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Following mitochondrial footprints through a long mucosal path to lung cancer.

Dasgupta S, Yung RC, Westra WH, Rini DA, Brandes J, Sidransky D - PLoS ONE (2009)

Bottom Line: These observations shed light on the extent of disease in the airway of smokers traceable through mtDNA mutation.MtDNA mutation could be a reliable tool for molecular assessment of respiratory epithelium exposed to continuous smoke as well as disease detection and monitoring.Functional analysis of the pathogenic mtDNA mutations may be useful to understand their role in lung tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT

Background: Mitochondrial DNA (mtDNA) mutations are reported in different tumors. However, there is no information on the temporal development of the mtDNA mutations/content alteration and their extent in normal and abnormal mucosa continuously exposed to tobacco smoke in lung cancer patients.

Methodology: We examined the pattern of mtDNA alteration (mtDNA mutation and content index) in 25 airway mucosal biopsies, corresponding tumors and normal lymph nodes obtained from three patients with primary lung cancers. In addition, we examined the pattern of mtDNA mutation in corresponding tumors and normal lymph nodes obtained from eight other patients with primary lung cancers. The entire 16.5 kb mitochondrial genome was sequenced on Affymetrix Mitochip v2.0 sequencing platform in every sample. To examine mtDNA content index, we performed real-time PCR analysis.

Principal findings: The airway mucosal biopsies obtained from three lung cancer patients were histopathologically negative but exhibited multiple clonal mtDNA mutations detectable in the corresponding tumors. One of the patients was operated twice for the removal of tumor from the right upper and left lower lobe respectively within a span of two years. Both of these tumors exhibited twenty identical mtDNA mutations. MtDNA content increased significantly (P<0.001) in the lung cancer and all the histologically negative mucosal biopsies except one compared to the control lymph node.

Conclusions/significance: Our results document the extent of massive clonal patches that develop in lifetime smokers and ultimately give rise to clinically significant cancers. These observations shed light on the extent of disease in the airway of smokers traceable through mtDNA mutation. MtDNA mutation could be a reliable tool for molecular assessment of respiratory epithelium exposed to continuous smoke as well as disease detection and monitoring. Functional analysis of the pathogenic mtDNA mutations may be useful to understand their role in lung tumorigenesis.

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Related in: MedlinePlus

MtDNA genetic mutation tree in patient 1.Possible clonal evolution of the lung tumors has been depicted. Each mucosal biopsy (Circled, M1-M5) shared some identical mtDNA mutations (Matched color) along with additional mutations in the heterogeneous mucosal field. The fittest clones emerged in the primary tumors (T1-T2) with the more selective mtDNA mutations (Total 20 mtDNA mutations, 16 were shared between M1-M5 as in Figure 1).
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pone-0006533-g005: MtDNA genetic mutation tree in patient 1.Possible clonal evolution of the lung tumors has been depicted. Each mucosal biopsy (Circled, M1-M5) shared some identical mtDNA mutations (Matched color) along with additional mutations in the heterogeneous mucosal field. The fittest clones emerged in the primary tumors (T1-T2) with the more selective mtDNA mutations (Total 20 mtDNA mutations, 16 were shared between M1-M5 as in Figure 1).

Mentions: It is likely that the biopsies contained heterogeneous patches of cells with clonal alterations acquired by random mitochondrial genetic drift [7]. As in patient 1, most of the clones shared a number of identical mtDNA mutations along with additional mutations necessary for the clonal expansion (Fig. 5). The fittest clones harboring more advantageous mtDNA/nDNA mutations progressed through the mucosa and eventually gave rise to two apparently independent primary tumors that are nevertheless surely linked by identical mtDNA mutations [7], [13]. Detection of all the mucosal mtDNA mutations in both the tumors resected within a span of 2 years strongly supports their clonal origin. Moreover, we have also shown that the two separate tumors from the opposite lungs exhibited multiple identical mtDNA mutations; the odds of this occurrence by chance are vanishingly low. The first tumor probably developed from one of the more dominant clones scattered on the right lung after acquiring the necessary mtDNA/nDNA alterations sufficient to promote tumorigenesis. The second tumor likely developed in the same way on the left lung but acquired nDNA mutational hits several months later or otherwise it could possibly be a pulmonary metastasis. The data from patient 2 also support the extensive clonal spread of mtDNA mutations and subsequent tumor development after acquiring sufficient mtDNA and/or nDNA changes. A high-resolution genome wide analysis of these biopsies and corresponding tumors revealed clonal alteration of a number of key nDNA encoded genes in these patients (Unpublished observation) further supporting this notion. However, due to unavailability, we could not examine the pattern of mtDNA alteration spectrum in a relatively large number of patients.


Following mitochondrial footprints through a long mucosal path to lung cancer.

Dasgupta S, Yung RC, Westra WH, Rini DA, Brandes J, Sidransky D - PLoS ONE (2009)

MtDNA genetic mutation tree in patient 1.Possible clonal evolution of the lung tumors has been depicted. Each mucosal biopsy (Circled, M1-M5) shared some identical mtDNA mutations (Matched color) along with additional mutations in the heterogeneous mucosal field. The fittest clones emerged in the primary tumors (T1-T2) with the more selective mtDNA mutations (Total 20 mtDNA mutations, 16 were shared between M1-M5 as in Figure 1).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2719062&req=5

pone-0006533-g005: MtDNA genetic mutation tree in patient 1.Possible clonal evolution of the lung tumors has been depicted. Each mucosal biopsy (Circled, M1-M5) shared some identical mtDNA mutations (Matched color) along with additional mutations in the heterogeneous mucosal field. The fittest clones emerged in the primary tumors (T1-T2) with the more selective mtDNA mutations (Total 20 mtDNA mutations, 16 were shared between M1-M5 as in Figure 1).
Mentions: It is likely that the biopsies contained heterogeneous patches of cells with clonal alterations acquired by random mitochondrial genetic drift [7]. As in patient 1, most of the clones shared a number of identical mtDNA mutations along with additional mutations necessary for the clonal expansion (Fig. 5). The fittest clones harboring more advantageous mtDNA/nDNA mutations progressed through the mucosa and eventually gave rise to two apparently independent primary tumors that are nevertheless surely linked by identical mtDNA mutations [7], [13]. Detection of all the mucosal mtDNA mutations in both the tumors resected within a span of 2 years strongly supports their clonal origin. Moreover, we have also shown that the two separate tumors from the opposite lungs exhibited multiple identical mtDNA mutations; the odds of this occurrence by chance are vanishingly low. The first tumor probably developed from one of the more dominant clones scattered on the right lung after acquiring the necessary mtDNA/nDNA alterations sufficient to promote tumorigenesis. The second tumor likely developed in the same way on the left lung but acquired nDNA mutational hits several months later or otherwise it could possibly be a pulmonary metastasis. The data from patient 2 also support the extensive clonal spread of mtDNA mutations and subsequent tumor development after acquiring sufficient mtDNA and/or nDNA changes. A high-resolution genome wide analysis of these biopsies and corresponding tumors revealed clonal alteration of a number of key nDNA encoded genes in these patients (Unpublished observation) further supporting this notion. However, due to unavailability, we could not examine the pattern of mtDNA alteration spectrum in a relatively large number of patients.

Bottom Line: These observations shed light on the extent of disease in the airway of smokers traceable through mtDNA mutation.MtDNA mutation could be a reliable tool for molecular assessment of respiratory epithelium exposed to continuous smoke as well as disease detection and monitoring.Functional analysis of the pathogenic mtDNA mutations may be useful to understand their role in lung tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT

Background: Mitochondrial DNA (mtDNA) mutations are reported in different tumors. However, there is no information on the temporal development of the mtDNA mutations/content alteration and their extent in normal and abnormal mucosa continuously exposed to tobacco smoke in lung cancer patients.

Methodology: We examined the pattern of mtDNA alteration (mtDNA mutation and content index) in 25 airway mucosal biopsies, corresponding tumors and normal lymph nodes obtained from three patients with primary lung cancers. In addition, we examined the pattern of mtDNA mutation in corresponding tumors and normal lymph nodes obtained from eight other patients with primary lung cancers. The entire 16.5 kb mitochondrial genome was sequenced on Affymetrix Mitochip v2.0 sequencing platform in every sample. To examine mtDNA content index, we performed real-time PCR analysis.

Principal findings: The airway mucosal biopsies obtained from three lung cancer patients were histopathologically negative but exhibited multiple clonal mtDNA mutations detectable in the corresponding tumors. One of the patients was operated twice for the removal of tumor from the right upper and left lower lobe respectively within a span of two years. Both of these tumors exhibited twenty identical mtDNA mutations. MtDNA content increased significantly (P<0.001) in the lung cancer and all the histologically negative mucosal biopsies except one compared to the control lymph node.

Conclusions/significance: Our results document the extent of massive clonal patches that develop in lifetime smokers and ultimately give rise to clinically significant cancers. These observations shed light on the extent of disease in the airway of smokers traceable through mtDNA mutation. MtDNA mutation could be a reliable tool for molecular assessment of respiratory epithelium exposed to continuous smoke as well as disease detection and monitoring. Functional analysis of the pathogenic mtDNA mutations may be useful to understand their role in lung tumorigenesis.

Show MeSH
Related in: MedlinePlus