SCG3 transcript in peripheral blood is a prognostic biomarker for REST-deficient small cell lung cancer.
OBJECTIVE
Specific markers of circulating tumor cells may be informative in managing lung cancer. Because the RE-1 silencing transcription factor (REST/NRSF) is a transcriptional repressor that is inactivated in neuroendocrine lung cancer, we identified REST-regulated transcripts (CHGA, CHGB, SCG3, VGF, and PCSK1) for evaluation as biomarkers in peripheral blood.


METHODS
Transcripts were screened across lung cancer and normal cell lines. Candidates were assessed by reverse transcription-PCR and hybridization of RNA extracted from the peripheral blood of 111 lung cancer patients obtained at clinical presentation and from 27 cancer-free individuals.


RESULTS
Expression profiling revealed multiple chromogranin transcripts were readily induced on REST depletion, most notably SCG3 was induced >500-fold. The SCG3 transcript was also overexpressed by 12,000-fold in neuroendocrine compared with nonneuroendocrine lung cancer cells. In peripheral blood of lung cancer patients and cancer-free individuals, we found that SCG3 was more tumor-specific and more sensitive than other chromogranin transcripts as a biomarker of circulating tumor cells. Overall, 36% of small cell lung cancer (SCLC) and 16% of non-SCLC patients scored positively for normalized SCG3 transcript. This correlated with worse survival among SCLC patients with limited disease (n = 33; P = 0.022) but not extensive disease (n = 29; P = 0.459). Interestingly, the subcohort of 6 SCLC patients with resistance to platinum/etoposide chemotherapy all scored positively for peripheral blood SCG3 transcript (P = 0.022).


CONCLUSIONS
SCG3 mRNA, a component of the REST-dependent neurosecretory transcriptional profile, provides a sensitive prognostic biomarker for noninvasive monitoring of neuroendocrine lung cancer.
Moss
Adrian C
AC
Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, United Kingdom.
Jacobson
Gregory M
GM
Walker
Lauren E
LE
Blake
Neil W
NW
Marshall
Ernie
E
Coulson
Judy M
JM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D045744:Cell Line, Tumor; D002864:Chromogranins / Q000097:blood*; D016172:DNA Fingerprinting; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000097:blood*; D011379:Prognosis; D012333:RNA, Messenger / Q000097:blood; D055752:Small Cell Lung Carcinoma / Q000097:blood* / Q000188:drug therapy
D014408:Biomarkers, Tumor; D002864:Chromogranins; D012333:RNA, Messenger; C506136:SCG3 protein, human