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Schlintl, V.
Molecular characterization of early (pT1a) pulmonary adenocarcinomas with metastasis
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2016. pp. [OPEN ACCESS]
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Authors Med Uni Graz:
Advisor:: Stacher-Priehse Elvira
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Abstract:: Metastatic lung cancer (with more than 40% adenocarcinomas) represents the most common cause of cancer-related death worldwide, which is why identification of molecular mechanisms for dissemination is pivotal for both early detection and therapeutic intervention. This thesis elucidates carcinogenesis and strategies for metastasis of early pulmonary adenocarcinomas as well as underlying genetic aberrations and methods for their detection. We performed a retrospective molecular analysis of 21surgically resected pT1a pulmonary adenocarcinomas with next-generation sequencing. The samples were split into two groups whereby group A was recurrence-free and group B had developed metastases during the 5-year postsurgical follow-up. Tumor DNA was extracted from FFPE tissue, processed and examined by means of the Ion Proton™ Sequencer with regard to somatic mutations of frequently altered genes (KRAS, EGFR, BRAF, PIK3CA, AKT1, ERBB2, PTEN, NRAS, STK11, MAP2K1, ALK, DDR2, CTNNB1, MET, TP53, SMAD4, FBX7, FGFR3, NOTCH1, ERBB4, FGFR1, FGFR2) included in the Ion AmpliSeq™ Colon and Lung Cancer Research Panel. The number of distinct identified tumor grades and histopathological subtypes was balanced between group A and B. The tumor cell proportion accounted for 55% in group A and for 78.5% in group B. Within both groups following mutations were detected: EGFR, KRAS, PIK3CA, PTEN, STK11, TP53 and ß-catenin, whereby 6 samples showed no mutations. PIK3CA, PTEN and ß-catenin were detected in group A exclusively, whereas STK11 was only present within group B. EGFR, KRAS and TP53 were found in both groups. Our results exclude PIK3CA, PTEN and ß-catenin as potential driver mutations for metastasis of early pulmonary adenocarcinomas and strongly recommend STK11 as candidate gene. TP53 seems to a play a crucial role as co-mutation.