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Short stature homeobox 2 methylation as a potential noninvasive biomarker in bronchial aspirates for lung cancer diagnosis.

ABSTRACT: Gene methylation has been frequently observed in lung cancer. However, the use of methylated genes in bronchial aspirates of patients with lung cancer remains to be evaluated. The purpose of this study was to analyze whether the detection of genes with aberrant promoter methylation can be useful noninvasive biomarkers in bronchial aspirates from lung cancer. We found that the methylation status of the cyclin-dependent kinase inhibitor 2A (P16), Ras association domain family 1 isoform (RASSF1A), adenomatous polyposis coli (APC) and short stature homeobox 2 (SHOX2) genes was significantly correlated with lung cancer in bronchial aspirates. The P16, RASSF1A and APC methylation had a bad diagnostic effect in bronchial aspirates of patients with lung cancer compared with non-tumor controls (P16: sensitivity = 0.26, specificity = 0.99, area under the curve (AUC) = 0.67; RASSF1A: sensitivity = 0.40, specificity = 0.99, AUC = 0.66; APC: sensitivity = 0.17, specificity = 0.98, AUC = 0.65). The pooled sensitivity, specificity, and AUC of the SHOX2 methylation were 0.75, 0.94, and 0.94, respectively. Moreover, when squamous cell carcinoma (SCC) was compared to adenocarcinoma (AC), the SHOX2 gene had a significantly higher methylation rate in SCC than in AC (P < 0.001). Methylated P16, RASSF1A, APC and retinoic acid receptor beta2 (RAR?2) genes had similar frequencies in these two histotypes (P > 0.1). Our findings suggest that methylated SHOX2 gene could be a specific and potential noninvasive biomarker using bronchial aspirates for lung cancer diagnosis, especially for SCC.

SUBMITTER: Ni S

PROVIDER: S-EPMC5617421 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Short stature homeobox 2 methylation as a potential noninvasive biomarker in bronchial aspirates for lung cancer diagnosis.

Ni Shumin S Ye Meng M Huang Tao T

Oncotarget 20170522 37

Gene methylation has been frequently observed in lung cancer. However, the use of methylated genes in bronchial aspirates of patients with lung cancer remains to be evaluated. The purpose of this study was to analyze whether the detection of genes with aberrant promoter methylation can be useful noninvasive biomarkers in bronchial aspirates from lung cancer. We found that the methylation status of the cyclin-dependent kinase inhibitor 2A (<i>P16</i>), Ras association domain family 1 isoform (<i> ...[more]

PMID: 28977861

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Project description:BackgroundSHOX mutations have previously been described as causes of Léri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia (LMD), and idiopathic short stature. The loss of X chromosome-Turner syndrome or mosaic 45,X/46,XX or 46,XY-also leads to the heterozygous loss of SHOX in patients with short stature only or with features similar to LWD. The aim of this study was to assess the efficacy of the targeted screening for SHOX variants, which involved different methods in the laboratory analysis of short stature. We determined the significance and positive predictive value of short stature for the detection of SHOX variants.MethodsTargeted screening for variants in SHOX involving MLPA, sequencing, karyotyping and FISH was performed in the short stature cohort (N = 174) and control cohort (N = 91). The significance of short stature and particular characteristics for the detection of SHOX variants was determined by Fisher's exact test, and the probability of SHOX mutation occurrence was calculated using a forward/stepwise logistic regression model.ResultsIn total, 27 and 15 variants influencing SHOX were detected in the short stature and control cohorts, respectively (p > 0.01). Sex chromosome aberrations and pathogenic CNV resulting in diagnosis were detected in eight (4.6%) and five (2.9%) patients of the short stature group and three (3.3%) and one (1.1%) individuals of the control group. VUS variants were discovered in 14 (8.0%) and 11 (12.1%) individuals of the short stature and control groups, respectively. MLPA demonstrated the detection rate of 13.22%, and it can be used as a frontline method for detection of aberrations involving SHOX. However, only mosaicism of monosomy X with a higher frequency of monosomic cells could be reliably discovered by this method. Karyotyping and FISH can compensate for this limitation; their detection rates in short stature group were 3.55% and 13.46% (N = 52), respectively. FISH proved to be more effective than karyotyping in the study as it could reveal cryptic mosaics in some cases where karyotyping initially failed to detect such a clone. We suggest adding FISH on different tissue than peripheral blood to verify sex-chromosome constitution, especially in cases with karyotypes: 45,X; mosaic 45,X/46,XX or 46,XY; 46,Xidic(Y) detected from blood; in children, where mosaic 45,X was detected prenatally but was not confirmed from peripheral blood. The correlation of short stature with the occurrence of SHOX mutations was insignificant and short stature demonstrates a low positive predictive value-15.5% as unique indicator for SHOX mutations. The typical skeletal signs of LWD, including Madelung deformity and disproportionate growth, positively correlate with the findings of pathogenic SHOX variants (p < 0.01) by Fisher's exact test but not with the findings of VUS variants in SHOX which are more prevalent in the individuals with idiopathic short stature or in the individuals with normal height.

Dataset Information

Short stature homeobox 2 methylation as a potential noninvasive biomarker in bronchial aspirates for lung cancer diagnosis.

Publications

Short stature homeobox 2 methylation as a potential noninvasive biomarker in bronchial aspirates for lung cancer diagnosis.

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