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Poster display session

4546 - Investigation of AMBRA1 as a melanoma susceptibility gene


10 Sep 2017


Poster display session


Cancers in Adolescents and Young Adults (AYA);  Translational Research;  Melanoma


Veronica Hoeiom


Annals of Oncology (2017) 28 (suppl_5): v428-v448. 10.1093/annonc/mdx377


V. Hoeiom1, M. Yang1, K. Nosrati1, A. Azimi2, S. Egyhazi Brage1, R. Tuominen1

Author affiliations

  • 1 Oncology And Pathology, Karolinska Institutet, 17176 - Stockholm/SE
  • 2 Oncology-pathology, Karolinska Institutet, 17176 - Stockholm/SE


Abstract 4546


Melanoma is the most lethal form of skin cancer, which shows a rapid increase in incidence in many countries including Sweden. To date, the annual increase is over 5% and there is an urgent need to improve possibilities for prevention and early diagnoses when the prognosis is far favorable compared to disseminated disease. Melanoma is caused by an interplay of environmental and genetic factors and is one of the cancer forms showing highest heritability. Still a substantial extent of the genes underlying melanoma susceptibility is unknown.


We have executed whole-exome sequencing of melanoma-prone families to identify novel melanoma predisposing genes. Further genetic and functional studies of strong candidate genes using patient samples and melanoma cell lines has been performed. Various in vitro assays have been used to determine the role of these genes in for example autophagy and cell proliferation.


One gene discovered was the autophagy/beclin-1 regulator 1 (AMBRA1), where a putative splice variant was co-segregating with the melanoma phenotype in a 4-case family. This mutation was not found among over 6000 Swedish population-based controls nor in any additional melanoma patients. AMBRA1 is essential in the regulation of autophagy and apoptosis and has been suggested to function as a tumor suppressor. By gene expression analysis we identified several transcripts of AMBRA1, with differential expression in melanoma tumors and in various melanoma cell lines. In tumor material from the splice variant carrier AMBRA1 showed low levels of expression. In melanoma cell lines, AMBRA1 was up-regulated when adding an autophagy activating reagent while down-regulated when treating the cells with Chloroquine, a drug inhibiting autophagy. AMBRA1 was also significantly up regulated when treating the cells with Crizotinib, a drug that targets the tyrosine kinase receptor c-MET and may induce autophagy, whereas no effect was seen when using the BRAF-inhibitor Vemurafenib. Thus, AMBRA1 may be involved in the Crizotinib-induced autophagy pathway.


Preliminary data suggest AMBRA1 as a candidate melanoma susceptibility gene with a role during autophagy in melanoma cells. Further studies are needed to elucidate the specific role of this gene in melanoma development.

Clinical trial identification

Legal entity responsible for the study

Karolinska Institutet


The Swedish Cancer Society, The Swedish Research Council, Regnérs foundation


All authors have declared no conflicts of interest.

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