KAT6A amplifications are associated with shorter progression-free survival and overall survival in patients with endometrial serous carcinoma.

Ozlen Saglam,L Jeffrey Medeiros,Zhenya Tang,Guilin Tang,Gokce A Toruner,Jesús Maria Paramio

doi:10.1371/journal.pone.0238477

Ozlen Saglam, L Jeffrey Medeiros + Show 4 more

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https://doi.org/10.1371/journal.pone.0238477

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Abstract

Somatic copy number alterations (CNA) are common in endometrial serous carcinoma (ESC). We used the Tumor Cancer Genome Atlas Pan Cancer dataset (TCGA Pan Can) to explore the impact of somatic CNA and gene expression levels (mRNA) of cancer-related genes in ESC. Results were correlated with clinico-pathologic parameters such as age of onset, disease stage, progression-free survival (PFS) and overall survival (OS) (n = 108). 1,449 genes with recurrent somatic CNA were identified, observed in 10% or more tumor samples. Somatic CNA and mRNA expression levels were highly correlated (r> = 0.6) for 383 genes. Among these, 45 genes were classified in the Tier 1 category of Cancer Genome Census-Catalogue of Somatic Mutations in Cancer. Eighteen of 45 Tier 1 genes had highly correlated somatic CNA and mRNA expression levels including ARNT, PIK3CA, TBLXR1, ASXL1, EIF4A2, HOOK3, IKBKB, KAT6A, TCEA1, KAT6B, ERBB2, BRD4, KEAP1, PRKACA, DNM2, SMARCA4, AKT2, SS18L1. Our results are in agreement with previously reported somatic CNA for ERBB2, BRD4 and PIK3C in ESC. In addition, AKT2 (p = 0.002) and KAT6A (p = 0.015) amplifications were more frequent in tumor samples from younger patients (<60), and CEBPA (p = 0.028) and MYC (p = 0.023) amplifications were more common with advanced (stage III and IV) disease stage. Patients with tumors carrying KAT6A and MYC amplifications had shorter PFS and OS. The hazard ratio (HR) of KAT6A was 2.82 [95 CI 1.12–7.07] for PFS and 3.87 [95 CI 1.28–11.68] for OS. The HR of MYC was 2.25 [95 CI 1.05–4.81] and 2.62[95 CI 1.07–6.41] for PFS and OS, respectively.

Highlights

Somatic copy number alterations (CNA), including aneuploidy, segmental duplications and focal aberrations are frequently observed in neoplasia
PTEN [1] and RB1 [2] deletions result in decreased gene expression of tumor suppressor genes, whereas MET [3], ERBB2 [4] and MYC [5] amplifications lead to increased gene expression levels
The secondary objective of this study is to explore associations of identified Tier 1 Cancer Gene Census (CGC)-Catalogue of Somatic Mutations in Cancer (COSMIC) genes with clinic-pathological parameters such as disease stage, age of onset, overall survival (OS) and progression free survival (PFS), to identify potential biomarkers associated with these cancers

Summary

Introduction

Somatic copy number alterations (CNA), including aneuploidy, segmental duplications and focal aberrations are frequently observed in neoplasia. For critical oncogenes and tumor suppressor genes, changes in gene copy number might result in alteration of gene expression. Somatic copy number aberrations and gene expression in endometrial serous cancer and drive the neoplastic process. PTEN [1] and RB1 [2] deletions result in decreased gene expression of tumor suppressor genes, whereas MET [3], ERBB2 [4] and MYC [5] amplifications lead to increased gene expression levels. The frequency of somatic CNAs varies significantly according to the histologic type of neoplasm as well as anatomical site. For example somatic CNAs are very common in endometrial serous cancers (ESC), but not in other endometrial cancer (EC) histologic types. ESC is one of the high-grade EC with a worse clinical outcome compared to low-grade (type 1) EC [7]

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