Abstract
Simple SummaryLung cancer causes the largest number of cancer-related deaths worldwide. Circulating tumor DNA (ctDNA) has been suggested as a diagnostic and prognostic biomarker in non-small cell lung cancer, but the optimal target for measuring ctDNA has not been established. We aimed to compare a gene methylation biomarker with a gene mutation biomarker in order to determine the mutual agreement. Mutation analysis requires a broad and expensive test like next-generation sequencing, while methylation analysis can be performed by the less expensive droplet digital PCR. We found a good correlation between methylated HOXA9 and mutated KRAS in plasma from patients with lung adenocarcinoma. Circulating tumor DNA (ctDNA) has been suggested as a biomarker in non-small cell lung cancer. The optimal target for measuring ctDNA has not yet been established. This study aimed to investigate methylated Homeobox A9 (meth-HOXA9) as an approach to detect ctDNA in advanced lung adenocarcinoma and compare it with mutated Kirsten rat sarcoma viral oncogene homolog (mut-KRAS) in order to determine the mutual agreement. DNA was purified from formalin-fixed, paraffin-embedded non-malignant lung tissue and lung adenocarcinoma tissue, and plasma from healthy donors and lung adenocarcinoma patients, respectively. KRAS mutations in tumor tissue were identified by next-generation sequencing and quantified in tumor and plasma by droplet digital polymerase chain reaction (ddPCR). The meth-HOXA9 analysis was based on bisulfite-converted DNA from tumor and plasma and quantified by ddPCR. Samples consisted of 20 archival non-malignant lung tissues, 48 advanced lung adenocarcinomas with matched plasma samples, and 100 plasma samples from healthy donors. A KRAS mutation was found in the tumor in 34/48 (70.8%) adenocarcinoma patients. All tumors were positive for meth-HOXA9, while none of the non-malignant lung tissues were. Meth-HOXA9 was detected in 36/48 (75%) of plasma samples, and the median level was 0.7% (range of 0–46.6%, n = 48). Mut-KRAS was detected in 29/34 (85.3%) of the plasma samples, and the median level was 1.2% (range of 0–46.1%, n = 34). There was a good correlation between meth-HOXA9 and mut-KRAS in plasma (Spearman’s rho 0.83, p < 0.001). Meth-HOXA9 is present in tissue from incurable lung adenocarcinoma but not in non-malignant lung tissue. It may be used as an approach for detecting ctDNA. The results demonstrated a high agreement between meth-HOXA9 and mut-KRAS in patients with advanced lung adenocarcinoma.
Highlights
Lung cancer causes the largest number of cancer-related deaths worldwide [1], and the prognosis remains poor with a 5-year survival rate of less than 20% [2,3]
Meth-Homeobox A9 (HOXA9) is present in tissue from incurable lung adenocarcinoma but not in non-malignant lung tissue
It may be used as an approach for detecting Circulating tumor-specific DNA (ctDNA)
Summary
Lung cancer causes the largest number of cancer-related deaths worldwide [1], and the prognosis remains poor with a 5-year survival rate of less than 20% [2,3]. Survival may be improved by implementing biomarkers in areas such as screening and treatment monitoring. Circulating tumor-specific DNA (ctDNA) has been suggested as a biomarker in a wide range of malignant tumors. The obvious advantages are the easy access, the overcoming of tumor heterogeneity, the minimal discomfort to the patient, and the possibility of serial measurements. It is most commonly measured in a blood sample, but other body fluids such as urine, sputum, or bronchial lavage fluid have been suggested [4,5,6]. There is no consensus on the best approach to measuring ctDNA, and the method is not yet widely used in routine clinical practice [7,8]
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