Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH

Lindholm, Pamela; Salmenkivi, Kaisa; Vauhkonen, Hanna; Nicholson, Andrew G.; Anttila, Sisko; Kinnula, Vuokko L.; Knuutila, Sakari

doi:10.1159/000109618

Cited by 62 publications

(40 citation statements)

References 62 publications

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“…In two recent array comparative genomic hybridization studies on mesothelioma patient samples, 3 of 26 and 3 of 17 tumors showed CNA at 9q. Notably, three of those cases harbored losses initiating at 9q33.1 (31,32). Furthermore, asbestos has previously been shown to cause specific breaks at the centromeric region of chromosome 9 in amniotic fluid cells (6).…”

Section: Chromosomal Microsatellitementioning

confidence: 94%

“…DBC1 has been found to be downregulated by hypermethylation or loss in early stages of several other types of cancer (27 -29). CNA at 9q have been reported in 10% to 15% of mesotheliomas, a cancer type strongly associated with asbestos exposure (30,31). In two recent array comparative genomic hybridization studies on mesothelioma patient samples, 3 of 26 and 3 of 17 tumors showed CNA at 9q.…”

Section: Chromosomal Microsatellitementioning

confidence: 99%

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Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer

Nymark

Kettunen²,

Aavikko³

et al. 2009

Clinical Cancer Research

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Purpose: Asbestos causes DNA damage and the fibers, together with tobacco smoke, have a synergistic effect on lung cancer risk. We recently identified 18 chromosomal regions that showed differences in DNA copy number between the lung tumors of asbestos-exposed and nonexposed patients. One of the previously identified asbestos-associated chromosomal regions at 9q was further analyzed for allelic imbalance and DNA copy number alterations (CNA) in the lung tumors of asbestos-exposed and nonexposed patients. In addition, the ploidy level of the tumors was studied. Experimental Design: Allelic imbalance was analyzed at 9q31.3-34.3 with 15 microsatellite markers in 52 lung tumor samples from asbestos-exposed and nonexposed patients. CNA at 9q32-34.3 were characterized by fluorescent in situ hybridization (FISH) with six bacterial artificial chromosome probes in 95 lung tumors. The ploidy level was analyzed in 100 lung tumors with FISH using three to five centromere probes. Results: Allelic imbalance at 9q31.3-q34.3 was found in all asbestos-exposed patient tumors (100%, 17 of 17) compared with 64% (14 of 22) in the nonexposed cases (P = 0.005). The most significant difference was detected at 9q33.1 (P = 0.002). FISH results showed that also CNA were more frequent at 9q33.1in the three major histologic types of non^small-cell lung tumors of exposed patients, and the association showed a dose-dependent trend (P = 0.03). Furthermore, we detected more frequent polyploidy among the exposed (48%, 28 of 58) than among the nonexposed (29%, 12 of 42) patient tumors (P < 0.05). Conclusions:These results provide a basis for the development of a method to identify asbestos-related lung cancer on a molecular level.

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Section: Chromosomal Microsatellitementioning

confidence: 94%

Section: Chromosomal Microsatellitementioning

confidence: 99%

Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer

Nymark

Kettunen²,

Aavikko³

et al. 2009

Clinical Cancer Research

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“…MM CN analyses using whole-genome aCGH and SNP arrays revealed the presence of occasional large genomic deletions (22)(23)(24)(25)(26); however, the presence of smaller deletions [i.e., minute deletions (i.e., <3 kb)] has not been specifically investigated. Deletions in that size range fall in a gray area: they are too large to be reliably detected by NGS and Sanger sequencing and too small to be reliably detected by commercial aCGH.…”

Section: Significancementioning

confidence: 99%

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

Yoshikawa

Emi

Hashimoto-Tamaoki

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

132

128

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We used a custom-made comparative genomic hybridization array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1 (breast cancer 1)-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minute biallelic deletions (<3 kb) in 46 of 251 genes: four were cancer-associated genes: SETD2 (SET domain-containing protein 2) (7 of 33), BAP1 (8 of 33), PBRM1 (polybromo 1) (3 of 33), and SMARCC1 (switch/sucrose nonfermentable-SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily c, member 1) (2 of 33). These four genes were further investigated by targeted next-generation sequencing (tNGS), which revealed sequence-level mutations causing biallelic inactivation. Combined high-density aCGH and tNGS revealed biallelic gene inactivation in SETD2 (9 of 33, 27%), BAP1 (16 of 33, 48%), PBRM1 (5 of 33, 15%), and SMARCC1 (2 of 33, 6%). The incidence of genetic alterations detected is much higher than reported in the literature because minute deletions are not detected by NGS or commercial aCGH. Many of these minute deletions were not contiguous, but rather alternated with segments showing oscillating copy number changes along the 3p21 region. In summary, we found that in MM: (i) multiple minute simultaneous biallelic deletions are frequent in chromosome 3p21, where they occur as distinct events involving multiple genes; (ii) in addition to BAP1, mutations of SETD2, PBRM1, and SMARCC1 are frequent in MM; and (iii) our results suggest that high-density aCGH combined with tNGS provides a more precise estimate of the frequency and types of genes inactivated in human cancer than approaches based exclusively on NGS strategy.

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“…Large-scale molecular studies of MPM have demonstrated tumor heterogeneity at the level of chromosomal abnormalities, gene mutations, epigenetic alterations, and gene expression (3)(4)(5)(6). MPM is characterized by numerous chromosomal abnormalities involving alterations in both chromosome number and structure (7).…”

Section: Introductionmentioning

confidence: 99%

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Reyniès

Jaurand

Renier

et al. 2014

Clinical Cancer Research

129

165

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Purpose: Despite research efforts to develop more effective diagnostic and therapeutic approaches, malignant pleural mesothelioma (MPM) prognosis remains poor. The assessment of tumor response to therapy can be improved by a deeper phenotypical classification of the tumor, with emphasis on its clinicobiological heterogeneity. The identification of molecular profiles is a powerful approach to better define MPM subclasses and targeted therapies.Experimental Design: Molecular subclasses were defined by transcriptomic microarray on 38 primary MPM cultures. A three-gene predictor, identified by quantitative reverse transcription PCR, was used to classify an independent series of 108 frozen tumor samples. Gene mutations were determined in BAP1, CDKN2A, CDKN2B, NF2, and TP53. Epithelial-to-mesenchymal transition (EMT) markers were studied at the mRNA and protein levels.Results: Unsupervised hierarchical clustering on transcriptomic data defined two robust MPM subgroups (C1 and C2), closely related to prognosis and partly to histologic subtypes. All sarcomatoid/desmoplastic MPM were included in the C2 subgroup. Epithelioid MPM were found in both subgroups, with a worse survival prognosis in the C2 subgroup. This classification and its association with histologic subtypes and survival were validated in our independent series using the three-gene predictor. Similar subgroups were found after classification of other MPM series from transcriptomic public datasets. C1 subgroup exhibited more frequent BAP1 alterations. Pathway analysis revealed that EMT was differentially regulated between MPM subgroups. C2 subgroup is characterized by a mesenchymal phenotype.Conclusions: A robust classification of MPM that defines two subgroups of epithelioid MPM, characterized by different molecular profiles, gene alterations, and survival outcomes, was established. Clin Cancer Res; 20(5); 1323-34. Ó2014 AACR.

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Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH

Cited by 62 publications

References 62 publications

Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer

Molecular Alterations at 9q33.1 and Polyploidy in Asbestos-Related Lung Cancer

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

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