A gene expression and pre-mRNA splicing signature that marks the adenoma-adenocarcinoma progression in colorectal cancer.

International audienceIt is widely accepted that most colorectal cancers (CRCs) arise from colorectal adenomas (CRAs), but transcriptomic data characterizing the progression from colorectal normal mucosa to adenoma, and then to adenocarcinoma are scarce. These transition steps were investigated using microarrays, both at the level of gene expression and alternative pre-mRNA splicing. Many genes and exons were abnormally expressed in CRAs, even more than in CRCs, as compared to normal mucosae. Known biological pathways involved in CRC were altered in CRA, but several new enriched pathways were also recognized, such as the complement and coagulation cascades. We also identified four intersectional transcriptional signatures that could distinguish CRAs from normal mucosae or CRCs, including a signature of 40 genes differentially deregulated in both CRA and CRC samples. A majority of these genes had been described in different cancers, including FBLN1 or INHBA, but only a few in CRC. Several of these changes were also observed at the protein level. In addition, 20% of these genes (i.e. CFH, CRYAB, DPT, FBLN1, ITIH5, NR3C2, SLIT3 and TIMP1) showed altered pre-mRNA splicing in CRAs. As a global variation occurring since the CRA stage, and maintained in CRC, the expression and splicing changes of this 40-gene set may mark the risk of cancer occurrence from analysis of CRA biopsies

Characteristics of colorectal biopsy samples used in the present study.

<p>Abbreviations: NOR: colorectal normal mucosa; CRA: colorectal adenoma; CRC: colorectal cancer.</p

Hierarchical clustering (Euclidean, average linkage) considering the expression signature of 44 probes.

<p>Branches represent individual colorectal samples. Different colors were used to identify the sample groups: red, group of normal mucosae (N: normal); green, group of adenomas (A: adenoma); blue, group of adenocarcinomas (C: cancer). The first sample annotation corresponds to the sample group. The subgroups of adenomas are specified: A1, adenomas with areas of micro-invasive adenocarcinomas; A2, adenomas with areas of intra-mucosa adenocarcinomas; A3, adenomas with areas of dysplasia. The second sample annotation corresponds to the sample number.</p

Hierarchical clustering considering the gene expression in colorectal lesions.

<p>Heat map of the expression data was constructed using Euclidean distance with average linkage. The heat map of the deregulated probes with a fold-change ≥3.0 and a P-value ≤0.001 is shown for CRA <i>vs</i>. NOR (<b>A</b>; complete heat map in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087761#pone.0087761.s001" target="_blank">Figure S1</a>), for CRC <i>vs</i>. NOR (<b>B</b>), and CRC <i>vs</i>. CRA (<b>C</b>).</p

Venn diagrams of probe level alterations in colorectal lesions.

<p>An intersectional analysis of probe level alterations was performed. Cut-off values were P-value ≤0.01 and fold-change ≥2. The CRA <i>vs</i>. NOR comparison showed the largest number of probe level changes (2,393 deregulated probes), while the CRC <i>vs</i>. CRA comparison showed the lowest (669 deregulated probes). The probes that showed alterations in two or in the three comparisons were of interest. (<b>A</b>) Signature of 954 probes deregulated in both CRA and CRC lesions as compared to NOR. (<b>B</b>) Signature of 172 probes deregulated in CRC in comparison to both CRA and NOR. (<b>C</b>) Signature of 265 probes deregulated in CRC as compared to CRA, which levels were already abnormal in CRA as compared to NOR. (<b>D</b>) Signature of 44 probes showing alterations in the three comparisons (CRA <i>vs</i>. NOR, CRC <i>vs</i>. CRA and CRC <i>vs</i>. NOR). Abbreviations: NOR: colorectal normal mucosa; CRA: colorectal adenoma; CRC: colorectal cancer.</p

List of the up- and down-regulated genes of the gene expression signature of 44 probes.

<p>Signature of 44 probes corresponding to genes showing alterations in the three comparisons (CRA <i>vs</i>. NOR, CRC <i>vs</i>. CRA and CRC <i>vs</i>. NOR; ≥2.0 FC, P-value ≤0.01 by <i>t</i>-test with FDR).</p

Worldwide trends in population-based survival for children, adolescents, and young adults diagnosed with leukaemia, by subtype, during 2000–14 (CONCORD-3): analysis of individual data from 258 cancer registries in 61 countries

Background: Leukaemias comprise a heterogenous group of haematological malignancies. In CONCORD-3, we analysed data for children (aged 0–14 years) and adults (aged 15–99 years) diagnosed with a haematological malignancy during 2000–14 in 61 countries. Here, we aimed to examine worldwide trends in survival from leukaemia, by age and morphology, in young patients (aged 0–24 years). Methods: We analysed data from 258 population-based cancer registries in 61 countries participating in CONCORD-3 that submitted data on patients diagnosed with leukaemia. We grouped patients by age as children (0–14 years), adolescents (15–19 years), and young adults (20–24 years). We categorised leukaemia subtypes according to the International Classification of Childhood Cancer (ICCC-3), updated with International Classification of Diseases for Oncology, third edition (ICD-O-3) codes. We estimated 5-year net survival by age and morphology, with 95% CIs, using the non-parametric Pohar-Perme estimator. To control for background mortality, we used life tables by country or region, single year of age, single calendar year and sex, and, where possible, by race or ethnicity. All-age survival estimates were standardised to the marginal distribution of young people with leukaemia included in the analysis. Findings: 164 563 young people were included in this analysis: 121 328 (73·7%) children, 22 963 (14·0%) adolescents, and 20 272 (12·3%) young adults. In 2010–14, the most common subtypes were lymphoid leukaemia (28 205 [68·2%] patients) and acute myeloid leukaemia (7863 [19·0%] patients). Age-standardised 5-year net survival in children, adolescents, and young adults for all leukaemias combined during 2010–14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia. Individuals with lymphoid leukaemia had better age-standardised survival (from 43% in Ecuador to ≥80% in parts of Europe, North America, Oceania, and Asia) than those with acute myeloid leukaemia (from 32% in Peru to ≥70% in most high-income countries in Europe, North America, and Oceania). Throughout 2000–14, survival from all leukaemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries. Interpretation: This study offers the first worldwide picture of population-based survival from leukaemia in children, adolescents, and young adults. Adolescents and young adults diagnosed with leukaemia continue to have lower survival than children. Trends in survival from leukaemia for adolescents and young adults are important indicators of the quality of cancer management in this age group