Dataset Information

Molecular profiles and tumor mutational burden analysis in Chinese patients with gynecologic cancers.

ABSTRACT: The goal of this work was to investigate the tumor mutational burden (TMB) in Chinese patients with gynecologic cancer. In total, 117 patients with gynecologic cancers were included in this study. Both tumor DNA and paired blood cell genomic DNA were isolated from formalin-fixed paraffin-embedded (FFPE) specimens and blood samples, and next-generation sequencing was performed to identify somatic mutations. TP53, PTEN, ARID1A, and PIK3CA alterations were significantly different in various types of gynecologic cancers (p?=?0.001, 1.15E-07, 0.004, and 0.009, respectively). The median TMB of all 117 gynecologic tumor specimens was 0.37 mutations/Mb, with a range of 0-41.45 mutations/Mb. Despite the lack of significant difference, endometrial cancer cases had a higher median TMB than cervical and ovarian cancer cases. Younger gynecologic cancer patients (age <40 years) had a significantly lower TMB than older patients (age ?40 years) (p?=?0.04). In addition, TMB was significantly increased with increasing clinical stage of disease (p?=?0.001). PTEN alterations were commonly observed in patients with a moderate to high TMB (n?=?8, 38.10%, p?=?9.95E-04). Although limited by sample size, all of the patients with TSC2 (n?=?3, p?=?3.83E-11) or POLE (n?=?2, p?=?0.005) mutations had a moderate to high TMB. Further large-scale, prospective studies are needed to validate our findings.

SUBMITTER: Wang M

PROVIDER: S-EPMC5997642 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Molecular profiles and tumor mutational burden analysis in Chinese patients with gynecologic cancers.

Wang Min M Fan Wensheng W Ye Mingxia M Tian Chen C Zhao Lili L Wang Jianfei J Han Wenbo W Yang Wen W Gu Chenglei C Li Mingxia M Zhang Zhe Z Wang Yongjun Y Zhang Henghui H Meng Yuanguang Y

Scientific reports 20180612 1

The goal of this work was to investigate the tumor mutational burden (TMB) in Chinese patients with gynecologic cancer. In total, 117 patients with gynecologic cancers were included in this study. Both tumor DNA and paired blood cell genomic DNA were isolated from formalin-fixed paraffin-embedded (FFPE) specimens and blood samples, and next-generation sequencing was performed to identify somatic mutations. TP53, PTEN, ARID1A, and PIK3CA alterations were significantly different in various types o ...[more]

PMID: 29895933

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Project description:IntroductionThymic epithelial tumors (TETs) are malignancies arising from the epithelium of the thymic gland, rare but with relatively favorable prognosis. TETs have different pathological subtypes: thymomas and thymic carcinoma, and they show different clinical characteristics regarding prognosis, pathology, and molecular profiles, etc. Although some studies have investigated the pathogenesis of TETs, more molecular data is still needed to further understand the underlying mechanisms among different TETs subtypes and populations.MethodsIn this study, we performed targeted gene panel sequencing and whole transcriptome sequencing on the tumor tissues from 27 Chinese TET patients, including 24 thymomas (A, AB, and B subtypes) and 3 thymic squamous cell carcinomas. We analyzed the genetic variations and differentially expressed genes among multiple TET subtypes. Moreover, we compared our data with the published The Cancer Genome Atlas (TCGA) TET data on both the genetic and transcriptomic levels.ResultsCompared with the TCGA TET genomic data, we found that NF1 and ATM were the most frequently mutated genes (each with a frequency of 11%, 3/27). These mutations were not mutually exclusive, since one B1 thymoma showed mutations of both genes. The GTF2I mutation was mainly enriched in subtype A and AB thymomas, consistent with the previous reports. RNA-seq results unveiled that the genes related to thymus development (FGF7, FGF10 and CLDN4) were highly expressed in certain TET subtypes, implicating that the developmental process of thymus might be linked to the tumorigenesis of these subtypes. We found high expression of CD274 (PD-L1) in B2 and B3 thymoma samples, and validated its expression using immunohistochemistry (IHC). Based on the expression profiles, we further established a machine learning model to predict the myasthenia gravis status of TET patients and achieved 90% sensitivity and 70.6% specificity in the testing cohort.ConclusionThis study provides the first genomic and transcriptomic analysis of a Chinese TET cohort. The high expression of genes involved in thymus developmental processes suggests the potential association between tumorigenesis of TETs and dysregulation of developmental pathways. The high expression of PD-L1 in B2 and B3 thymomas support the potential application of immunotherapy on certain thymoma subtypes.

Project description:BackgroundLung cancer is the leading cause of cancer death worldwide. With the growing number of targeted therapies and the introduction of immuno-oncology (IO), personalized medicine has become standard of care in patients with metastatic disease. The development of predictive and prognostic biomarkers is of great importance. Mutational signatures harbor potential clinical value as predictors of therapy response in cancer. Here we set out to investigate particular mutational processes by assessing mutational signatures and associations with clinical features, tumor mutational burden (TMB) and targetable mutations.MethodsIn this retrospective study, we studied tumor DNA from patients with non-small cell lung cancer (NSCLC) irrespective of stage. The samples were sequenced using a 2 megabase (Mb) gene panel. On each sample TMB was determined and defined as the total number of single nucleotide mutations per Mb (mut/Mb) including non-synonymous mutations. Mutational signature profiling was performed on tumor samples in which at least 30 somatic single base substitutions (SBS) were detected.ResultsIn total 195 samples were sequenced. Median total TMB was 10.3 mut/Mb (range 0-109.3). Mutational signatures were evaluated in 76 tumor samples (39%; median TMB 15.2 mut/Mb). SBS signature 4 (SBS4), associated with tobacco smoking, was prominently present in 25 of 76 samples (33%). SBS2 and/or SBS13, both associated with activity of the AID/APOBEC family of cytidine deaminases, were observed in 11 of 76 samples (14%). SBS4 was significantly more present in early stages (I and II) versus advanced stages (III and IV; P = .005).ConclusionIn a large proportion of NSCLC patients tissue panel sequencing with a 2 Mb panel can be used to determine the mutational signatures. In general, mutational signature SBS4 was more often found in early versus advanced stages of NSCLC. Further studies are needed to determine the clinical utility of mutational signature analyses.

Dataset Information

Molecular profiles and tumor mutational burden analysis in Chinese patients with gynecologic cancers.

Publications

Molecular profiles and tumor mutational burden analysis in Chinese patients with gynecologic cancers.

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