Identification of genomic alterations in oesophageal squamous cell cancer

Abstract

Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide. Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

Results and prognostic factors of 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy for esophageal carcinoma

“…Finally, our results indicated that female sex was independently associated with better OS and PFS, similar to a previous study [34].Previous research [30] also indicated that the risk of esophageal squamous cell carcinoma correlated with alcohol consumption and that drinking was a prognostic factor for OS in univariate (p = 0.010) and multivariate analyses (p = 0.037). This is also in agreement with our results.…”

“…Similar results were reported in a study of patients with nasopharyngeal carcinoma who were treated by IMRT [29]. These results suggest a common underlying pathogenesis for esophageal squamous cell carcinoma (ESCC) and head and neck squamous cell carcinoma (HNSCC) [30]. Our patients with stage I and II cancer had significantly better OS and PFS than those with stage III and IV cancer.…”

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

“…Loss-of-function mutations in Notch1 are found in diverse epithelial cancers. Notch mutations may predict Wnt dependency and sensitivity to upstream inhibitors, but confirmatory studies are needed (60).…”

WNT Signaling in Cutaneous Squamous Cell Carcinoma: A Future Treatment Strategy?

“…For example in oesophageal SCC, the frequency of ctnnb1 mutations is only 1.1%, but yet 86.4% of oesophageal SCC tumours contain mutated WNT pathway genes (Song, et al 2014), suggesting the mechanisms by which WNT signaling function is peterbed in SCC tumours, are potentially diverse. Epigenetic inactivation of WNT signaling antagonists such as the SFRP genes is not restricted to cSCC, but rather is detected in a variety of other types of SCC tumours, including oral (Paluszczak, et al 2015;Pannone, et al 2010;Sogabe, et al 2008), oesphageal (Kishino, et al 2016;Liu, et al 2011;Meng, et al 2011;Saito, et al 2014;Yang, et al 2012), cervical (Delmas, et al 2011;Siegel, et al 2015) and head & neck (HN) SCCs (Marsit, et al 2006), and thus could represent a universal mechanism of WNT activation in SCC tumours.…”