Unbalanced translocation, a major chromosome alteration causing loss of heterozygosity in human lung cancer

Ogiwara, Hideaki; Nakanishi, Hirofumi; Nagayama, Kazuhiro; Sato, Masanori; Yokota, Jun

doi:10.1038/onc.2008.113

Cited by 36 publications

(30 citation statements)

References 37 publications

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“…Thus, AI regions were defined by the criterion of containing at least six consecutive AI loci. Under the same criterion and by combination of SNP array data with spectral karyotyping and arraycomparative genomic hybridization data, 1 of 13 (7.7%) trisomic chromosomes was judged as AI, and 14 of 215 (6.5%) AI regions were due to amplification/gain of one allele in our recent study (22). Therefore, one of allelic chromosomal segments was likely to be lost in most (>90%) of AI regions defined in this study.…”

Section: Methodsmentioning

confidence: 99%

Whole Genome Comparison of Allelic Imbalance between Noninvasive and Invasive Small-Sized Lung Adenocarcinomas

Nakanishi

Matsumoto

Iwakawa³

et al. 2009

Cancer Research

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Seventy-two small-sized (V2 cm in diameter) lung adenocarcinomas consisting of 15 noninvasive and 57 invasive tumors were subjected to whole genome allelic imbalance (AI) scanning and mutational analysis of the EGFR, KRAS, and TP53 genes to elucidate genetic pathways of early-stage lung adenocarcinomas. The chromosome 13q13 region showed the most frequent AI (58%) and was affected at similar frequencies between noninvasive and invasive tumors (53% and 60%, respectively), as EGFR and KRAS mutations were. The number of AI regions as well as the frequency of TP53 mutations in invasive tumors was significantly higher than those in noninvasive ones [9.8 F 5.6 versus 4.8 F 2.8 (P = 0.00002) and 61% versus 13% (P = 0.001), respectively]. In particular, AIs at the chromosome 11p11-p12, 17p12-p13, and 18p11 regions in invasive tumors were significantly more frequent than those in noninvasive ones (P < 0.01). The results indicated that noninvasive tumors were developed by EGFR, KRAS, and 13q alterations and progressed to invasive ones by subsequent alterations of several tumor suppressor genes, including those on 11p11-p12, 17p12-p13, and 18p11 and TP53. AI at 8p21 was significantly more frequent in advanced stages (>IA) and associated with worse prognoses (P = 0.04) and, thus, would be involved in invasion and/or metastasis of adenocarcinoma cells and useful for the prediction of prognosis of patients with small-sized lung adenocarcinoma.

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Section: Methodsmentioning

confidence: 99%

Whole Genome Comparison of Allelic Imbalance between Noninvasive and Invasive Small-Sized Lung Adenocarcinomas

Nakanishi

Matsumoto

Iwakawa³

et al. 2009

Cancer Research

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“…The development of high-density SNP genotyping technology for genomic profiling represents a further advance, because simultaneous measurement of both signal intensity variations and changes in allelic composition makes it possible to detect both copy number changes and copy-neutral LOH events (30). This is particularly important, because copy-neutral LOH is receiving greater attention as a mechanism of possible tumor initiation (4)(5)(6)(7)(8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that acquired UPD is frequently encountered in hematologic malignancies (4)(5)(6)(7). In some studies, acquired UPD has also been observed in solid tumors (8)(9)(10), indicating that UPD can occur not only in familial diseases but also in acquired sporadic tumors. However, our knowledge about acquired UPD regions in sporadic tumors is still very limited.…”

Section: Introductionmentioning

confidence: 99%

Copy-Neutral Loss of Heterozygosity at the p53 Locus in Carcinogenesis of Esophageal Squamous Cell Carcinomas Associated with p53 Mutations

Saeki¹,

Kitao²,

Yoshinaga³

et al. 2011

Clinical Cancer Research

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Purpose: LOH at the p53 locus has been reported to be associated with esophageal squamous cell carcinogenesis. The aim of this study is to identify potential mechanisms resulting in LOH around the p53 locus in its carcinogenesis.Experimental Design: We investigated 10 esophageal cancer cell lines and 91 surgically resected specimens, examining them for LOH at the p53 locus on chromosome 17. We examined the p53 gene by using microsatellite analysis, comparative genomic hybridization (CGH), FISH, and single-nucleotide polymorphism-CGH (SNP-CGH).Results: In an analysis of specimens by microsatellite markers, a close positive correlation was found between p53 mutations and LOH at the p53 locus (P < 0.01). Although four cell lines were found to be homozygous for p53 mutations, LOH at the p53 locus was not detected by CGH. Among two p53 mutant cancer cell lines and five p53 mutant/LOH cancer specimens analyzed by FISH, both the cell lines and four of the specimens exhibited no obvious copy number loss at the p53 locus. SNP-CGH analysis, which allows both determination of DNA copy number and detection of copy-neutral LOH, showed that LOHs without copy number change were caused by whole or large chromosomal alteration.Conclusions: LOH without copy number change at the p53 locus was observed in p53 mutant esophageal squamous cell carcinomas. Our data suggest that copy-neutral LOH occurring as a result of chromosomal instability might be the major mechanism for inactivation of the intact allele in esophageal squamous cell carcinogenesis associated with p53 mutation.

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“…LOH is the result of genetic and/or environmental variations through genomic instabilities including mitotic nondisjunction and recombination, chromosomal loss, DNA deletion and mutation, gene conversion and translocation [Cavenee et al, 1983;Ogiwara et al, 2008;Yokota et al, 1987]. LOH has been recognized as one of the most frequent chromosomal aberrations in the human genome.…”

Section: Introductionmentioning

confidence: 99%

LOHAS: loss‐of‐heterozygosity analysis suite

Yang

Chang

Huggins

et al. 2011

Genetic Epidemiology

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Detection of loss of heterozygosity (LOH) plays an important role in genetic, genomic and cancer research. We develop computational methods to estimate the proportion of homozygous SNP calls, identify samples with structural alterations and/or unusual genotypic patterns, cluster samples with close LOH structures and map the genomic segments bearing LOH by analyzing data of genome-wide SNP arrays or customized SNP arrays. In addition to cancer genetics/genomics, we also apply the methods to study long contiguous stretches of homozygosity (LCSH) in general populations. The LCSH analysis aids in the identification of samples with complex LCSH patterns indicative of nonrandom mating and/or meiotic recombination cold spots, separation of samples with different genetic backgrounds and sex, and mapping of regions of LCSH. Affymetrix Human Mapping 500K Set SNP data from an acute lymphoblastic leukemia study containing 304 cancer patients and 50 normal controls and from the HapMap Project containing 30 African trios, 30 Caucasian trios and 90 independent Asian samples were analyzed. We identified common gene regions of LOH, e.g., ETV6 and CDKN1B, and identified frequent regions of LCSH, e.g., the region that encompasses the centromeric gene desert region of chromosome 16. Unsupervised analysis separated cancer subtypes and ethnic subpopulations by patterns of LOH/LCSH. Simulation studies considering LOH width, effect size and heterozygous interference fraction were performed, and the results show that the proposed LOH association test has good test power and controls type 1 error well. The developed algorithms are packaged into LOHAS written in R and R GUI.

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Unbalanced translocation, a major chromosome alteration causing loss of heterozygosity in human lung cancer

Cited by 36 publications

References 37 publications

Whole Genome Comparison of Allelic Imbalance between Noninvasive and Invasive Small-Sized Lung Adenocarcinomas

Whole Genome Comparison of Allelic Imbalance between Noninvasive and Invasive Small-Sized Lung Adenocarcinomas

Copy-Neutral Loss of Heterozygosity at the p53 Locus in Carcinogenesis of Esophageal Squamous Cell Carcinomas Associated with p53 Mutations

LOHAS: loss‐of‐heterozygosity analysis suite

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