Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Robledo, Cristina; Garcı́a, Juan Luis; Caballero, Dolores; Conde, Eulogio; Arranz, Reyes; Flores, Teresa; Grande, Carlos; Rodríguez, José A.; Garcı́a, Ernesto; Sáez, Ana I.; González, Marcos; Gutiérrez, Norma C.; Piris, Miguel Á.; Hernández, Jesús M.

doi:10.1002/cncr.24430

Cited by 29 publications

(27 citation statements)

References 48 publications

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“…In this study, we found no significant correlation between the loss of 6p21.32 (HLA locus) and outcome. Another recurrent aberration in PCNSL was the loss of chromosome 6q (27% to 37%), which seems to occur at a higher rate than in systemic DLBCLs, where a lower frequency has been reported (32,33). We found 3 distinct minimal common deletion regions (MCRs), 6q14.1-16.3, 6q16.3, and 6q21-25.1.…”

Section: Discussionmentioning

confidence: 54%

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

González-Aguilar

Idbaïh

Boisselier

et al. 2012

Clinical Cancer Research

219

171

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Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance.Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n ¼ 29) and whole-exome sequencing (n ¼ 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis.Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P ¼ 0.006 and P ¼ 0.01) and CDKN2A homozygous deletion (P ¼ 0.02 and P ¼ 0.01) were significantly associated with shorter progression-free survival and overall survival.Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-kB signaling pathway, which may be promising targets for future therapeutic strategies.

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Section: Discussionmentioning

confidence: 54%

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

González-Aguilar

Idbaïh

Boisselier

et al. 2012

Clinical Cancer Research

219

171

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“…DCNAs are often associated with aberrant expression of oncogenes and tumor-suppressor genes, and many reports have shown that particular DCNAs are linked with poor prognosis of patients in many kinds of cancers (38,39). The association between DCNAs and outcome after surgery was analyzed by the χ 2 test, and DCNAs of 16 BAC clone regions, including gain of 11 and loss of 5 BAC clone regions, were identified as candidate prognostic markers for OSCC (p<0.01, Table IV).…”

Section: Discussionmentioning

confidence: 99%

Loss of 3p26.3 is an independent prognostic factor in patients with oral squamous cell carcinoma

et al. 2011

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Abstract. Oral squamous cell carcinoma (OSCC) is a common malignancy worldwide and the prognosis for patients with advanced-stage OSCC is particularly poor. To identify DNA copy number aberrations and candidate genes associated with a poor or favorable outcome, we analyzed the genome profiles of OSCC tumors by array-based comparative genomic hybridization (A-CGH). This technique uses DNA microarray technology to detect genomic copy number variations at a higher resolution level than chromosome-based CGH. Fifty patients with primary OSCCs were included in the study. Of these 50 patients, 37 were treated surgically and 13 were treated without surgery and had received irradiation and/or chemotherapy. All samples were analyzed by A-CGH. Gains were detected frequently (>50%) at chromosomal regions 5p15. 33, 7p22.3, 8q21.1-24.3, 9q34.3, 11q13, 16p13.3 and 20q13.3. Losses were frequently detected at 3p22, 3p14 and 4q35.2. High-level gains were recurrently (>10%) detected at each of 5p15, 7p22, 7p11, 8q24, 11q13, 11q22 and 22q11. Gains of 2p25.1, 11p15, 16p13.3, 16q24.3 and 20q13.3 were inversely correlated with nodal metastasis. In 37 of the 50 OSCC patients treated with surgery, gains of 8q12.1-24.22 and losses of 3p26.2-3 were associated with disease-specific survival (p<0.01). Loss of a 0.2 Mb chromosomal region in 3p26.3 was associated with a poor prognostic outcome in the Kaplan-Meier analysis (p<0.01 by the log-rank test). Multivariate analysis revealed that loss of 3p26.3 is an independent prognostic factor (p<0.01) of OSCC. Loss of a 0.2 Mb chromosomal region in 3p26.3 including the CHL1 (cell adhesion molecule with homology to L1CAM1) gene was identified as a novel potential marker for predicting the prognosis of patients with OSCC.

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“…Interestingly, in non-Hodgkin's B-cell lymphomas (NHLs) including Burkitt's lymphoma and DLBCL, recurring deletions and rearrangements of 10q23, which harbors PTEN, are observed in 5%-10% of patients (Butler et al 1999). In addition, the reduction or loss of PTEN expression is often associated with inferior survival (Abubaker et al 2007;Robledo et al 2009). These findings implicate the importance of the PTEN pathway in the progression and prognosis of specific human B-cell malignancies.…”

Section: Mir-17-92 Encodes a Mirna Polycistron That Yields Six Indivimentioning

confidence: 99%

miR-19 is a key oncogenic component of mir-17-92

Olive¹,

Bennett²,

Walker³

et al. 2009

Genes Dev.

565

527

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Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Em-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt-mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis.

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Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Cited by 29 publications

References 48 publications

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Loss of 3p26.3 is an independent prognostic factor in patients with oral squamous cell carcinoma

miR-19 is a key oncogenic component of mir-17-92

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