Identification of molecular signatures associated with early relapse after complete resection of lung adenocarcinomas
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ABSTRACT:
PROVIDER: PRJNA548775 | ENA |
REPOSITORIES: ENA
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Project description:The study comprised 97 patients with totally resected stage IA-IIIA lung adenocarcinoma. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years.
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Project description:The only potentially curative treatment for lung adenocarcinoma patients remains complete resection of early-stage tumors. However, many patients develop recurrence and die of their disease despite curative surgery. Underlying mechanisms leading to establishment of systemic disease after complete resection are mostly unknown. We therefore aimed at identifying molecular signatures of resected lung adenocarcinomas associated with the risk of an early relapse. The study comprised 89 patients with totally resected stage IA-IIIA lung adenocarcinomas. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years. Patients were clinically and molecular pathologically characterized. Tumor tissues were immunohistochemically analyzed for the expression of Ki67, CD45, CD4, CD8, PD1, PD-L1, PD-L2 and CD34, by Nanostring nCounter PanCancer Immune Profiling Panel as well as a comprehensive methylome profiling using the Infinium MethylationEPIC BeadChip. We detected differential DNA methylation patterns as well as significantly differentially expressed genes associated with an early relapse after complete resection. Especially, CD1A was identified as a potential biomarker, whose reduced expression is associated with an early relapse. These findings might help to develop biomarkers improving risk assessment and patient selection for adjuvant therapy as well as establish novel targeted therapeutic strategies.
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Project description:Identification of genes up-regulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. To elucidate molecular characteristics of lung adenocarcinomas (ADCs) with ALK mutations and those without EGFR, KRAS and ALK mutations, 226 primary lung ADCs of pathological stage I-II, examined for the status of EGFR, KRAS and ALK mutations, were subjected to genome-wide expression profiling, and genes up-regulated in lung ADCs with ALK mutations and those without EGFR, KRAS and ALK mutations were identified. One hundred and seventy-four genes, including ALK, were selected as being up-regulated specifically in 79 lung ADCs without EGFR and KRAS mutations. These 79 cases were divided into: 11 cases of ALK-positive ADCs, 36 cases of group A triple-negative ADCs, and 32 cases of group B triple-negative ADCs, by unsupervised clustering according to the expression of the 174 genes. In ALK-positive ADCs, 30 genes, including ALK itself and GRIN2A, were significantly overexpressed. Group A triple-negative ADC cases showed significantly worse prognoses for relapse and death than ADC cases with EGFR, KRAS or ALK mutations and group B triple-negative ADC cases. Nine genes were identified as being significantly up-regulated in group A triple-negative ADC cases and critical for predicting their prognosis. The nine genes included DEPDC1, which had been identified as a candidate diagnostic and therapeutic target in bladder and breast cancers. Genes discriminating this group of ADCs will be useful for selection of patients who will benefit from adjuvant chemotherapy after surgical resection of stage I-II triple-negative ADCs and also informative for the development of molecular targeting therapies for these patients. Expression profiles in of 226 lung adenocarcinomas (127 with EGFR mutation, 20 with KRAS mutation, 11 with EML4-ALK fusion and 68 triple negative cases).
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