C, Lartigue L, Baud J, et al. Recurrent TRIO Fusion in Nontranslocation-Related Sarcomas. Clin Cancer Res 23, 857-867 (2017)

Karlsson J, Lilljebjörn H, Holmquist Mengelbier L, Valind A, Rissler M, et al. Activation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney. Cancer Lett 357, 498-501 (2015)

Juratli TA, Silverman IM, Shankar GM, Tummala SS, Ely HA, Christiansen JH, et al. TERT rearrangements to identify a subset of aggressive meningiomas. J Clin Oncol 36 (Suppl 15), e14028 (2018)

Kruslin B, Gatalica Z, Hes O, Xiu J, Florento E, Swensen J. TERT gene fusions characterize a subset of metastatic Leydig cell tumours. Ann Oncol 30 (Suppl 5), 981P (2019)

Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun 5, 3116 (2014)

Ross JS, Wang K, Chmielecki J, Gay L, Johnson A, Chudnovsky J, et al. The distribution of BRAF gene fusions in solid tumors and response to targeted therapy. Int J Cancer 138, 881-890 (2016)

Kim HS, Jung M, Kang HN, Kim H, Park CW, Kim SM, et al. Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition. Oncogene 36, 3334-3345 (2017)

Lee J, Lee J, Hong SD, Jang KT, Lee SJ. FGFR3-TACC3: a novel gene fusion in malignant melanoma. Preci Future Med 2, 71-75 (2018)

Bahrami A, Lee S, Wu G, Kerstetter J, Rahvar M, Li X, et al. Pigment-Synthesizing Melanocytic Neoplasm With Protein Kinase C Alpha (PRKCA) Fusion. JAMA Dermatol 152, 318-322 (2016)

Yeh I, Jorgenson E, Shen L, Xu M, North JP, Shain AH, et al. Targeted Genomic Profiling of Acral Melanoma. J Natl Cancer Inst 111, 1068-1077 (2019)

Singh S, Qin F, Kumar S, Elfman J, Lin E, Pham LP, et al. The landscape of chimeric RNAs in non-diseased tissues and cells. Nucleic Acids Res 48, 1764-1778 (2020)

Zhang Y, Gong M, Yuan H, Park HG, Frierson HF, Li H. Chimeric transcript generated by cis-splicing of adjacent genes regulates prostate cancer cell proliferation. Cancer Discov 2, 598-607 (2012)