title: Drug-sensitive FGFR3 mutations in lung adenocarcinoma.
abstract: Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin.
  
  
  
  Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models.
  
  
  
  We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations.
  
  
  
  We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.|Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
authors.forename: P
authors.initials: P
authors.lastname: Chandrani
authors.affiliation: Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.|Department of Medical Oncology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: K
authors.initials: K
authors.lastname: Prabhash
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.
authors.forename: R
authors.initials: R
authors.lastname: Prasad
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.
authors.forename: V
authors.initials: V
authors.lastname: Sethunath
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.
authors.forename: M
authors.initials: M
authors.lastname: Ranjan
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.|Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
authors.forename: P
authors.initials: P
authors.lastname: Iyer
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.
authors.forename: J
authors.initials: J
authors.lastname: Aich
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.
authors.forename: H
authors.initials: H
authors.lastname: Dhamne
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.
authors.forename: D N
authors.initials: DN
authors.lastname: Iyer
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.|Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
authors.forename: P
authors.initials: P
authors.lastname: Upadhyay
authors.affiliation: Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.
authors.forename: B
authors.initials: B
authors.lastname: Mohanty
authors.affiliation: AceProbe Technologies Pvt. Ltd, New Delhi, India.
authors.forename: P
authors.initials: P
authors.lastname: Chandna
authors.affiliation: Department of Pathology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: R
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: A
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: V
authors.initials: V
authors.lastname: Noronha
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: V
authors.initials: V
authors.lastname: Patil
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: A
authors.initials: A
authors.lastname: Ramaswamy
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: A
authors.initials: A
authors.lastname: Karpe
authors.affiliation: Department of Pathology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: R
authors.initials: R
authors.lastname: Thorat
authors.affiliation: Small Animal Imaging Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.
authors.forename: P
authors.initials: P
authors.lastname: Chaudhari
authors.affiliation: Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India.
authors.forename: A
authors.initials: A
authors.lastname: Ingle
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Navi Mumbai, India.
authors.forename: A
authors.initials: A
authors.lastname: Choughule
authors.affiliation: Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai,  India.|Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
authors.forename: A
authors.initials: A
authors.lastname: Dutt
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D041681:NIH 3T3 Cells; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C117307:KRAS protein, human; C115711:PD 173074; D011743:Pyrimidines; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D016283:Proto-Oncogene Proteins p21(ras)
keywords: FGFR inhibitors; actionable mutations; fibroblast growth factor receptor 3; lung adenocarcinoma; mass spectrometry; oncogene