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L. Boldrini



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    MA02 - RNA in Lung Cancer (ID 377)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      MA02.05 - Distinct Angiogenic microRNA-mRNA Expression Profiles among Subtypes of Lung Adenocarcinoma (ID 5464)

      14:20 - 15:50  |  Author(s): L. Boldrini

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancers and adenocarcinoma (ADC) represents the most common histological type with a heterogeneous pattern of growth classified as lepidic, acinar, papillary, solid, and micropapillary. For ADC there are restricted available therapeutic options except for patients that could benefit from target therapy. A valuable therapeutic strategy is represented by angiogenesis inhibitors such as bevacizumab that has been approved for the treatment of NSCLC patients. However, there are concerns about its treatment-related toxicity and the identification of new reliable biomarkers to stratify patients who can really benefit from antiangiogenic drugs is urgently needed. Using miRNA target prediction tools, we selected and investigated the expression level of a panel of miRNAs togheter with their mRNA target involved in the angiogenesis pathway.

      Methods:
      We designed a custom codeset including probes for six genes (VEGF-A, FLT1, KDR, FLT4, PDGFRa and PDGFRb) and sixteen miRNAs. The expression analysis was performed by the nCounter System® (NanoString Technologies) directly on RNA, enriched of small RNA, purified from the formalin­-fixed and paraffin­-embedded tumor tissues of 80 ADC patients. Of these 25 were predominatly lepidic (31.25%), 24 were predominatly solid (30%), 20 were predominatly acinar (16%), 11 were predominatly papillary (13.75%).

      Results:
      Comparing the expression levels of mRNAs with the different histological ADC subtypes we found a significant higher expression of VEGF-A in papillary than in other subtypes (p=0.02). In contrast PDGFRa and PDGFRb were upregulated in lepidic and downregulated in papillary subtypes (both p=0.03). Among 16 miRNAs that target the angiogenic mRNA, 6 were significantly downregulated in papillary compared to other groups.

      Conclusion:
      Our data suggest a distinct angiogenic miRNA-mRNA expression profile among the subtypes of ADC. The higher level of VEGF-A in papillary than in lepidic subtypes could represent a useful biomarker to stratify patients who can effectively treated with bevacizumab, which is directed against VEGF. Moreover, the regulation of angiogenic mRNA factors by miRNAs could provide a novel therapeutic approach based on their expression pattern specific for distinct ADC subtypes. Further studies are nedeed in a larger cohort of patients to confirm our results and to investigate whether different rates of response to treatment are observed among patients stratified according to the proposed biomarkers.

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    P1.02 - Poster Session with Presenters Present (ID 454)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-078 - Expression Profiling of LKB1 Pathway in Young and Old Lung Adenocarcinoma Patients (ID 5484)

      14:30 - 15:45  |  Author(s): L. Boldrini

      • Abstract
      • Slides

      Background:
      The youthful lung cancer may constitute an entity with distinct clinicopathologic characteristics. The serine/threonine kinase LKB1, also known as Serine/Threonine Kinase 11-STK11, is a known tumor suppressor gene involved in cellular responses such as energy metabolism, cell polarity and cell growth, but the role of LKB1 pathway in lung adenocarcinoma (ADC) is barely studied, especially in young patients

      Methods:
      Fifty lung ADC patients were retrospectively analysed. After RNA purification from formalin fixed and paraffin embedded tumor tissues, we analysed the mRNA expression levels of LKB1 and of genes involved in its pathway, such as cyclin D1 (CCND1), beta catenin (CCNNB1), lysyl oxidase (LOX), yes-associated protein-1 (YAP-1), and survivin, with NanoString technology, a new tool for a more accurate expression profiling. KRAS mutations were investigated by pyrosequencing analysis. Clinicopathologic characteristics and survival analysis were available for all patients.

      Results:
      Patients under 50 years old (including 50) were defined as the younger group and patients above 50 years old were defined as the older group. Among all the clinicopathologic characteristics, in the younger group there were more women, less solid and more acinar adenocarcinoma prevalent pattern in comparison to the older group. Younger and older groups showed similar survival rates, as well as KRAS mutations frequencies. Also, in the comparison between the gene expression level of the analyzed genes and the two different age subgroups,no statistical difference was found. We then focused on the LKB1 pathway in all series, independently from the age stratification, founding LKB1 low expression associated with low cyclin D1 (CCND1) (p<0.0001), beta catenin (CCNNB1) (p<0.0001), and YAP1 (p=0.0024) levels, suggesting a target regulation by LKB1. We next tested the expression level of LOX, one of its downstream target, and we found that lung ADC with a high LOX mRNA expression showed a significantly worse prognosis, either in terms of disease-free interval or overall post-operative survival.

      Conclusion:
      Based on our preliminary results young patients seem to show similar LKB1 pathway expression levels to older group, even if further investigations will be necessary. Moreover, our data suggest LKB1 as a key pathway in lung ADC regardless of age, with a relevant sfavorable role of LOX. A robust assessment of LKB1 and of its downstream gene, LOX in particular, may elucidate the role of this pathway deregulation in lung adenocarcinoma in order to identify potential target for lung cancer therapy.

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-018 - Differential microRNA Expression Profile between Young and Old Lung Adenocarcinoma Patients (ID 5478)

      14:30 - 15:45  |  Author(s): L. Boldrini

      • Abstract
      • Slides

      Background:
      Lung cancer is the leading cause of cancer related mortality and approximately 80% is represented by non-small cell lung cancer (NSCLC). In the last decade, age of patients at diagnosis has decreased, with an incidence of approximately 13.4% in patients under 50 years. Previous studies have hypotesized that lung cancer in young patients could represent a separated clinicalpathological entity, however it is still controversial whether younger patients have a different outcome compared with their older counterparts. MicroRNAs (miRNAs) have recently been defined to play a key role in cancer pathogenesis and their aberrant expression has been suggested as a potential biomarker of prognosis in lung adenocarcinoma. To understand the molecular features of young and old adenocarcinoma patients, we investigated the expression levels of a panel of miRNAs selected from recent literature.

      Methods:
      Thirty-five lung ADC from patients under 50 years old were enrolled as the younger group and thirty-five ADC older than 50 years were collected as the older group. After miRNA isolation from formalin-fixed and paraffin-embedded tumor tissues, the expression levels of 30 miRNAs were analyzed by NanoString technology and compared between the two groups. Survival data were used to assess the prognostic impact of miRNAs. The software miRgator v3.0 was used to predict the putative pathways targeted by miRNAs.

      Results:
      The analysis revealed that 7 miRNAs (miR-25-3p, miR-29c-3p, miR-33a-5p, miR-144-3p, miR-153-3p, miR-342-5p and miR-485-3p) were differently expressed in the two groups (Mann-Whitney U test, p<0.05). All these miRNAs showed higher expression levels in young compared to old patients, and their predicted targets included EGFR, MET, VEGF-A, TP53 and PDGFRa. miR-144-3p had an opposite influence on overall survival, since its upregulation was associated with a better outcome in young patients (p= 0.01) and a worse prognosis in the old group (p= 0.03).

      Conclusion:
      Our study provides new insights about the role of miRNAs in lung adenocarcinoma occurring in young patients. We observed that lung cancer in young and old patients may be influenced by different regulatory mechanisms since we found 7 miRNAs as downregulated in the older group, probably due to distinct age-related genetic and epigenetic alterations. Moreover, one of the deregulated miRNAs showed a different prognostic impact in the two groups thus confirming that young and old patients deserve a specific clinical approach. Further validations are needed to better define if an age-based genomic signature could be used as prognostic marker in lung cancer.

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