bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2111: Genomic rearrangements in BRCA1 and BRCA2 loci in Chilean breast cancer families
Authors: Carvallo Pilar , Sánchez Alejandro , Faúndez Paola , Camus Mauricio , Alvarez Manuel 
Published: February 2011

Abstract
Mutations in BRCA1 and BRCA2 are responsible of about 20% of hereditary breast cancer in Chilean families. Studies in breast cancer families from other populations have identified the amplification and/or deletion of one or more exons in these genes, as the cause of the disease. In the present study we determined the presence of these types of alterations in BRCA1 and BRCA2, in 76 Chilean families, non carriers of BRCA1/BRCA2 mutations, by using MLPA analysis (Multiple Ligation-dependent Probe Amplification). We identified 2 different alterations in the BRCA1 gene: in one family 1.6 times amplification of exon 10 was found, and amplification of exons 3, 5 and 6 was detected in 3 families, with ratios 1.5; 5.5 and 4.5. These alterations, confirmed in a second MLPA analysis, have not been previously described in other populations. To validate the MLPA results and to characterize these genomics alterations we performed qPCR, long range PCR and sequencing. Amplification of exon 10 was confirmed by qPCR, but sequencing was not possible due, in part, to the presence of several repeats in the adjacent introns. In the two unrelated patients showing amplification ratios of 5.5 and 4.5 for exons 3, 5 and 6, qPCR results were concordant with amplification of only exon 5. Long range PCR and sequencing of these gene fragments revealed the presence of exon 5 duplicated and contiguous to exon 6. The third unrelated patient showing amplification of exons 3, 5 and 6 with a ratio of 1.4, did not show differences with control DNA in qPCR analysis. This study reveals the necessity to confirm MLPA results with qPCR and/or sequencing of the involved gene fragments to validate exonic amplifications. Financed by Fondecyt 1080595.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2111.
Abstract 212: Targeting p73 as a strategy for enhancing anticancer efficiency of chemotherapeutic drugs to triple-negative human breast cancers
Authors: Yu Weiping , Tiwary Richa , Kline Kimberly , Sanders Bob 
Published: February 2011

Abstract
Successful treatment of p53-mutant, triple-negative breast cancer (TNBC) remains a daunting challenge. Chemotherapeutic drugs such as doxorubicin (DOX) and cisplatin (CDDP) remain the first line treatments for TNBC; however, chemotherapy eventually fails due to acquired drug resistance and toxicity. Therefore, new treatments for overcoming drug resistance and toxicity in TNBC are badly needed. Here we report on the reconstitution of the p53 tumor suppressor pathway in a p53-independent manner via p53 homolog p73 as an exciting possibility for improving cancer therapy in p53 mutant breast cancers. α-TEA, a small bio-active lipid analog of vitamin E, exhibits potent anticancer actions in human breast and murine mammary cancer both in vitro and in vivo. Treatments with combinations of α-TEA plus DOX or CDDP enhances in vitro apoptotic killing of two p53-mutant TNBC cells; namely, MDA-MB-231 and BT-20 cells. Sub-apoptotic doses of α-TEA plus non-apoptotic doses of DOX or CDDP significantly enhanced caspase-8 and 9 mediated apoptosis in both cell lines. The combination treatments enhanced p73 protein expression, enhanced levels of death receptors-5 (DR5), CD95/APO-1 (Fas), pro-apoptotic Bax and Noxa proteins, and reduced pro-survival Bcl-2 protein levels, all of which are p53 regulated genes. The combination treatments induced enhanced levels of phospho-c-Ab1 and JNK, upstream mediators for p73. Furthermore, combination treatments activated Yes-associated protein (Yap), a transcriptional coactivator which has been demonstrated to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Taken together, our data suggest that combination of α-TEA with clinically relevant chemotherapeutic drugs (DOX or CDDP) enhances apoptosis of MDA-MB-231 and BT-20 p53-mutant TNBC cells via p73, and that c-Abl/JNK and Yap may contribute to the enhanced anti-cancer efficacy of the combination treatments. These data provide the rationale for conducting pre-clinic TNBC xenograft studies testing the safety and efficacy of this new therapeutic approach. Supported by DOD concept grant W81XWH-09-1-0564 (Yu).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 212.
Abstract 2124: The analysis of EGFR genetic heterogeneity on mixed adenocarcinoma of the lung
Authors: Tomonaga Nanae , Nakatomi Katsumi , Nakamura Yoichi Nakamura , Ogawara Daiki , Senju Hiroaki , Ikeda Takaya , Yamaguchi Hiroyuki , Doi Seiji , Iida Tetsuya , Hayashi Tomayoshi , Nagayasu Takeshi , Tsukamoto Kazuhiro , Kohno Shigeru 
Published: February 2011

Abstract
Background: The epidermal growth factor receptor thyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, every patient eventually relapse even if the treatment of EGFR-TKIs was effective remarkably. It have been reported a secondary T790M mutation, MET amplification and some mechanisms attribute to the drug resistance. Intratumor EGFR genetic heterogeneity has also been considered as a potential cause of the acquired resistance. We previously reported a patient with mixed adenocarcinoma of the lung that had different EGFR mutations in papillary, acinar and BAC subtypes. In this study, we analyzed EGFR mutations in each histological subtypes of mixed adenocarcinoma after surgery and pre EGFR-TKIs treatment.
Material and Methods: We recruited twelve mixed adenocarcinoma patients who were treated surgical therapy. Tumor cells in different histological subtypes were microdissected from paraffin-embedded surgical specimens with AS LMD system. Genomic DNA was extracted from each sampled area. EGFR mutations, limited to exon19 deletions and L858R mutations, were examined using the simple polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) methods.
Results: Acinar, BAC and papillary sanmples were microdissected from six, ten and eleven tumor tissues. Exon19 deletions and L858R mutation were detected in five and one tissues. From acinar, BAC and papillary samples, one exon19 deletion, two exon19 deletions and three exon19 delitions and one L858R were detected. Out of the six mixed adenocarcinoma, five tissues consisted both mutated and non-mutated cells. Conclusions: Our results indicates that 41% of lung adenocarcinoma with mixed subtypes have intratoumor genetic heterogeneity. EGFR mutations were detected most frequently in papillary samples. There may be some relations between histological subtype and EGFR mutation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2124.
Abstract 2129A: Clinical implications of infrequent BRAF mutation in advanced stage low-grade ovarian serous carcinomas
Authors: Wong Kwong-Kwok , Tsang Yvonne TM , Deavers Michael T. , Mok Samuel C. , Gershenson David M. 
Published: February 2011

Abstract
Serous carcinoma is the most common histologic subtype of epithelial ovarian cancer. Recent evidence strongly suggests that a 2-tier system stratifying serous carcinoma into low-grade and high-grade categories is biologically and clinically relevant. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-borderline-carcinoma sequence. We analyzed 91 ovarian tumor samples for mutations in BRAF, KRAS, and TP53. No TP53 mutations were detected in serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43), but 73% of high-grade serous carcinomas (n = 18) carried a TP53 mutation. BRAF and KRAS mutations together were detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas, only 2% had a BRAF mutation and 19% had a KRAS mutation. The low frequency of BRAF mutations in advanced stage low-grade serous carcinomas suggests that low-grade serous carcinomas are likely derived from serous borderline tumors without BRAF mutations. This hypothesis is further supported by the fact that 2 of the patients with serous borderline tumors without BRAF or KRAS mutations developed recurrent low-grade serous carcinoma 17 and 60 months after the initial diagnosis of a serous borderline tumor. Moreover, it is interesting that 4 of the 8 patients with either BRAF or KRAS mutations have had no evidence of disease after optimal debulking surgery and standard platinum-taxane-based chemotherapy, while patients without mutations are either diseased or alive with recurrent disease. Thus, mutational analysis of BRAF may have prognostic utility in that a finding of a BRAF mutation may suggest a low risk of recurrent low-grade serous carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2129A.
Abstract 213: Combinative treatment for prostate cancer by adenoviral-mediated gene therapy expressing a novel apoptosis gene and chemotherapy
Authors: Lu Yi , Beheshti Ben , Zhang Xiongwen 
Published: February 2011

Abstract
A novel gene, rat pHyde, and its human homologue, hpHyde, have been cloned from prostate cancer cells. Database search and FISH analysis consistently indicated that hpHyde gene localizes at human chromosome 2q14. Protein sequence analysis suggests that hpHyde may be a plasma membrane protein with calcium channel function. hpHyde is differentially expressed in various normal human tissues and organs, suggesting that hpHyde may play roles in development and differentiation. A recombinant adenovirus containing pHyde cDNA gene (AdRSVpHyde) showed significant growth inhibition on human prostate cancer cells, both in vitro and in vivo, through a caspase-3 dependent apoptosis induction. The anti-prostate cancer effects of pHyde in conjunction with chemotherapy agent were analyzed by in vitro and in vivo assays using AdRSVpHyde in combination with DNA damaging chemotherapeutic agent, cisplatin, and docetaxel, respectively. Growth suppression and induction of apoptosis were additively greater in DU145 human prostate cancer cells treated with AdRSVpHyde and cisplatin than either agent alone both in vitro and in vivo. Moreover, AdRSVpHyde and docetaxel also have a similar additively inhibitory effect on DU145 cell growth. Taken together, these results support the potential use of pHyde for prostate cancer gene therapy coupled with chemotherapy to improve therapeutic index. Our results also suggest that pHyde may play important physiological and pathological roles in normal prostate development and prostate carcinogenesis.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 213.
Abstract 2131: Accurate quantitation of absolute allelic copy-numbers in primary solid tumor samples from SNP-array / WGS data reveals patterns of tumor progression
Authors: Carter Scott L. , Getz Gad , Meyerson Matthew L. 
Published: February 2011

Abstract
Genomic imbalances are a hallmark of cancer cells. Genomic regions recurrently gained or lost in many cancer samples often harbor oncogenes or tumor suppressors, making whole-genome characterization of copy-number a widely adopted strategy for the study of cancer
In practice, copy-number analysis is typically performed using techniques such as array-CGH, SNP-array, or whole genome sequencing (WGS) analysis. Because a fixed quantity of DNA is extracted from a tumor sample for each of these methods, the concentration of each genomic locus is dependant on both the fraction of tumor cells and the ploidy (DNA mass) of each tumor cell. Because these quantities are generally unknown, downstream analysis of copy-number changes has been limited to consideration of relative gains/losses.
Here we describe a recently developed computational method capable of accurately inferring the tumor purity, ploidy, and genome-wide absolute allelic copy-numbers from data obtained by either SNP-array (several platforms are supported), or WGS. Validation data comprised of tumor-normal cell-line mixing experiments verify the accuracy of the method.
Application of these methods to large tumor-cohorts allowed for systematic re-assessment of homozygous deletion and LOH in heavily contaminated samples. These results allow for the assessment of preferential allelic deletion or amplification in genomic regions of recurrent copy loss or gain, respectively.
Our data suggest that the distribution of tumor-ploidy is bi-modal for many common epithelial tumor types, with a hypo-diploid subset and a second subset of samples with ploidy ranging from three to five [haploid genomes]. The observed patterns of allelic copy-number are consistent with a model of tumor progression by which high-ploidy samples arose via whole-genome doubling from an intermediate hypo-diploid state. These analyses allow us to define characteristic “early” genomic events in several tumor types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2131.
Abstract 2145: Identification of genomic alterations and integrated gene expression profiles for MSS colon tumors
Authors: Loo Lenora W.M , Tiirikainen Maarit , Cheng Iona , Okimoto Gordon , Lum-Jones Annette , Seifried Ann , Gallinger Steven , Thibodeau Steven N. , Casey Graham , Marchand Loic Le 
Published: February 2011

Abstract
Colon cancer is the result of a multi-step process involving the accumulation of genetic and epigenetic alterations leading to the transformation of normal colon epithelium to adenocarcinoma. Identification of characteristic genetic alterations is of critical importance to increase our understanding of the transformation process. We focused our analysis on the most common molecular sub-type of colon cancers, microsatellite stable (MSS) and CpG island methylator phenotype (CIMP)-negative, to identify characteristic copy number alteration (CNA) events and associated gene expression profiles using high-resolution genome-wide microarrays.
DNA and RNA were extracted from 41 fresh-frozen paired colon tumors and adjacent normal tissue collected by the Colon Cancer Family Registry. Genomic profiles, such as CNAs and loss of heterozygosity (LOH), were identified with the Affymetrix Genome-Wide Human SNP 6.0 array for both tumor and adjacent normal tissue. Gene expression profiles of tumors and adjacent normal tissue were identified with the Affymetrix GeneChip Human Exon 1.0 ST array. Partek Genomics Suite software was used for analysis and data integration.
We identified recurrent (&gt;25%) CNAs in several chromosomal regions: gain in 1q, 7p, 7q, 8q, 13q, 20p, 20q, Xp, Xq and loss in 5q, 8p, 14q, 16p, 17p, 18p, and 18q. In addition, based on the allele information from the SNP arrays, we found a subset of these recurrent CNAs were associated with LOH. Preliminary results from the integration of CNA and gene expression data in tumors indicate that a subset of these recurrent CNAs is associated with the disruption of gene expression. For example, we observed recurrent copy number gain in 8q24.21, the genomic region containing the c-MYC gene, and associated up-regulation of c-MYC gene expression in tumors compared to adjacent normal tissue. In another example, recurrent copy number loss at 5q22.2 was associated with down-regulation of APC gene expression; loss of function of this tumor suppressor is associated with both hereditary and sporadic colon cancer.
This genome-wide characterization of both genomic alterations and gene expression may help identify key genes and pathways that are disrupted in this common molecular subtype of colon cancer. We will present detailed results from this integrated and comprehensive genetic profiling of MSS and CIMP-negative colon cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2145.
Abstract 2147: Molecular allelokaryotyping to identify mechanism of development of Asian chronic lymphocytic leukemia
Authors: Kawamata Norihiko , Ogawa Seishi , Kato Motohiro , Raynauld Sophie , Saitoh Takayuki , Nakahashi Hirotaka , Karasawa Masamitsu , Koeffler H. Phillip 
Published: February 2011

Abstract
Chronic lymphocytic leukemia (CLL) is a common hematological malignancy in western countries. However, this disease is very rare in Asian countries. It is not clear whether the mechanisms of development of CLL in Caucasian and Asian are same. To answer this question, we compared genomic abnormalities in Asian and Caucasian CLL using single-nucleotide-polymorphism genomic microarray (SNP-chip). We analyzed 75 cases of Japanese CLL (Binet stage A: 51 cases, B: 8 cases, C: 16 cases, unknown: 3 cases) using 250-k GeneChip from Affymetrix. We compared these results to 56 cases of Caucasian CLL. Asian CLL had 4 common genomic abnormalities: deletion of 13q14.3 (36 cases, 49 %), trisomy 12 (23 cases, 30 %), abnormalities of 11q (9 cases, 13 %: 7 deletions and 2 uniparental disomy), and abnormalities of 17p (5 cases, 8 %: 4 deletions and 1 uniparental disomy). These 4 common genomic abnormalities were also identified in Caucasian CLL cases. Interestingly, in both racial groups, trisomy 12 and deletion of 13q14.3 were mutually exclusive (p = 0.01). Nevertheless, frequency of trisomy 12 was higher in Japanese CLL cases (23/75 cases, 30 %) than in Caucasian cases (4/56 cases; 7 %) while frequency of deletion of 13q14.3 was comparable in Japanese and Caucasian (49 % and 48 %, respectively). Frequency of deletion of 11q23.1 was similar in both racial groups. Notably, not only did all these cases involve deletion of ATM but always also deleted miR 34b and 34c. Furthermore, one case had a homozygous deletion of 11q22.3 involving caspase 1/4/5 and COP1. Interestingly, all except one CLL case with 11q abnormalities had either deletion or acquired uniparental disomy. Both Asian and Caucasian CLL had a commonly deleted region at 13q14.3 involving miR 15-a and 16-1. Interestingly, one case had two distinct deletions in this region; one involved miR 15-a and 16-1; the other involved Rb1. On close inspection, 36 % of cases with deletion of 13q, had a deletion of Rb1, suggesting that Rb1 might be another target of deletion of 13q. In summary, the new findings of this study are: 1) Genomic abnormalities in Asian and Caucasian CLL were comparable except for a higher frequency of trisomy 12 in Asian CLL; 2)Trisomy 12 and 13q deletions were mutually exclusive suggesting that either lesion can substitute for the other and may involve a common cellular pathway; 3)New CLL genomic abnormalities include deletion of miR 34b and 34c, caspase 1/4/5 and COP1 (11q), and Rb1 (13q).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2147.
Abstract 2157: Is CDK6 the target of amplification at 7q21 in esophageal adenocarcinoma
Authors: Ismail Amin , Zhou Zhongren , Toia Liana , Reveiller Marie , Bandla Santhoshi , Pennathur Arjun , Luketich James , Godfrey Tony 
Published: February 2011

Abstract
Introduction: The cyclin-dependent kinase 6 (CDK6) is a positive regulator of the cell cycle. It binds to D-type cyclins and phosphorylates the pRb tumor suppressor proteins allowing progression through the G1-phase of the cell cycle. Amplification of the 7q21 chromosomal region has been reported in esophageal adenocarcinoma (EAC) and it has been proposed that CDK6 is the key gene targeted by this event. However, overexpression of CDK6 in vitro suppresses proliferation of breast cancer cells and causes nuclear accumulation of pRb2 tumor suppressor protein. Thus, it remains unclear whether amplification and overexpression of CDK6 is truly driving the 7q21 amplicon in EAC.
Methods: For DNA copy number analysis we analyzed genomic DNA from 83 EAC tumors using Affymetrix 6.0 SNP arrays. Protein expression was analyzed in tissue microarrays comprised of 116 independent EAC samples and pre-EAC lesions (15 high grade dysplasia (HGD), 18 low grade dysplasia (LGD), and 283 cases of columnar cell change (CCM)) using a monoclonal antibody against CDK6. CDK6 was overexpressed by stable transfection of OE19, OE33 and Flo1A esophageal cancer cells using CDK6 cDNA under the control of the pCMV promoter.
Results: The microarray DNA copy number analysis showed amplification of the 7q21 region in at least 25% of cases. The minimal amplicon contained CDK6 along with 4 other genes. Immunohistochemistry showed both cytoplasmic and nuclear CDK6 staining in EAC (36, 31.3%), HGD (6, 40.0%), LGD (5, 27.7%), and the CCM (29, 10.2%).
Overexpression of CDK6 in EAC cell lines caused either suppression of proliferation and anchorage independence (OE19 cells) or had no effect on proliferation (OE33 and Flo1A cells). The suppression of proliferation in OE19/CDK6 cells is dependent on the kinase activity of CDK6 as OE19 cells overexpressing a kinase-deficient form of CDK6 proliferate normally. As previously reported in breast cancer cells, pRb2 (p130) tumor suppressor protein is upregulated in OE19/CDK6 cells. The upregulation of pRb2, however, does not seem to account for the hypo-proliferative effect of OE19/CDK6 cells as it is also upregulated in normally proliferative cells that overexpress the kinase-negative form of CDK6.
Conclusion: Although CDK6 is amplified and overexpressed in EAC and its preneoplastic lesions, it does not seem to account for the tumorigenic importance of the 7q21 amplicon. CDK6 overexpression in vitro does not show any mitogenic phenotype in EAC tumor cells. The presence of other genes within the minimal amplicon raises the possibility that one or more of them might drive such a potential.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2157.