In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 3_Supplement ( 2012-02-01), p. B41-B41
Kurzfassung:
Lung cancer's pathogenesis from normal cell to metastatic disease involves vast and complex genetic alterations. However, a patient's genetic alterations do not completely explain the pathogenic process, for tumors with the same alterations have different features and therapy responses. We hypothesized that differences in ancestral anatomical regions affect pathogenesis and as such would correlate with differences in cancer histology, subtype, and mutations. Anatomical distal and proximal region specimens from normal lungs were collected and assayed by Agilent 44K gene expression microarrays and immunohistochemistry (IHC). 271 surgically extracted lung cancers were assayed by gene expression, IHC, and gene sequencing for EGFR, KRAS, STK11, and TP53. Using the normal lung specimens, a novel classifier was created to assign cancers with an anatomical region using gene expression alone. Cancers classified as distal by gene expression were 84% adenocarcinoma, while 73% of those classified as proximal were squamous cell carcinoma (P & lt;0.001). While this trend of histology and region is consistent with conventional wisdom, our results also suggest that lung cancers retain substantial gene expression from their ancestral anatomical region. Interestingly, the remainder of the cancers that did not follow this trend was explained by our previously described molecular subtypes (1, 2). Of adenocarcinomas classified proximal, 92% were in the Magnoid molecular subtype. Of squamous cell carcinomas classified distal, 60% were in the Secretory molecular subtype. Complementing microarray gene expression, TTF1 IHC protein expression was greater in distal normal specimens compared to proximal. Consistent with distal classification, adenocarcinomas had the greatest TTF1 expression. Of the squamous molecular subtypes, the Secretory subtype exhibited the greatest TTF1 expression, consistent with its distal classification. This Secretory subtype may explain previously reported TTF1-positive squamous cell carcinomas. Finally, gene mutation rates were significantly different between cancers classified as proximal and as distal. EGFR and KRAS mutation rates were greater in distal tumors compared to proximal tumors. In contrast, TP53 mutation rates were greater in proximally classified tumors. These results suggest that ancestral anatomical regions may affect lung cancer pathogenesis by modifying susceptibility to and dependency on different gene mutations. In summary, normal lung anatomical gene expression classifies lung cancers with different histologies, molecular subtypes, and gene mutation rates.
Materialart:
Online-Ressource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.12AACRIASLC-B41
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2012
ZDB Id:
1225457-5
ZDB Id:
2036787-9
