The blood-borne miRNA signature of lung cancer patients is independent of histology but influenced by metastases
Petra Leidinger
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Christina Backes
Michael Blatt
Andreas Keller
Hanno Huwer
Philipp Lepper
Robert Bals
Eckart Meese
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Department of Human Genetics, Medical School, Saarland University
,
Building 60, Homburg/Saar 66421
,
Germany
Objectives: In our previous studies we reported a panel of 24 miRNAs that allowed discrimination between blood of lung tumor patients independent of the histological subtype and blood of healthy controls with an accuracy of 95.4% [94.9%-95.9%]. Here, we now separately analyzed the miRNA expression in blood of non-small cell lung cancer (NSCLC), including squamous cell lung cancer and adenocarcinoma, and small cell lung cancer (SCLC) patients. Patients and methods: In total, we examined the expression levels of 1,205 miRNAs in blood samples from 20 patients from each of the three histological groups and determined differentially expressed miRNAs between histological subtypes and metastatic and non-metastatic lung cancer. We further determined the overlap of miRNAs expressed in each subgroup with the 24-miRNA signature of lung tumor patients. Results: Based on a raw p-value < 0.05, only 18 blood-borne miRNAs were differentially expressed between patients with adenocarcinoma and with squamous cell lung carcinoma, 11 miRNAs between adenocarcinoma and SCLC, and 2 between squamous cell lung carcinoma and SCLC. Likewise, the comparison based on a fold change of 1.5 did not reveal major differences of the blood-borne miRNA expression pattern between NSCLC and SCLC. In addition, we found a large overlap between the blood-borne miRNAs detected in the three histological subgroups and the previously described 24-miRNA signature that separates lung cancer patients form controls. We identified several miRNAs that allowed differentiating between metastatic and non-metastatic tumors both in blood of patients with adenocarcinoma and in blood of patients with SCLC. Conclusion: There is a common miRNA expression pattern in blood of lung cancer patients that does not allow a reliable further subtyping into NSCLC or SCLC, or into adenocarcinoma and squamous cell lung cancer. The previously described 24-miRNA signature for lung cancer appears not primarily dependent on histological subtypes. However, metastatic adenocarcinoma and SCLC can be predicted with 75% accuracy.
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Background
Lung cancer is worldwide the leading cause of cancer
related deaths in both men and women with estimated
1,608,055 (12.72%) new cases and 1,376,579 (18.2%)
cancer deaths in 2008 ([1] available from: http://globocan.
iarc.fr, accessed on 09/01/2013). Primarily, lung cancer is
divided into two main histological subtypes depending
on their cells of origin. Non-small cell lung cancer
(NSCLC) account for about 80% of all lung cancers and
are further divided by their origin into adenocarcinoma
(Adeno-Ca, about 40%), squamous cell carcinoma (sqCLC,
about 30%) and large cell carcinoma (about 9%). Small cell
lung cancer (SCLC) is far more aggressive than NSCLC
and accounts for about 15% of all lung cancers. The
classification into the different histological lung cancer types
plays a prominent role in clinical management and
prognosis of the disease [2].
As most SCLC have spread to other parts of the body
at the time of diagnosis surgery is often ineffective, but
they respond well to chemotherapy and radiation. For
early stage I and II NSCLCs, surgery is the treatment of
choice. However, as these two stages combined account
for only 25 to 30% of all patients with lung cancer the
most common treatment is systemic therapy (chemo- or
targeted therapy) and/or radiotherapy [3-5]. Among
NSCLCs, adenocarcinoma and squamous cell carcinoma
differ with regards to the clinical management and the
prognosis. Adenocarcinoma are, for example, more likely
to metastasize to the lymph nodes and the brain than
squamous cell lung cancer [6]. Lung cancer diagnosis
and subclassification is normally based on light
microscopic criteria but an accurate diagnosis of histological
lung cancer subtypes is often hampered by small tissue
biopsies and high observer variability [7-9].
Since several years, microRNAs (miRNAs) have shifted
more and more into focus as cancer biomarkers.
MiRNAs are small non-coding RNA molecules that are
involved in many physiological and pathological processes
due to their ability to regulate the expression of most
human genes. In the recent past, it was shown that
miRNAs are tissue specific and suitable to classify human
cancers [10,11]. Especially for lung cancer it was recently
shown that classification of different subtypes due to the
miRNA expression pattern is possible [12-15]. While
these studies were done on lung cancer tissue or cells,
there is an increasing number of investigations on
miRNAs in the circulation as potential biomarkers [16-27].
In our previous studies, we were able to show that
blood-based miRNA expression profiles differentiate
between lung cancer patients, patients with COPD and
healthy individuals [24,2 (...truncated)