title: Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer.
abstract: BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model.
  
  
  
  We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point.
  
  
  
  The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p = 0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p = 0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0-1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p = 0.03) and of death (p = 0.004).
  
  
  
  These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model.
authors.affiliation: Medical Oncology 2 Unit, Istituto Oncologico Veneto I.R.C.C.S, Via Gattamelata 64, 35128, Padova, Italy. laura.bonanno@ioveneto.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonanno
authors.affiliation: Laboratory of translational Oncology, Pangaea Biotech, Sabino de Arana, 5-9, Barcelona, Spain.
authors.forename: Carlota
authors.initials: C
authors.lastname: Costa
authors.affiliation: Medical Oncology Service, Hospital de Sant Pau, Sant Antoni Maria Claret, 167, Barcelona, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Majem
authors.affiliation: Autonomous University of Madrid, Ciudad Universitaria de Cantoblanco, 28049, Madrid, Spain.
authors.forename: Jose-Javier
authors.initials: JJ
authors.lastname: Sanchez
authors.affiliation: Department Obstetrics, Gynecology and Reproduction, Dexeus Universisty Hospital, av Sabino de Arana 5-9, Barcelona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rodriguez
authors.affiliation: Laboratory of translational Oncology, Pangaea Biotech, Sabino de Arana, 5-9, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gimenez-Capitan
authors.affiliation: Laboratory of translational Oncology, Pangaea Biotech, Sabino de Arana, 5-9, Barcelona, Spain.
authors.forename: Miquel Angel
authors.initials: MA
authors.lastname: Molina-Vila
authors.affiliation: Hospital du Cluzeau, 23, rue Larey, Limoges, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Vergnenegre
authors.affiliation: Medical Oncology, General Hospital of Alicante, 11, Baeza, 03010, Alicante, Spain.
authors.forename: Bartomeu
authors.initials: B
authors.lastname: Massuti
authors.affiliation: Medical Oncology 2 Unit, Istituto Oncologico Veneto I.R.C.C.S, Via Gattamelata 64, 35128, Padova, Italy.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Favaretto
authors.affiliation: Cytology and Pathology, Università degli Studi di Padova, Via Gabelli 61, Padova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.affiliation: Medical Oncology Service, Hospital de Sant Pau, Sant Antoni Maria Claret, 167, Barcelona, Spain.
authors.forename: Cinta
authors.initials: C
authors.lastname: Pallares
authors.affiliation: Laboratory of translational Oncology, Pangaea Biotech, Sabino de Arana, 5-9, Barcelona, Spain.|Catalan Institute of Oncology, Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Taron
authors.affiliation: Catalan Institute of Oncology, Barcelona, Spain. rrosell@iconcologia.net.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D020662:Guanine Nucleotide Exchange Factors; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: BRCA1; DNA repair; HERC2; Non-small-cell lung cancer; Platinum; Predictive markers