A partir d'échantillons tumoraux prélevés sur 34 patients pédiatriques atteints d'un carcinome corticosurrénalien, cette étude identifie un ensemble d'anomalies génomiques permettant d'élaborer un modèle de la tumorigenèse dans cette maladie rare à pronostic défavorable

Genomic landscape of paediatric adrenocortical tumours

Pinto, Emilia M. ; Chen, Xiang ; Easton, John ; Finkelstein, David ; Liu, Zhifa ; Pounds, Stanley ; Rodriguez-Galindo, Carlos ; Lund, Troy C. ; Mardis, Elaine R. ; Wilson, Richard K. ; Boggs, Kristy ; Yergeau, Donald ; Cheng, Jinjun ; Mulder, Heather L. ; Manne, Jayanthi ; Jenkins, Jesse ; Mastellaro, Maria J. ; Figueiredo, Bonald C. ; Dyer, Michael A. ; Pappo, Alberto ; Zhang, Jinghui ; Downing, James R. ; Ribeiro, Raul C. ; Zambetti, Gerard P.

Paediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here we analyse 37 adrenocortical tumours (ACTs) by whole-genome, whole-exome and/or transcriptome sequencing. Most cases (91%) show loss of heterozygosity (LOH) of chromosome 11p, with uniform selection against the maternal chromosome. IGF2 on chromosome 11p is overexpressed in 100% of the tumours. TP53 mutations and chromosome 17 LOH with selection against wild-type TP53 are observed in 28 ACTs (76%). Chromosomes [...]

Cet article passe en revue les travaux récents sur le rôle des anomalies chromosomiques dans la diversité clonale d'une leucémie myéloïde chronique et la progression de la maladie

Role of chromosomal aberrations in clonal diversity and progression of acute myeloid leukemia

Bochtler, T. ; Frohling, S. ; Kramer, A.

Genetic abnormalities are a hallmark of cancer. Hereby, cytogenetic aberrations and small-scale abnormalities, such as single-nucleotide variations and insertion/deletion mutations, have emerged as two alternative modes of genetic diversification. Both mechanisms are at work in acute myeloid leukemia (AML), in which conventional karyotyping and molecular studies demonstrate that gene mutations occur predominantly in cytogenetically normal AML, whereas chromosomal changes are a driving force of [...]

A partir d'échantillons tumoraux prélevés sur 11 patients atteints d'un carcinome à cellules acineuses du pancréas, cette étude identifie notamment des mutations fréquentes dans les gènes BCRA2 et FAT

Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas

Furukawa, Toru ; Sakamoto, Hitomi ; Takeuchi, Shoko ; Ameri, Mitra ; Kuboki, Yuko ; Yamamoto, Toshiyuki ; Hatori, Takashi ; Yamamoto, Masakazu ; Sugiyama, Masanori ; Ohike, Nobuyuki ; Yamaguchi, Hiroshi ; Shimizu, Michio ; Shibata, Noriyuki ; Shimizu, Kyoko ; Shiratori, Keiko

Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we [...]

Menée à l'aide de modèles murins de cancer du poumon, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation EGFR, un récepteur couplé aux protéines G (GPRC5A) exerce une fonction de suppresseur de tumeurs

Lung tumor suppressor GPRC5A binds EGFR and restrains its effector signaling

Deng, Jiong ; Zhong, Shuangshuang ; Yin, Huijing ; Liao, Yueling ; Yao, Feng ; Li, Qi ; Zhang, Jie ; Jiao, Huike ; Zhao, Yongxu ; Xu, Dongliang ; Liu, Shuli ; Song, Hongyong ; Gao, Yong ; Liu, Jingyi ; Ma, Lina ; Pang, Zhi ; Yang, Ruixu ; Ding, Chengyi ; Sun, Beibei ; Lin, Xiaofeng ; Ye, Xiaofeng ; Guo, Wenzheng ; Han, Baohui ; Zhou, Binhua P. ; Chin, Y. Eugene

GPRC5A is a G-protein coupled receptor expressed in lung tissue but repressed in most human lung cancers. Studies in Gprc5a-/- mice have established its role as a tumor suppressor function in this setting, but its the basis for its role have been obscure. Here we report that GPRC5A functions as a negative modulator of EGFR signaling. Mouse tracheal epithelial cells (MTEC) from Gprc5a-/- mice exhibited a relative increase in EGFR and downstream STAT3 signaling, whereas GPRC5A expression [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant la signalisation Sonic Hedgehog, la protéine p63 favorise le renouvellement des cellules souches de cancer du sein

p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling

Memmi, Elisa Maria ; Sanarico, Anna Giulia ; Giacobbe, Arianna ; Peschiaroli, Angelo ; Frezza, Valentina ; Cicalese, Angelo ; Pisati, Federica ; Tosoni, Daniela ; Zhou, Huiqing ; Tonon, Giovanni ; Antonov, Alexey ; Melino, Gerry ; Pelicci, Pier Giuseppe ; Bernassola, Francesca

The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en activant la signalisation ErbB2, la perte d'expression du gène Smad4 favorise la progression tumorale et le processus métastatique d'un cancer du poumon

ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis

Liu, Jian ; Cho, Sung-Nam ; Akkanti, Bindu ; Jin, Nili ; Mao, Jianqiang ; Long, Weiwen ; Chen, Tenghui ; Zhang, Yiqun ; Tang, Ximing ; Wistub, Ignacio I ; Creighton, Chad J ; Kheradmand, Farrah ; DeMayo, Francesco J

Lung cancer remains the leading cause of cancer death. Genome sequencing of lung tumors from patients with squamous cell carcinoma has identified SMAD4 to be frequently mutated. Here, we use a mouse model to determine the molecular mechanisms by which Smad4 loss leads to lung cancer progression. Mice with ablation of Pten and Smad4 in airway epithelium develop metastatic adenosquamous tumors. Comparative transcriptomic and in vivo cistromic analyses determine that loss of PTEN and SMAD4 results [...]

Menée sur le rat-taupe nu (une espèce résistante aux maladies liées à l'âge, notamment le cancer) et 9 autres espèces de rongeurs, cette étude met en évidence une association entre une activation de la signalisation Nrf2 et la longévité

Regulation of Nrf2 signaling and longevity in naturally long-lived rodents

Lewis, Kaitlyn N. ; Wason, Emily ; Edrey, Yael H. ; Kristan, Deborah M. ; Nevo, Eviatar ; Buffenstein, Rochelle

The preternaturally long-lived naked mole-rat, like other long-lived species and experimental models of extended longevity, is resistant to both endogenous (e.g., reactive oxygen species) and environmental stressors and also resists age-related diseases such as cancer, cardiovascular disease, and neurodegeneration. The mechanisms behind the universal resilience of longer-lived organisms to stress, however, remain elusive. We hypothesize that this resilience is linked to the activity of a highly [...]

Menée sur une lignée cellulaire de cancer du côlon, cette étude met en évidence le rôle joué par la méthylation de l'ADN dans l'organisation fonctionnelle de l'épigénome cancéreux

The role of DNA methylation in directing the functional organization of the cancer epigenome

Lay, Fides D. ; Liu, Yaping ; Kelly, Theresa K. ; Witt, Heather ; Farnham, Peggy J. ; Jones, Peter A. ; Berman, Benjamin P.

The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. Here we perform a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation-deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised, and inactive genomic elements. DNA methylation abolished this phasing [...]

A partir de l'analyse de l'histoire naturelle d'une xénogreffe de tumeur, cette étude présente un modèle évolutif permettant de rendre compte de l'hétérogénéité génétique intra- et inter-tumorale

The reverse evolution from multicellularity to unicellularity during carcinogenesis

Chen, Han ; Lin, Fangqin ; Xing, Ke ; He, Xionglei

Theoretical reasoning suggests that cancer may result from a knockdown of the genetic constraints that evolved for the maintenance of metazoan multicellularity. By characterizing the whole-life history of a xenograft tumour, here we show that metastasis is driven by positive selection for general loss-of-function mutations on multicellularity-related genes. Expression analyses reveal mainly downregulation of multicellularity-related genes and an evolving expression profile towards that of [...]