Evidence for common clonal origin of multifocal lung cancers

J Natl Cancer Inst. 2009 Apr 15;101(8):560-70. doi: 10.1093/jnci/djp054. Epub 2009 Apr 7.


Background: Lung cancer is the most common cause of cancer death in the United States. Multiple anatomically separate but histologically similar lung tumors are often found in the same patient. The clonal origin of multiple lung tumors is uncertain.

Methods: We analyzed 70 lung tumors from 30 patients (23 females and seven males) who underwent surgical resection for lung epithelial tumors, of whom 26 had non-small cell carcinomas and four had carcinoid/atypical carcinoid tumors. All patients had multiple tumors (two to five) involving one or both lungs. Genomic DNA was extracted from paraffin-embedded tissue sections using laser capture microdissection and analyzed for loss of heterozygosity, TP53 mutations, and X-chromosome inactivation status. The percentage (95% confidence interval [CI]) of patients in whom there were concordant patterns of genetic alteration was calculated.

Results: All 30 case subjects showed loss of heterozygosity (LOH) in at least one and at most four of the six polymorphic microsatellite markers. Completely concordant LOH patterns between synchronous and metachronous cancers in individual patients were seen in 26 (87%) of 30 informative patients (95% CI = 75% to 99%). Identical point mutations were present in eight of 10 patients who exhibited TP53 mutation by sequencing. Tumors in 18 (78%) of 23 female patients (95% CI = 67% to 98%) showed identical X-chromosome inactivation patterns. Combining the results of LOH studies, TP53 mutation screening analyses, and X-chromosome inactivation data, we demonstrated that the multiple separate tumors in 23 (77%) of 30 patients (95% CI = 62% to 92%) had identical genetic changes, consistent with monoclonal origin of the separate tumors.

Conclusions: Our data indicate that the great majority of multifocal lung cancers have a common clonal origin and that multifocality in lung cancer represents local and regional intrapulmonary metastasis.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / secondary
  • Carcinoid Tumor / genetics
  • Carcinoid Tumor / secondary
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Chromosomes, Human, X
  • Confidence Intervals
  • DNA, Neoplasm / genetics*
  • Female
  • Humans
  • Laser Therapy
  • Loss of Heterozygosity*
  • Lung Neoplasms / etiology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology*
  • Male
  • Microdissection
  • Microsatellite Repeats
  • Neoplasms, Multiple Primary / genetics
  • Neoplasms, Multiple Primary / pathology
  • Neoplasms, Second Primary / genetics
  • Neoplasms, Second Primary / pathology
  • Point Mutation*
  • Research Design
  • Retrospective Studies
  • Risk Factors
  • Sequence Analysis, DNA
  • Smoking / adverse effects*
  • Tumor Suppressor Protein p53 / genetics*
  • X Chromosome Inactivation*


  • DNA, Neoplasm
  • TP53 protein, human
  • Tumor Suppressor Protein p53