Antonella Manca

@article{pmid31455347,

title = {Mutational concordance between primary and metastatic melanoma: a next-generation sequencing approach},

author = {Manca, A. and Paliogiannis, P. and Colombino, M. and Casula, M. and Lissia, A. and Botti, G. and Carac?, C. and Ascierto, P. A. and Sini, M. C. and Palomba, G. and Pisano, M. and Doneddu, V. and Cossu, A. and Palmieri, G. and Dedola, M. F. and Fedeli, M. A. and Montesu, M. A. and Rubino, C. and Satta, R. and Scotto, T. and Sini, G. and Maio, M. and Massi, D. and Anichini, A. and Pfeffer, U. and Ghiorzo, P. and Queirolo, P. and Quaglino, P. and Sileni, V. C. and Di Giacomo, A. M.},

year  = {2019},

date = {2019-01-01},

journal = {J Transl Med},

volume = {17},

number = {1},

pages = {289},

abstract = {Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. Limited information is available in the current scientific literature on the concordance of genetic alterations between primary and metastatic CMM. In the present study, we performed next-generation sequencing (NGS) analysis of the main genes participating in melanoma pathogenesis and progression, among paired primary and metastatic lesions of CMM patients, with the aim to evaluate levels of discrepancies in mutational patterns. Paraffin-embedded tumor tissues of the paired lesions were retrieved from the archives of the institutions participating in the study. NGS was performed using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup (IMI) to explore the mutational status of selected regions (343 amplicons; amplicon range: 125-175 bp; coverage 100%) within the main 25 genes involved in CMM pathogenesis; sequencing was performed with the Ion Torrent PGM System. A discovery cohort encompassing 30 cases, and a validation cohort including eleven Sardinian patients with tissue availability from both the primary and metachronous metastatic lesions were identified; the global number of analyzed tissue specimens was 90. A total of 829 genetic non-synonymous variants were detected: 101 (12.2%) were pathogenic/likely pathogenic, 131 (15.8%) were benign/likely benign, and the remaining 597 (72%) were uncertain/unknown significance variants. Considering the global cohort, the consistency in pathogenic/pathogenic like mutations was 76%. Consistency for BRAF and NRAS mutations was 95.2% and 85.7% respectively, without statistically significant differences between the discovery and validation cohort. Our study showed a high level of concordance in mutational patterns between primary and metastatic CMM, especially when pathogenic mutations in driver genes were considered.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid30218391,

title = {Molecular Pathways in Melanomagenesis: What We Learned from Next-Generation Sequencing Approaches},

author = {Palmieri, G. and Colombino, M. and Casula, M. and Manca, A. and Mandal?, M. and Cossu, A.},

year  = {2018},

date = {2018-01-01},

journal = {Curr Oncol Rep},

volume = {20},

number = {11},

pages = {86},

abstract = {Conventional clinico-pathological features in melanoma patients should be integrated with new molecular diagnostic, predictive, and prognostic factors coming from the expanding genomic profiles. Cutaneous melanoma (CM), even differing in biological behavior according to sun-exposure levels on the skin areas where it arises, is molecularly heterogeneous. The next-generation sequencing (NGS) approaches are providing data on mutation landscapes in driver genes that may account for distinct pathogenetic mechanisms and pathways. The purpose was to group and classify all somatic driver mutations observed in the main NGS-based studies. Whole exome and whole genome sequencing approaches have provided data on spectrum and distribution of genetic and genomic alterations as well as allowed to discover new cancer genes underlying CM pathogenesis. After evaluating the mutational status in a cohort of 686 CM cases from the most representative NGS studies, three molecular CM subtypes were proposed: BRAFmut, RASmut, and non-BRAFmut/non-RASmut.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26322273,

title = {Multiple Molecular Pathways in Melanomagenesis: Characterization of Ŧherapeutic Ŧargets},

author = {Palmieri, G. and Ombra, M. and Colombino, M. and Casula, M. and Sini, M. and Manca, A. and Paliogiannis, P. and Ascierto, P. A. and Cossu, A.},

year  = {2015},

date = {2015-01-01},

journal = {Front Oncol},

volume = {5},

pages = {183},

abstract = {Molecular mechanisms involved in pathogenesis of malignant melanoma have been widely studied and novel therapeutic treatments developed in recent past years. Molecular targets for therapy have mostly been recognized in the RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways; small-molecule inhibitors were drawn to specifically target key kinases. Unfortunately, these targeted drugs may display intrinsic or acquired resistance and various evidences suggest that inhibition of a single effector of the signal transduction cascades involved in melanoma pathogenesis may be ineffective in blocking the tumor growth. In this sense, a wider comprehension of the multiple molecular alterations accounting for either response or resistance to treatments with targeted inhibitors may be helpful in assessing, which is the most effective combination of such therapies. In the present review, we summarize the known molecular mechanisms underlying either intrinsic and acquired drug resistance either alternative roads to melanoma pathogenesis, which may become targets for innovative anticancer approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22614978,

title = {BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma},

author = {Colombino, M. and Capone, M. and Lissia, A. and Cossu, A. and Rubino, C. and De Giorgi, V. and Massi, D. and Fonsatti, E. and Staibano, S. and Nappi, O. and Pagani, E. and Casula, M. and Manca, A. and Sini, M. and Franco, R. and Botti, G. and Carac?, C. and Mozzillo, N. and Ascierto, P. A. and Palmieri, G.},

year  = {2012},

date = {2012-07-01},

journal = {J Clin Oncol},

volume = {30},

number = {20},

pages = {2522--2529},

abstract = {The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues. In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites. BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples. In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid21424129,

title = {Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (AĐI) in melanoma cells},

author = {Manca, A. and Sini, M. C. and Izzo, F. and Ascierto, P. A. and Tatangelo, F. and Botti, G. and Gentilcore, G. and Capone, M. and Mozzillo, N. and Rozzo, C. and Cossu, A. and Tanda, F. and Palmieri, G.},

year  = {2011},

date = {2011-06-01},

volume = {25},

number = {6},

pages = {1495--1502},

abstract = {Arginine deiminase (ADI), an arginine-degrading enzyme, has been used in the treatment of tumours sensitive to arginine deprivation, such as malignant melanoma (MM) and hepatocellular carcinoma (HCC). Endogenous production of arginine is mainly dependent on activity of ornithine transcarbamylase (OTC) and argininosuccinate synthetase (ASS) enzymes. We evaluated the effect of ADI treatment on OTC and ASS expression in a series of melanoma cell lines. Twenty-five primary melanoma cell lines and normal fibroblasts as controls underwent cell proliferation assays and Western blot analyses in the presence or absence of ADI. Tissue sections from primary MMs (N = 20) and HCCs (N = 20) were investigated by immunohistochemistry for ASS expression. Overall, 21/25 (84%) MM cell lines presented a cell growth inhibition by ADI treatment; none of them presented constitutive detectable levels of the ASS protein. However, 7/21 (33%) ADI-sensitive melanoma cell lines presented markedly increased expression levels of the ASS protein following ADI treatment, with a significantly higher IC50 median value. Growth was not inhibited and the IC50 was not reached among the remaining 4/25 (16%) MM cell lines; all of them showed constitutive ASS expression. The OTC protein was found expressed in all melanoma cell lines before and after the ADI treatment. Lack of ASS immunostaining was observed in all analyzed in vivo specimens. Our findings suggest that response to ADI treatment in melanoma is significantly correlated with the ability of cells to express ASS either constitutively at basal level (inducing drug resistance) or after the treatment (reducing sensitivity to ADI).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}