PMID- 22014070
OWN - NLM
STAT- MEDLINE
DCOM- 20120131
LR  - 20211020
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 11
DP  - 2011 Oct 20
TI  - Genome wide single cell analysis of chemotherapy resistant metastatic cells in a 
      case of gastroesophageal adenocarcinoma.
PG  - 455
LID - 10.1186/1471-2407-11-455 [doi]
AB  - BACKGROUND: Metastatic progression due to development or enrichment of 
      therapy-resistant tumor cells is eventually lethal. Molecular characterization of 
      such chemotherapy resistant tumor cell clones may identify markers responsible 
      for malignant progression and potential targets for new treatment. Here, in a 
      case of stage IV adenocarcinoma of the gastroesophageal junction, we report the 
      successful genome wide analysis using array comparative genomic hybridization 
      (CGH) of DNA from only fourteen tumor cells using a bead-based single cell 
      selection method from a bone metastasis progressing during chemotherapy. CASE 
      PRESENTATION: In a case of metastatic adenocarcinoma of the gastroesophageal 
      junction, the progression of bone metastasis was observed during a chemotherapy 
      regimen of epirubicin, oxaliplatin and capecitabine, whereas lung-, liver and 
      lymph node metastases as well as the primary tumor were regressing. A bone marrow 
      aspirate sampled at the site of progressing metastasis in the right iliac bone 
      was performed, and single cell molecular analysis using array-CGH of Epithelial 
      Specific Antigen (ESA)-positive metastatic cells, and revealed two distinct 
      regions of amplification, 12p12.1 and 17q12-q21.2 amplicons, containing the KRAS 
      (12p) and ERBB2 (HER2/NEU) (17q) oncogenes. Further intrapatient tumor 
      heterogeneity of these highlighted gene copy number changes was analyzed by 
      fluorescence in situ hybridization (FISH) in all available primary and metastatic 
      tumor biopsies, and ErbB2 protein expression was investigated by 
      immunohistochemistry. ERBB2 was heterogeneously amplified by FISH analysis in the 
      primary tumor, as well as liver and bone metastasis, but homogenously amplified 
      in biopsy specimens from a progressing bone metastasis after three initial cycles 
      of chemotherapy, indicating a possible enrichment of erbB2 positive tumor cells 
      in the progressing bone marrow metastasis during chemotherapy. A similar 
      amplification profile was detected for wild-type KRAS, although more 
      heterogeneously expressed in the bone metastasis progressing on chemotherapy. 
      Correspondingly, the erbB2 protein was found heterogeneously expressed by 
      immunohistochemical staining of the primary tumor of the gastroesophageal 
      junction, while negative in liver and bone metastases, but after three initial 
      cycles of palliative chemotherapy with epirubicin, oxaliplatin and capecetabine, 
      the representative bone metastasis stained strongly positive for erbB2. 
      CONCLUSION: Global analysis of genetic aberrations, as illustrated by performing 
      array-CGH analysis on genomic DNA from only a few selected tumor cells of 
      interest sampled from a progressing bone metastasis, can identify relevant 
      therapeutic targets and genetic aberrations involved in malignant progression, 
      thus emphasizing the importance and feasibility of this powerful tool on the road 
      to more personalized cancer therapies in the future.
FAU - Hjortland, Geir Olav
AU  - Hjortland GO
AD  - Oslo University Hospital, Division for Cancer and Surgery, Department of 
      Oncology, The Norwegian Radium Hospital, Nydalen, N-0424 Oslo, Norway. 
      Geir.Olav.Hjortland@oslo-universitetssykehus.no
FAU - Meza-Zepeda, Leonardo A
AU  - Meza-Zepeda LA
FAU - Beiske, Klaus
AU  - Beiske K
FAU - Ree, Anne H
AU  - Ree AH
FAU - Tveito, Siri
AU  - Tveito S
FAU - Hoifodt, Hanne
AU  - Hoifodt H
FAU - Bohler, Per J
AU  - Bohler PJ
FAU - Hole, Knut H
AU  - Hole KH
FAU - Myklebost, Ola
AU  - Myklebost O
FAU - Fodstad, Oystein
AU  - Fodstad O
FAU - Smeland, Sigbjorn
AU  - Smeland S
FAU - Hovig, Eivind
AU  - Hovig E
LA  - eng
PT  - Case Reports
PT  - Journal Article
DEP - 20111020
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Biomarkers, Tumor)
SB  - IM
MH  - Adenocarcinoma/drug therapy/*genetics/pathology
MH  - Adult
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use
MH  - Biomarkers, Tumor/genetics
MH  - *Comparative Genomic Hybridization
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Esophageal Neoplasms/drug therapy/*genetics/pathology
MH  - *Esophagogastric Junction/pathology
MH  - Fatal Outcome
MH  - Humans
MH  - Male
MH  - Neoplasm Metastasis
MH  - Palliative Care
MH  - *Single-Cell Analysis
MH  - Stomach Neoplasms/drug therapy/*genetics/pathology
MH  - Treatment Outcome
PMC - PMC3208621
EDAT- 2011/10/22 06:00
MHDA- 2012/02/01 06:00
PMCR- 2011/10/20
CRDT- 2011/10/22 06:00
PHST- 2011/06/21 00:00 [received]
PHST- 2011/10/20 00:00 [accepted]
PHST- 2011/10/22 06:00 [entrez]
PHST- 2011/10/22 06:00 [pubmed]
PHST- 2012/02/01 06:00 [medline]
PHST- 2011/10/20 00:00 [pmc-release]
AID - 1471-2407-11-455 [pii]
AID - 10.1186/1471-2407-11-455 [doi]
PST - epublish
SO  - BMC Cancer. 2011 Oct 20;11:455. doi: 10.1186/1471-2407-11-455.