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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - SCUBA CANCERS (Finding the genetic causes of contagious metastases under the sea)

Teaser

Summary

Clonally transmissible cancers are somatic cell lineages that are transmitted between individuals via the transfer of living cancer cells. There are only three known types of naturally occurring clonally transmissible cancers, one of which is a leukemia-like cancer found in marine bivalves, called hemic neoplasia (HN). HN in cockles Cerastoderma edule offers an unique opportunity, over the other naturally occurring transmissible cancers, for the discovery of the genetic drivers of cancer transmissibility. Using HN in cockles as a model for clonally transmissible cancers, this project intends to identify the genomic alterations and mutational processes that drive transmissible cancers to depart from their hosts and evolve as parasitic clonal lineages in the marine environment, for illuminating universal processes that make a cancer contagious, and to identify new/unexpected biological insights into the general mechanisms of cancer metastasis. We will first characterize the clonal structure of cockle transmissible cancers by phylogenetic approaches. Then, we will use NGS analysis to catalogue the somatic alterations that characterize different HN clonal lineages, figure out the mutational processes that operate in marine transmissible cancers, and identify the putative cancer genes that drive cancer transmissibility, which will be finally validated by genome editing approaches.

Work performed

Here, we report the preliminary results of the Scuba Cancers Project. During the first 2.5 years of the project, we have collected 6,300 cockles (Cerastoderma edule) along the Atlantic Coast of Europe, from Marocco to Russia; this includes 30 sampling points from 11 countries, covering all the area of distribution of the species. We diagnosed 342 cockles (5.4%, 342/6,300) with hemic neoplasia by means of cytological and histological methods. The affected animals corresponded to 7 sampling points from 5 different countries (Portugal, Spain, France, England, and Ireland). The clonal structure of this cancer was assessed by means of whole mitochondrial genome single-molecule sequencing of both tumour and normal tissues from 60 cockles severely affected by hemic neoplasia (grade N3, showing more than 90% tumour cells in the haemolymph). In addition, we sequenced the whole mitochondrial genomes from an additional panel of 144 non-neoplastic animals from all sampled European populations. We run our bioinformatic algorithms to identify different types of genetic variation on the mentioned mitochondrial sequencing data to infer their molecular phylogeny. Our results support at least five different clonal lineages currently coexisting in cockle populations and most likely suggesting a polyphyletic origin of the disease, with different clones having independently arisen throughout cockles\' evolution.

Final results

During the next 2.5 years of the project we will identify the genetic causes that make a cancer transmissible. For that purpose, we will sequence the whole-genomes from 50 tumours and 450 normal tissues using Illumina technologies. We will then call somatic genetic variants (single-nucleotide variants and rearrangements) on the tumours, and identify the genes and genetic mutations that characterize the disease. We will also analyse the patterns of mutation to identify the mutational processes that make these cancers evolve (u.e., ultra-violate light, internal processes,...). Finally, we will confirm the genes involved in cancer transmissibility by looking for similar (orthologous) genes mutated in other species infected with hemic neoplasia (i.e., Polititapes aureus and Mya arenaria).