Involvement of multiple developmental genes on chromosome 1p in lung tumorigenesis.
Lung cancer is the leading cause of cancer death in North America. Despite advances in lung cancer treatment, the overall 5 year survival rate for those diagnosed with the disease is bleak presumably due to the late stage of diagnosis. Owing to the difficulty of early detection, preneoplastic specimens are rare. However, studying both preinvasive and invasive stages of disease is necessary to fully understand lung cancer progression. Aberration of chromosome arm 1p is common in lung and other cancers. In this study, we used a genomic array with complete tiling coverage of 1p to profile preinvasive and invasive squamous non-small cell lung carcinoma samples. With this technology, multiple novel submegabase alterations were identified. Three of the 1p alterations harbored genes belonging to gene families known to be involved in cancer development through either the Wnt or the Notch developmental pathways. Our finding of a 0.4 Mb amplified region at 1p36.12 containing WNT4 in preinvasive lung cancer, coupled with the identification of three additional alterations in invasive tumors that also contain genes related to the Notch and Wnt pathways, strongly suggests an intricate role of these pathways in early and late stages of lung cancer development. Furthermore, ectopic expression of DVL1, LRP8 and Notch2 in malignant lung tissue validates the biological impact of these genetic alterations. Importantly, this implication of pathways known only to be activated in fetal lung development lends support to the proposed model of lung cancer ontology whereby tumors arise from dysregulated pleuripotent stem cells.
Garnis
Cathie
C
British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada. cgarnis@bccrc.ca
Campbell
Jennifer
J
Davies
Jonathan J
JJ
Macaulay
Calum
C
Lam
Stephen
S
Lam
Wan L
WL
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D000072261:Dishevelled Proteins; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D026502:LDL-Receptor Related Proteins; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins; D060528:Wnt4 Protein
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; D026502:LDL-Receptor Related Proteins; C497764:NOTCH2 protein, human; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C098773:low density lipoprotein receptor-related protein 8