Somatic evolution of marine transmissible leukemias in the common cockle, Cerastoderma edule

Abstract

Transmissible cancers are malignant cell clones that spread among individuals through transfer of living cancer cells. Several such cancers, collectively known as bivalve transmissible neoplasia (BTN), are known to infect and cause leukaemia-like disease in marine bivalve molluscs. This is the case of BTN clones affecting the common cockle, Cerastoderma edule, which inhabits the Atlantic coasts of Europe and north-west Africa. To investigate the origin and evolution of contagious cancers in common cockles, we collected 6,854 C. edule specimens and diagnosed 390 cases of BTN. We then generated a reference genome for the species and assessed genomic variation in the genomes of 61 BTN tumours. Analysis of tumour-specific variants confirmed the existence of two cockle BTN lineages with independent clonal origins, and gene expression patterns supported their status as haemocyte-derived blood cancers. Examination of mitochondrial DNA sequences revealed several mitochondrial capture events in BTN, as well as co-infection of cockles by different tumour lineages. Mutational spectrum analyses identified two lineage-specific mutational signatures, one of which resembles a signature associated with DNA alkylation. Cytogenetic and copy number analyses uncovered genomes marked by pervasive instability and karyotypic plasticity. Whole-genome duplication, amplification of oncogenes CCND3, MDM2 and MYC, and deletion of the DNA alkylation repair gene MGMT, are likely drivers of BTN evolution. Characterization of satellite DNA identified elements that are absent from tumours despite vast expansions in the cockle germ line, suggesting ancient BTN clonal origins. Our study illuminates the evolution of transmissible cancers under the sea, and reveals long-term tolerance of extreme instability in neoplastic genomes.

Unravelling epigenetic mechanisms in Cerastoderma edule genome: a comparison of healthy and neoplastic cockles

“…While not conclusively demonstrated, we speculate that this increased 5hmC density at these tandems may be linked to distinct chromatin condensation or secondary DNA structures related to chromatin accessibility. However, a remarkable exception was found in CedS4, the major satellite DNA occupying the heterochromatic regions in the healthy lineage (Bruzos et al 2023 ), which was found largely depleted of CpG modifications (Supplementary Table 5 ), as also observed in the methylation and hydroxymethylation desert at the end of Chromosome 11, primarily composed of this satellite (Figs. 1 a, 3 a).…”

“…Transmissible cancers defy all conventional thinking, as they involve neoplastic cells spreading between individuals beyond their original host (Murchison 2008 ) either through direct contact, as in the canine venereal tumour or the Tasmanian devil facial tumour (Murgia et al 2006 ; Murchison et al 2012 ) or by the absorption of cells freed to the media, as in hemic neoplasia in bivalves (Metzger et al 2015 , 2016 ; Bruzos et al 2023 ; Hart et al 2023 ). Nowadays, this phenomenon extends to, at least, six bivalve species (Metzger et al 2015 ; Hart et al 2023 ), among which, the common cockle, Cerastoderma edule , exhibits two transmissible cancer lineages, differentiated by cytological and genomic features (Bruzos et al 2023 ). These neoplasias are evolutionary relics, accumulating mutations over time (Bruzos et al 2023 ; Hart et al 2023 ) and thus constitute unique models of tumour dynamics, metastasis and evolution (Garcia-Souto et al 2022 ).…”

“…Nowadays, this phenomenon extends to, at least, six bivalve species (Metzger et al 2015 ; Hart et al 2023 ), among which, the common cockle, Cerastoderma edule , exhibits two transmissible cancer lineages, differentiated by cytological and genomic features (Bruzos et al 2023 ). These neoplasias are evolutionary relics, accumulating mutations over time (Bruzos et al 2023 ; Hart et al 2023 ) and thus constitute unique models of tumour dynamics, metastasis and evolution (Garcia-Souto et al 2022 ). Beyond mere scientific interest these neoplasias also have ecological and economic impacts, provoking mass mortalities in bivalve beds, especially amid climate change phenomena (Bramwell et al 2021 ).…”

“…Our understanding of the epigenetic mechanisms underlying the evolution of bivalve transmissible neoplasia (BTN) remains unexplored (Bruzos et al 2023 ; Hart et al 2023 ). In vertebrates, DNA methylation in cancer cells undergoes notable alterations, often resulting in widespread hypomethylated genomes (Feinberg et al 2006 ), although certain promoters experience abnormal hypermethylation, leading to inappropriate gene silencing (Herman et al 1998 ; Feinberg et al 2006 ; Dumitrescu and Verma 2012 ).…”

A common garden experiment supports a genetic component underlying the increased resilience of common cockle (Cerastoderma edule) to the parasite Marteilia cochillia

“…Primers for the MassARRAY genotyping were chosen by their technical feasibility to be combined in two multiplex reactions, taking as reference the cockle genome assembly (Bruzos et al, in press) (Table S1). Briefly, the technique consists of a two‐step reaction: the first involves the PCR amplification of an amplicon which includes the selected SNP (i.e., locus‐specific PCR reaction), and the second a single‐base extension using mass‐modified dideoxynucleotide terminators of an oligonucleotide primer that anneals immediately upstream of the SNP of interest (Ellis & Ong, 2017; Oeth et al, 2009).…”