title: Clinical correlation of extensive-stage small-cell lung cancer genomics.
abstract: BACKGROUND
  Genomic studies in small-cell lung cancer (SCLC) lag far behind those carried out in nonsmall-cell lung cancer (NSCLC). To date, most SCLC studies have evaluated patients with surgically resectable disease. Here we sought to evaluate the genomic mutation spectrum of 'every-day' SCLC patient tumors with extensive stage disease (ES-SCLC) and to correlate mutations with the main clinical outcomes of response to chemotherapy, progression-free (PFS) and overall (OS) survival.
  
  
  METHODS
  A total of 50 SCLC patient tumors were examined in this study; targeted exome sequencing was obtained on 42 patients and whole-exome sequencing on 8 patients. Mutated genes were correlated with clinical outcomes using Kaplan-Meier methods (PFS, OS) and logistic regression (chemo-response). RB1 protein expression was detected by either western blotting of cultured cell lysates or immunohistochemistry of tumor specimens.
  
  
  RESULTS
  In all, 39 patients had ES-SCLC; 15 patients had either primary refractory/resistant disease and 21 patients had sensitive disease. The two most frequently mutated genes were TP53 (86%) and RB1 (58%); other frequently mutated genes (>10% patients) were involved in epigenetic regulation as well as the mTOR pathway. We identified a number of low-frequency, targetable mutations, including RICTOR, FGFR1, KIT, PTCH1 and RET. Using multivariate analysis, RB1 was the only significant factor (P = 0.038) in predicting response to first-line chemotherapy, with an odds ratio of 5.58 comparing mutant RB1 with wild-type. Patients with mutant RB1 had both better OS (11.7 versus 9.1 months P = 0.04) and PFS (11.2 versus 8.6 months, P = 0.06) compared with patients with wild-type RB1. Interestingly, ∼25% of SCLC cell lines and tumor specimens expressed RB1 protein, possibly representing the subgroup with wild-type RB1.
  
  
  CONCLUSIONS
  We found that SCLC tumors harboring no mutation in RB1 had a poor response to chemotherapy.
authors.affiliation: Division of Hematology and Oncology afshin.dowlati@case.edu.
authors.forename: A
authors.initials: A
authors.lastname: Dowlati
authors.affiliation: Division of Hematology and Oncology.
authors.forename: M B
authors.initials: MB
authors.lastname: Lipka
authors.affiliation: Division of Hematology and Oncology.
authors.forename: K
authors.initials: K
authors.lastname: McColl
authors.affiliation: Division of Hematology and Oncology.
authors.forename: S
authors.initials: S
authors.lastname: Dabir
authors.affiliation: Division of Hematology and Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Behtaj
authors.affiliation: Division of Pathology, Case Western Reserve University and University Hospitals Seidman Cancer Center, Cleveland.
authors.forename: A
authors.initials: A
authors.lastname: Kresak
authors.affiliation: Department of Genetics and Genomic Sciences.
authors.forename: A
authors.initials: A
authors.lastname: Miron
authors.affiliation: Division of Pathology, Case Western Reserve University and University Hospitals Seidman Cancer Center, Cleveland.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: Division of Hematology and Oncology.
authors.forename: N
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Fu
authors.affiliation: Division of Hematology and Oncology.
authors.forename: G
authors.initials: G
authors.lastname: Wildey
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D005260:Female; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics*; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: RB1; TP53; gene mutations; genomic analysis; small-cell lung cancer; survival