High-grade neuroendocrine lung malignancies (large-cell neuroendocrine cell carcinoma, LCNEC, and small-cell lung carcinoma, SCLC) are among the most deadly lung cancer conditions with no optimal clinical management. The biological relationships between SCLC and LCNEC are still largely unknown and a current matter of debate as growing molecular data reveal high heterogeneity with potential therapeutic consequences. Here we describe murine models of highgrade neuroendocrine lung carcinomas generated by the loss of 4 tumor suppressors. In an Rbl1-null background, deletion of Rb1, Pten, and Trp53 floxed alleles after Ad-CMVcre infection in a wide variety of lung epithelial cells produces LCNEC. Meanwhile, inactivation of these genes using Ad-K5cre in basal cells leads to the development of SCLC, thus differentially influencing the lung cancer type developed. So far, a defined model of LCNEC has not been reported. Molecular and transcriptomic analyses of both models revealed strong similarities to their human counterparts. In addition, a 68 Ga-DOTATOC-based molecular-imaging method provides a tool for detection and monitoring the progression of the cancer. These data offer insight into the biology of SCLC and LCNEC, providing a useful framework for development of compounds and preclinical investigations in accurate immunocompetent models.LCNEC | SCLC | cell of origin | tumor suppressor

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 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 marine leukaemias. Examination of mitochondrial DNA sequences revealed several mitochondrial capture events in BTN, as well as co-infection of cockles by different tumour lineages. Mutational analyses identified two lineage-specific mutational signatures, one of which resembles a signature associated with DNA alkylation. Karyotypic and copy number analyses uncovered genomes marked by pervasive instability and polyploidy. Whole-genome duplication, amplification of oncogenes CCND3 and MDM2, and deletion of the DNA alkylation repair gene MGMT, are likely drivers of BTN evolution. Characterization of satellite DNA identified elements with vast expansions in the cockle germ line, yet absent from BTN tumours, suggesting ancient clonal origins. Our study illuminates the evolution of contagious cancers under the sea, and reveals long-term tolerance of extreme instability in neoplastic genomes.

Background Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression. Results Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas. Conclusion Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.