PMID- 22705117
OWN - NLM
STAT- MEDLINE
DCOM- 20121221
LR  - 20220410
IS  - 1872-8332 (Electronic)
IS  - 0169-5002 (Linking)
VI  - 77
IP  - 3
DP  - 2012 Sep
TI  - Multiparametric molecular characterization of pulmonary sarcomatoid carcinoma 
      reveals a nonrandom amplification of anaplastic lymphoma kinase (ALK) gene.
PG  - 507-14
LID - 10.1016/j.lungcan.2012.05.093 [doi]
AB  - BACKGROUND: Genetic alterations for targeting therapy are largely unexplored 
      issues in pulmonary sarcomatoid carcinoma (PSC), a life-threatening tumor subset. 
      METHODS: EGFR, HER2, KRAS, p53, CTNNB1, BRAF and PIK3CA mutations were assessed 
      by direct sequencing, ALK, EGFR and HER2 gene status by fluorescence in situ 
      hybridization (FISH), and ALK protein expression by immunohistochemistry (IHC) in 
      20 pleomorphic carcinomas (PLC), two pulmonary blastomas (PB) and one 
      carcinosarcoma (CS). Surgical specimens and, in case of positivity, the 
      corresponding preoperative biopsies were analyzed. Furthermore, 51 consecutive 
      metastatic lung adenocarcinomas (MELAD) were used as controls for FISH and IHC 
      assays of ALK gene. RESULTS: While no rearrangements of ALK were detected in PSC, 
      relevant amplification was identified 5/23 (22%) surgical specimens and paired 
      biopsies (four PLC and one PB, two females and three males, four current and one 
      never smoker, aged 30-83 years). Considering tumor heterogeneity, the percentage 
      of ALK amplified tumor cells ranged from 11% to 43%, with a mean gene copy gain 
      (GCG +/- SD) of 6.9 +/- 0.8 and no signal differences between the epithelial (6.5 +/- 
      0.9) and the sarcoma-like components (6.8 +/- 0.9) of tumors. In the remaining 18 
      non-amplified PSC, the relevant value was 2.9 +/- 0.5 in 1-80% tumor cells 
      (p<0.001). ALK amplification was closely associated with chromosome 7 (EGFR) or 
      17 (HER2) polysomy (p<0.001). Out of 51 MELAD, 10 were ALK-rearranged (p=0.026) 
      and only one amplified (p=0.009). No amplified tumors, either PSC or MELAD, 
      expressed the relevant protein by IHC, while the 10 ALK-rearranged MELAD were 
      strongly positive. TP53, KRAS and CTNNB1 mutations accounted for 30%, 22%, and 4% 
      of cases, respectively, with no significant relationship with ALK amplification. 
      No mutations for EGFR, HER2, BRAF or PIK3CA gene were observed. CONCLUSION: ALK 
      gene amplification is a nonrandom and clonally related event in a subset of PSC, 
      but its biologic rationale deserves further investigation. KRAS mutation could 
      represent a novel tool for therapy of such so deadly tumors with MEK inhibitors.
CI  - Copyright (c) 2012 Elsevier Ireland Ltd. All rights reserved.
FAU - Pelosi, Giuseppe
AU  - Pelosi G
AD  - Department of Pathology and Laboratory Medicine, Fondazione IRCCS National Cancer 
      Institute, Milan, Italy. giuseppe.pelosi@unimi.it
FAU - Gasparini, Patrizia
AU  - Gasparini P
FAU - Cavazza, Alberto
AU  - Cavazza A
FAU - Rossi, Giulio
AU  - Rossi G
FAU - Graziano, Paolo
AU  - Graziano P
FAU - Barbareschi, Mattia
AU  - Barbareschi M
FAU - Perrone, Federica
AU  - Perrone F
FAU - Barberis, Massimo
AU  - Barberis M
FAU - Takagi, Masayuki
AU  - Takagi M
FAU - Kunimura, Toshiaki
AU  - Kunimura T
FAU - Yamada, Tetsuya
AU  - Yamada T
FAU - Nakatani, Yukio
AU  - Nakatani Y
FAU - Pastorino, Ugo
AU  - Pastorino U
FAU - Scanagatta, Paolo
AU  - Scanagatta P
FAU - Sozzi, Gabriella
AU  - Sozzi G
FAU - Garassino, Marina
AU  - Garassino M
FAU - De Braud, Filippo
AU  - De Braud F
FAU - Papotti, Mauro
AU  - Papotti M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120616
PL  - Ireland
TA  - Lung Cancer
JT  - Lung cancer (Amsterdam, Netherlands)
JID - 8800805
RN  - EC 2.7.10.1 (ALK protein, human)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anaplastic Lymphoma Kinase
MH  - Carcinoma, Non-Small-Cell Lung/enzymology/*genetics/therapy
MH  - DNA Mutational Analysis
MH  - Female
MH  - *Gene Amplification
MH  - Gene Expression
MH  - Genetic Association Studies
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Lung Neoplasms/enzymology/*genetics/therapy
MH  - Male
MH  - Middle Aged
MH  - Receptor Protein-Tyrosine Kinases/*genetics/metabolism
EDAT- 2012/06/19 06:00
MHDA- 2012/12/22 06:00
CRDT- 2012/06/19 06:00
PHST- 2012/02/16 00:00 [received]
PHST- 2012/04/28 00:00 [revised]
PHST- 2012/05/03 00:00 [accepted]
PHST- 2012/06/19 06:00 [entrez]
PHST- 2012/06/19 06:00 [pubmed]
PHST- 2012/12/22 06:00 [medline]
AID - S0169-5002(12)00311-X [pii]
AID - 10.1016/j.lungcan.2012.05.093 [doi]
PST - ppublish
SO  - Lung Cancer. 2012 Sep;77(3):507-14. doi: 10.1016/j.lungcan.2012.05.093. Epub 2012 
      Jun 16.