Journal of the National Cancer Institute Advance Access originally published online on April 7, 2009
JNCI Journal of the National Cancer Institute 2009 101(8):560-570; doi:10.1093/jnci/djp054
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© The Author 2009. Published by Oxford University Press.
ARTICLES |
Evidence for Common Clonal Origin of Multifocal Lung Cancers
Affiliations of authors: Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN (XW, MW, JNE, TDJ, OWC, SZha, SZhe, DDD, LC); Department of Pathology, Case Western Reserve University, Cleveland, OH (GTM, FWA-K, FO, RE); Department of Pathology, Cordoba University, Cordoba, Spain (AL-B); Institute of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy (RM); Department of Pathology, North China Coal Medical College, Tangshan, China (SZhe); Department of Biostatistics, Yale University, New Haven, CT (HL)
Correspondence to: Liang Cheng, MD, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th St, Clarian Pathology Laboratory Rm 4010, Indianapolis, IN 46202 (e-mail: liang_cheng{at}yahoo.com).
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.
| CONTEXT AND CAVEATS Prior knowledge Whether multifocal lung cancers arise from a single transformed cell whose progeny metastasize to different locations in the lung or occur independently via independent processes leading to transformation of distinct cells at different locations was unknown. Study design Three different methods were used to assess the genetic similarity of distinct tumors from a single patient and thus whether they arose from a single cell. Contribution The concordance of genetic changes in the separate tumors made a strong case for monoclonality of most multifocal lung cancers. Implications The finding suggest that the majority of multifocal malignant tumors do not arise from entirely independent mutational events in separate cells; more study will be required to determine if they arise from a single transformed cell, followed by replication and subsequent metastasis. Limitations The tumors analyzed were predominantly adenocarcinomas, so the results do not necessarily apply to all lung cancer types. From the Editors
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Manuscript received September 22, 2008; revised February 10, 2009; accepted February 16, 2009.
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J Natl Cancer Inst 2009 101: 539.
J Natl Cancer Inst 2009 101: 539.
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  N. Girard, I. Ostrovnaya, C. Lau, B. Park, M. Ladanyi, D. Finley, C. Deshpande, V. Rusch, I. Orlow, W. D. Travis, et al. Genomic and Mutational Profiling to Assess Clonal Relationships Between Multiple Non-Small Cell Lung Cancers Clin. Cancer Res., August 15, 2009; 15(16): 5184 - 5190. [Abstract] [Full Text] [PDF]
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