An asymptotic theory for model selection inference in general semiparametric problems

Hjort & Claeskens (2003) developed an asymptotic theoryfor model selection, model averaging and subsequent inferenceusing likelihood methods in parametric models, along with associatedconfidence statements. In this article, we consider a semiparametricversion of this problem, wherein the likelihood depends on parametersand an unknown function, and model selection/averaging is tobe applied to the parametric parts of the model. We show thatall the results of Hjort & Claeskens hold in the semiparametriccontext, if the Fisher information matrix for parametric modelsis replaced by the semiparametric information bound for semiparametricmodels, and if maximum likelihood estimators for parametricmodels are replaced by semiparametric efficient profile estimators.Our methods of proof employ Le Cam's contiguity lemmas, leadingto transparent results. The results also describe the behaviourof semiparametric model estimators when the parametric componentis misspecified, and also have implications for pointwise-consistentmodel selectors.     

Chromosome imbalances in oligodendroglial tumors detected by comparative genomic hybridization

Seven well-differentiated oligodendrogliomas, 16 anaplastic oligodendrogliomas and two cases of oligoastrocytomas were investigated by comparative genomic hybridization (CGH) on frozen tissue samples. The most frequent losses found involved 1p and 19q in 32% of cases. Loss of 9p was observed during malignant progression in 25% of anaplastic oligodendrogliomas. In two anaplastic oligodendrogliomas gain of 1q was found. The frequent losses of chromosome 16 and 22 have not been reported previously. These results underscore that CGH is a powerful tool for the classification of gliomas complementing the traditional histopathological approach.     

寡核苷酸阵列比较基因组杂交技术及其应用

阵列-比较基因组杂交技术（array comparative genomic hybridization, array CGH）能在全基因组水平和/或高分辨率基础上检测染色体拷贝数的变化,主要应用于遗传学和肿瘤学研究。Array CGH中微阵列探针通常是PCR扩增的BAC克隆或cDNA分子。最近几年,寡核苷酸阵列比较基因组杂交（oligonucleotide array CGH, oaCGH）逐渐开始应用。oaCGH与BAC array CGH比较,具有操作更简便、探针设计更灵活、分辨率更高等多项优点,预计oaCGH将逐步取代利用BAC克隆片段或cDNA分子的array CGH。oaCGH的应用及其与其它高通量检测技术的结合将促进新的癌症相关基因、肿瘤耐药基因的发现。本文综述了现有主要oaCGH平台在空间分辨率、探针长度、灵敏度、特异性等方面的特点及其应用,概括了oaCGH近年来的进展。     

Differential expansion of highly repeated DNA sequences in the swine subgenomes

Differences in highly repeated DNA sequences among three swine breeds genomes were detected by means of whole‐comparative genomic hybridization (W‐CGH). The results showed that Duroc, Iberian and Landrace/Large White breeds share similar DNA sequences in their centromeric regions, but the number of copies of the highly repeated DNA sequences building the blocks of heterochromatin in the metacentric chromosomes is differentially expanded among them. That is not the case in the acrocentric subgenome where the chromosomes share similar sequence composition and number of copies among the three breeds in the centromeric regions. The highly repeated DNA sequences in the chromosome Y also displayed differences among the breeds studied. The reported results are discussed in the light of the possible evolutionary tendencies of these particular DNA sequences.     

Biological significance of chromosomal imbalance aberrations in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Current criteria for the diagnosis of malignant GISTs do not always reliably predict patient outcomes. In order to search for genetic markers with prognostic potential, chromosomal imbalance aberrations (CIAs) were analyzed in 28 subjects with GIST using comparative genomic hybridization and correlated with clinicopathological features. Except for a small rectal tumor, CIAs were identified in all GISTs, including 14 from the stomach, 11 from the small intestine, 1 from the esophagus, and 1 from the rectum. Losses were more common than gains. The median number of CIAs in high-risk GISTs was significantly higher than that in low-risk GISTs (5.60±2.59 vs. 3.38±2.55; p<0.05), especially for losses (4.60±1.84 vs. 2.63±2.13; p<0.01). Loss of 14q was the most common CIA in both low-risk and high-risk GISTs, and can be regarded as an early event of GIST development. Losses of 1p and 15q were also very common, often coexisting, and were slightly more frequent in high-risk GISTs than in low-risk GISTs. Other recurrent CIAs, including losses of 10q, 13q, 15q, 18q, and 22q and gains of 5p, 12q, 17q, and 20q were relatively less common in this series. Among these CIAs, losses of 13q, 10q (with minimal overlapping on q11–q22), and 22q were most likely the chromosomal loci potentially harboring the tumor suppressor gene(s) which may be related to early recurrence and/or metastasis during malignant transformation of GISTs.     

西瓜与近缘种亲缘关系的比较基因组原位杂交分析

物种间亲缘关系的研究是杂交育种的理论基础,野生西瓜在西瓜育种中具有重要作用,然而目前对西瓜属物种间亲缘关系的研究十分有限,而且对西瓜属物种的分类问题还存在分歧.比较基因组原位杂交是分析物种间亲缘关系的有效手段,本研究以西瓜基因组DNA作探针,分别对缺须西瓜、热迷西瓜、药西瓜和诺丹西瓜有丝分裂中期染色体进行了比较基因组原位杂交分析,揭示了西瓜属物种间的亲缘关系,同时对分类地位尚存在争议的诺丹西瓜的归属问题进行了分析,发现诺丹西瓜和甜瓜之间具有非常近的亲缘关系,本研究结果为西瓜与近缘种间的远缘杂交提供了重要的理论依据.     

Genomic imbalances associated with methotrexate resistance in human osteosarcoma cell lines detected by comparative genomic hybridization-based techniques

Methotrexate (MTX) is one of the most important drugs for osteosarcoma (OS) treatment. To identify genetic aberrations associated with the development of MTX resistance in OS cells, in addition to the previously reported expression changes of dihydrofolate reductase (DHFR) and reduced folate carrier (RFC) genes, comparative genomic hybridization (CGH)-based techniques were used. The direct comparison between MTX-resistant variants of U-2OS or Saos-2 human OS cell lines with their respective parental cell lines by CGH on chromosomes revealed that development of MTX resistance was associated with gain of the chromosomal regions 5q12-q15 and 11q14-qter in U-2OS variants, and with gain of 8q22-qter in Saos-2 variants. Further analyses by CGH on microarrays demonstrated a progressively increasing gain of mixed lineage leukemia (MLL) gene (11q23) in U-2OS MTX-resistant variants, which was also confirmed by fluorescence in situ hybridization (FISH), in addition to gain of FGR (1p36), amplification/overexpression of DHFR, and slight decrease of RFC expression. In Saos-2 MTX-resistant variants, gain of MYC (8q24.12-q24.13) was detected, together with a remarkable decrease of RFC expression. Further analyses of DHFR, MLL, MYC, and RFC gene status in four additional human OS cell lines revealed that only gain of DHFR and MLL were associated with an inherent lower sensitivity to MTX. These data demonstrate that genetic analyses with complementary techniques are helpful for the identification of new candidate genes, which might be considered for an early identification of MTX unresponsive tumors.     

Comparison of Established Cell Lines at Different Passages by Karyotype and Comparative Genomic Hybridization

Two established cancer cell lines, MCF-7 and Ishikawa, were both obtained directly from a cell repository and through another laboratory. The karyotypes from the two MCF-7 cell lines had up to 83 chromosomes and similarities for chromosomal gain and structural abnormalities. The two Ishikawa cell lines had up to 60 chromosomes with only a missing X as the common chromosome abnormality. CGH studies were performed by co-hybridizing the two Ishikawa or MCF-7 cell lines to normal metaphases. The differences seen between the two MCF-7 cell cultures reflect changes due to passage number and culture conditions. For Ishikawa, DNA polymorphic data and mutation studies suggest that the two cell lines are not derived from the same established tumor cell line. Our study shows the utilization of CGH in comparing cell lines originating from the same specimen. Our study also demonstrates the necessity for periodically evaluating cell lines to confirm their origin.     

CGcgh: a tool for molecular karyotyping using DNA microarray-based comparative genomic hybridization (array-CGH)

Microarray-based comparative genomic hybridization (array-CGH) is a technique by which variations in copy numbers between two genomes can be analyzed using DNA microarrays. Array CGH has been used to survey chromosomal amplifications and deletions in fetal aneuploidies or cancer tissues. Herein we report a user-friendly, MATLAB-based, array CGH analyzing program, Chang Gung comparative genomic hybridization (CGcgh), as a standalone PC version. The analyzed chromosomal data are displayed in a graphic interface, and CGcgh allows users to launch a corresponding G-banding ideogram. The abnormal DNA copy numbers (gains and losses) can be identified automatically using a user defined window size (default value is 50 probes) and sequential student t-tests with sliding windows along with chromosomes. CGcgh has been tested in multiple karyotype-confirmed human samples, including five published cases and trisomies 13, 18, 21 and X from our laboratories, and 18 cases of which microarray data are available publicly. CGcgh can be used to detect the copy number changes in small genomic regions, which are commonly encountered by clinical geneticists. CGcgh works well for the data from cDNA microarray, spotted oligonucleotide microarrays, and Affymetrix Human Mapping Arrays (10K, 100K, 500K Array Sets). The program can be freely downloaded from . Y. S. Lee and A. Chao contributed equally to this work.