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P2X7 is a purinergic receptor-channel; its activation by ATP elicits a broad set of cellular actions, from apoptosis to signals for survival. Here, P2X7 expression and function was studied in human ovarian carcinoma (OCA) cells, and biopsies from non-cancerous and cancer patients were analyzed by immunohistochemistry. Ovarian surface epithelium in healthy tissue expressed P2X7 at a high level that was maintained throughout the cancer. The cell lines SKOV-3 and CAOV-3 were used to investigate P2X7 functions in OCA. In SKOV-3 cells, selective stimulation of P2X7 by 2'(3')-O-(4-benzoylbenzoyl) adenosine-5'-triphosphate (BzATP) induced a dose-dependent increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) but not cell death. Instead, BzATP increased the levels of phosphorylated ERK and AKT (pERK and pAKT), with an EC(50) of 44 ± 2 and 1.27 ± 0.5 μM, respectively; 10 μM BzATP evoked a maximum effect within 15 min that lasted for 120 min. Interestingly, basal levels of pERK and pAKT were decreased in the presence of apyrase in the medium, strongly suggesting an endogenous, ATP-mediated phenomenon. Accordingly: (i) mechanically stimulated cells generated a [Ca(2+)](i) increase that was abolished by apyrase; (ii) apyrase induced a decrease in culture viability, as measured by the MTS assay for mitochondrial activity; and (iii) incubation with 10 μM AZ10606120, a specific P2X7 antagonist and transfection with the dominant negative P2X7 mutant E496A, both reduced cell viability to 70.1 ± 8.9% and to 76.5 ± 5%, respectively, of control cultures. These observations suggested that P2X7 activity was auto-induced through ATP efflux; this increased pERK and pAKT levels that generated a positive feedback on cell viability.

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher’s exact test analyses identified 66 variants associated with melanoma risk. Sequential conditional logistic regression identified the distinct haplotypes on which variants reside, and massively parallel reporter assays (MPRA) provided biological insights into how these variants influence gene function. We performed further analyses to link variants to melanoma risk phenotypes and assessed their association with melanoma-specific survival. Our analyses replicate previously known associations in the MC1R and TYR loci, while identifying novel potentially causal variants at the MTAP/CDKN2A and CASP8 loci. These results improve our understanding of the architecture of melanoma risk and outcome.

Acral lentiginous melanoma (ALM) is the most common melanoma subtype in several countries in Africa, Asia, and Latin America, including Mexico. Comparatively fewer studies have been published of ALM than other subtypes of the disease. However, it is becoming clear that complex DNA structural aberrations, as well as several genes, such as NOTCH2, KIT, PTEN and TYRP1, in addition to the established melanoma drivers, play a role in its development. To date, no comprehensive genomic characterization has been performed on tumors from Latin American patients. The causes of ALM are unknown, and little is known about its transcriptomic profile and immune landscape. Because of these factors, therapeutic options are limited, while approaches such as immunotherapy are too costly for most patients in Latin American countries, and are of unknown efficacy in rarer forms of melanoma such as ALM. A better understanding of the molecular and immune profile of ALM would allow us to identify potential therapeutic targets and treatment strategies in this population. We have sequenced the exomes and transcriptomes of 113 ALM tumors (primaries, metastases and recurrences) from 86 patients being treated at the National Cancer Institute of Mexico, a national reference hospital. We have performed analyses to define the genomic landscape of the disease, its mutational signatures, the biological pathways involved in its development, and its immune profile. From these analyses, we have identified recurrently amplified and deleted genomic regions, potential causal agents, and the involvement of specific interleukins and cell-adhesion proteins in ulcerated and metastatic tumors. This study is one of the first to profile the molecular landscape of ALM in a Latin American population. We hope that it will contribute to increasing the diversity of cancer genomics datasets, help highlight differences in disease biology, and provide insights that may inform therapeutic strategies for all patients with this lethal malignancy. Citation Format: Martha E. Vázquez-Cruz, Patricia Basurto-Lozada, Christian Molina-Aguilar, Carolina Castaneda-Garcia, Ingrid Ferreira, Héctor Martínez-Said, Alethia Álvarez-Cano, Luis Alberto Tavares-de la Paz, Diego Hinojosa-Ugarte, Dorian Y. García-Ortega, Julia M. Martínez-Gómez, Mitchell P. Levesque, David J. Adams, Carla D. Robles-Espinoza. The molecular landscape of acral lentiginous melanoma in Mexican patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2222.