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Aberrant Signaling Pathways in Sinonasal Intestinal-Type Adenocarcinoma.

ABSTRACT: Sinonasal intestinal-type adenocarcinoma (ITAC) is strongly related to occupational exposure to wood and leather dust, however, little is known on the genetic alterations involved in tumor development and progression. The aim of this study was to identify tumorigenic signaling pathways affected by gene mutations and their relation to clinical features. We applied whole exome sequencing of 120 cancer-related genes in 50 ITACs and analyzed the signaling activity of four specific pathways frequently affected by mutations. Genes involved in DNA damage response showed somatic mutations in 30% of cases, including four tumors that also harbored germline mutations. Genes in Wnt, MAPK and PI3K pathways harbored mutations in 20%, 20% and 24% of cases, respectively. Mutations and copy number gains in receptor tyrosine kinases possibly affecting MAPK and PI3K pathways occurred in 44% of cases. Expression of key pathway proteins showed no correlation to mutations in these pathways, except for nuclear β-catenin and APC/CTNNB1 mutation. No specific gene mutation, mutated pathway, nor pathway activity level showed correlation to clinical data or survival. In addition, a similar mutational profile was observed among histological subtypes. The wide spectrum of gene mutations suggests that ITAC is a genetically heterogeneous without specific characterizing gene mutations.

SUBMITTER: Riobello C

PROVIDER: S-EPMC8507674 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Gene expression profiling in sinonasal adenocarcinoma.

Project description:Transcriptional profiling of ethmoïd tumors samples comparing normal samples from the controlateral sinus. RNA were extracted from biopsies. Sinonasal adenocarcinomas are uncommon tumors developping in ethmoid sinus after wood dust exposure. Although the etiology of these tumors is well defined very little is known regarding the molecular basis of these tumors. In an attempt to identify genes involved in this disease we proceed to a gene expression profiling using cancer-dedicated microarrays, on matched samples of nine sinonasal adenocarcinomas and non-tumoral sinusal tissue. Among the genes with significant differential expression we selected: LGALS4, ACS5, CLU, BAX, PDGFRa, SRI and CCT5 for further exploration by quantitative real-time reverse-transcription-PCR on a larger set of tumors and confirmed the microarray data. Protein expression alterations were shown for LGALS4, ACS5, and CLU by immunohistochemistry. Our results suggest that two genes might be involved in the pathogenesis of these tumors: LGALS4 highly up-regulated, particularly in the most differentiated tumors, and CLU, whose expression was lost. After further evaluation these genes could be used as markers for a better characterization of these tumors and will potentially help to an earlier detection of cancer in woodworkers, who have high risk of developing sinonasal adenocarcinomas.

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