bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ki-67 is a Luminal B marker that identifies a high-risk subgroup in hormone receptor positive and node negative breast cancer
Authors: Cheang M. , Voduc D. , Leung S. , Turbin D. , Bernard P. S. , Ellis M. , Mardis E. , Perou C. M. , Nielsen T. O. 
Published: March 2020

10521 Background: Gene expression profiling studies have revealed prognostically significant intrinsic breast cancer subtypes, designated Luminal A, Luminal B, Basal and Her2. Expression of ER and associated genes characterizes the luminal breast cancers. The Lum B subgroup is associated with poor outcome, but we lack immunohistochemical (IHC) markers to distinguish Lum A and Lum B subgroups. MKI67 is one gene known to be highly expressed in Lum B tumors, encoding the Ki-67 protein, a robust marker of cell proliferation. In this study, we perform IHC analysis of Ki-67 in a large breast cancer tissue microarray. Methods: Our patient cohort consists of 2222 consecutive cases of invasive breast cancer referred to the BC Cancer Agency from 1986 to 1992. Archival paraffin tissue blocks were used to construct a tissue microarray that was then stained for Ki-67 using a commercially available mouse monoclonal antibody. Ki-67 staining was scored quantitatively by automated image analysis and a tumor was positive if the percent positive nuclei was >30%’ Results: Of the 2,222 patients, there are 1,437 Luminal tumors as defined by IHC (ER or PR positive). As Her2 positive status is an established marker of poor prognosis, we excluded these tumors from our analysis. Of the remaining tumors, 9% were Ki-67 positive when using a ki-67 cut off of 30% positive nuclei. In survival analysis of patients ER/PR positive and Her2 negative, we found that Ki-67 identifies a population with poor prognosis (10-yr BCSS 60% vs. 80%). In a multivariate Cox regression we found that Ki-67 is independently prognostic. We repeated Cox regression analysis including only node negative patients and again found that Ki-67 is an independent predictor of poor outcome. Conclusions: Ki-67 has prognostic significance on multivariate survival analysis. Hormone receptor positive and node negative status is typically associated with a favorable outcome for breast cancer. However, Ki-67 is able to identify a small, but clinically significant subgroup with a particularly poor outcome. Defining the Luminal B subtype as (ER or PR) positive and (HER2 or Ki-67) positive, results in a subgroup that contains 18% of hormone receptor positive breast cancers with 10-yr BCSS of 61%. No significant financial relationships to disclose.
MC1R variants and melanoma risk: First study on Melan-Cohort
Authors: Soufir N. , Bagait Miss L. , Oudin Miss C. , Wolkenstein P. , Descamps V. , Dupin N. , Lebbé C. , Basset-Seguin N. , Saiag P. , Grandchamp B. 
Published: March 2020

10524 Background: The presence of functional variants of MC1R, has been shown to be associated with melanoma (MM) risk in different populations worldwide. We had previously shown in a first case - control pilot study that MC1R variants were associated the risk of melanoma (MM) in France. Methods: In order to confirm and precise these results on a larger sample, we performed a case-control study with patients from Melan-Cohort, a prospective cohort from the Paris’ region. After signature of informed consents and extraction of blood DNAs, MC1R variants were sought by automatic sequencing in 270 patients (95 familial MM, 54 multiple sporadic MM, and 121 ‘single‘ MM) and in 154 controls sex, age, and ethnic matched. Usual statistical calculations (Chi2, odd ratios, logistic regression) were carried out. Results: MC1R functional variants were present in 73% of the patients versus 43% of controls (p<0.0001). The presence of only one variant was significantly associated with melanoma risk (OR 2.9 [1.88–4.5]), and the presence of two variants doubled the risk (OR, 6.91 [3.33–14.3]). Furthermore, each of the seven variants, RHC (i.e associated with the Red Hair Phenotype; R142H, R151C, R160W, D294H) or non-RHC (V92M, V60L, R163Q) was individually associated with melanoma risk (OR ranging from 2.8 to 14). The frequency of variants was similar in each sub-group of MM examined (familial, multiple sporadic, or ‘single‘). However, RHC variants were significantly more frequent in the familial subgroup (p = 0.0045) and non RHC were significantly more frequent in the “single” MM subgroup (p = 0.0006). In addition, we confirm that the risk related to MC1R largely persisted after stratification on each clinical risk factor: hair and eyes color, skin type, and nevi count. On the other hand, there was no association between the presence of MC1R variant and the histological type of MM, the age at diagnosis, and the Breslow index. Conclusion: Our results confirm the important role of MC1R on melanoma risk in France and this independently of clinical risk factors. Surprisingly, both RHC and non-RHC variants were associated with melanoma risk, but RHC variants have possibly a higher penetrance. Finally, the presence of MC1R variants does not seem to be correlated with the speed of evolution (Breslow index) of melanoma. No significant financial relationships to disclose.
Cluster mir-17–92 is differentially expressed in colon cancer patients and embryonic colon tissue and may contribute to carcinogenesis through E2F1 expression
Authors: Garcia-Foncillas J. , Navarro A. , Bandres E. , Artells R. , Moreno I. , Gel B. , Ibeas R. , Moreno J. , Miguel M. , Gurpide A. , Monzo-Planella M. 
Published: March 2020

10525 Background: Mature microRNAs (miRNA) are small RNA molecules that act as negative regulators of gene expression, either inhibiting mRNA by blocking its translation into protein or destroying it by RNA interference. Many miRNAs participate in essential processes, including normal embryonic development and carcinogenesis. Methods: We have assessed 156 mature miRNAs in colon tissue from eleven 7–12-week human embryos and 44 colorectal human samples. Data were analyzed using TIGR Multiexperiment viewer. Two multivariate permutation test were performed. Potential target genes of differentially expressed miRNAs are evaluated by western blot. Results: 28 miRNAs were expressed in stage I tumor tissue but not in the corresponding normal tissue, and 13 of these 28 miRNAs (46%) were also expressed in embryonic tissue. Sixty-four miRNAs were differentially expressed in stage II tumor tissue, and 29 of these 64 miRNAs (45%) were also expressed in embryonic tissue. Some miRNAs that are active during embryogenesis, such as mir-17–92, miR-181a, miR-181b and miR-181c (linked to HOXA11), and miR-10a (linked to HOXB8)23, are also expressed during tumor growth. The analysis of 156 miRNAs by K-means support revealed two well-differentiated groups: the embryos of 7–8 weeks and those of 9–12 weeks. Lower miRNA expression was also observed in tumor tissue from stage I in comparison with stage II disease (P=0.014). Analysis of potential target genes revealed that cluster mir-17–92 is differentially expressed in colon cancer and embryonic tissue and may contribute to carcinogenesis through E2F1 expression. Conclusions: Our findings indicate that miRNAs expressed during the embryonic development of the human colon are also expressed in colon tumor tissue. During colon organogenesis, miRNA expression is at first high, while cells are still undifferentiated, but expression levels decrease as cells become more differentiated. In contrast, during the development of colorectal cancer, this process is reversed. No significant financial relationships to disclose.
Gene copy numbers of HER family in breast cancer
Authors: Wełnicka-Jaskiewicz M. , żaczek A. , Bielawski K. P. , Jańkiewicz J. , Badzio A. , Olszewski W. , Konopa K. , Rhone P. , Senkus-Konefka E. , Jassem J. 
Published: March 2020

10544 Background: Most clinicopathological analyses of HER alterations in breast cancer were limited to single HER family members. Since the activation of certain HER receptors is possible only as a result of their dimerization, determining the alterations of all four HER genes may be more relevant. The aim of the study was to estimate the frequency of disorders in all four HER genes, and to determine their correlation with the clinical and histological features in breast cancer patients. Methods: Gene copy number (GCN) of ERBB oncogenes was analyzed with double differential PCR (ddPCR) in a consecutive series of 225 breast cancer patients. Statistical analysis was performed with a set of nonparametric tests. Results: Amplifications of HER1, HER2, HER3 and HER4 were detected in 15%, 26%, 10% and 15% of cases respectively, and deletions in 31%, 2%, 2% and 7% cases respectively. Abnormal GCN of at least one, and at least two oncogenes was found in 65% and 31% of the tumors, respectively. Average GCNs of all HER oncogenes significantly correlated with each other. These correlations were particularly high for HER2/HER3, HER2/HER4 and HER3/HER4 (all p<10-8), and were much stronger in N(+) compared to N(-) tumors. HER1 deletions were associated with the lack of progesterone receptor (p=0.03), whereas HER3 and HER4 amplifications were more common in well differentiated tumors (p=0.03 and 0.047 respectively). At univariate analysis disease-free survival (DFS) and overall survival (OS) were related with T and N stage, and HER1 amplification. The multivariate analysis showed that DFS was influenced by T, N and HER1 amplification, whereas OS by T, N and tumor grade. Conclusions: Our results indicate a key role of HER heterodimers in tumor progression and confirm that HER2 is the preferred partner for other HER oncogenes in this process. Deletions of HER1 were associated with unfavourable characteristics, whereas HER3 and HER4 amplifications may be linked with less aggressive phenotypes. No significant financial relationships to disclose.
Leukemic blasts fail to differentiate into mature antigen presenting cells, and may hinder dendritic cell maturation in vitro and in vivo
Authors: Rosenblatt J. , Stone R. , Lenahan C. , Wu Z. , Vasir B. , Bissonnette A. , Galinsky I. , Miller K. , Levine J. D. , Joyce R. , Avigan D. 
Published: March 2020

10556 Background: Dendritic cells (DC) play a key role in the development of tumor specific immune responses. Dendritic cells differentiated from leukemic blasts (LDC) are being explored as a tumor vaccine in AML. We examined the phenotypic and functional characteristics of LDC, the phenotypic characteristics of native DC in AML patients, and the effect of leukemic blasts on the phenotype of DC generated from normal donors. Methods: Leukemia blasts were isolated from peripheral blood of 24 patients with AML. LDC were generated by culturing blasts in the presence of GM-CSF, IL-4 and TNFa for 7 days. The phenotype of circulating DC1 (CD11C+/lin-) and DC2 (CD123+/ lin-) in AML patients was assessed by multichannel FACS analysis. To assess the effect of blasts on DC maturation, adherent mononuclear cells were isolated from normal donors, combined with leukemia cells in a 10:1 ratio, and cultured with GM-CSF, IL-4, and TNFa. Results: LDC demonstrate only modest expression of the costimulatory molecules CD80 and CD86 (mean expression 10% and 32%) and poorly express the maturation marker CD83 (mean expression 4%). Interferon gamma production by autologous T cells was not higher after stimulation with LDC than with blasts. LDC stimlation resulted in a 2 fold increase in both CD4+/CD25+/CD69+ (activated) and CD4+/CD25+/FOXP3+ (regulatory) T cells. Given the inability of leukemia progenitors to differentiate into phenotypically mature DC, we assessed whether leukemia cells directly inhibit differentiation of DC from normal progenitors. Expression of costimulatory molecules was decreased in DC differentiated in the presence of blasts. Mean expression of CD80, CD83, and CD86 was 16%, 2%, 83% and 49%, 10%, 99% for DCs generated in the presence or absence blasts respectively. Phenotypic characteristics of native DC in patients with AML were examined. In 3 experiments, a predominance of DC2 was seen (ratio DC2/DC1 5), and both DC1 and DC2 poorly expressed CD83 (mean expression 9% DC1, 0.9% DC2). Conclusions: LDC have phenotypic and functional deficiencies, limiting their efficacy as a tumor vaccine. Contact with leukemic blasts may inhibit DC maturation in vitro and in vivo, which may contribute to the lack of effective antitumor immunity in AML patients. No significant financial relationships to disclose.
Role of GADD45α as a potential therapeutic target for prostate cancer
Authors: Singal R. , Ramachandran K. , Gopisetty G. , Navarro L. , Gordian E. , Manoharan M. 
Published: March 2020

10566 Background: Defects in the apoptotic pathway contribute to uncontrolled cell proliferation of cancer cells and confer resistance to chemotherapeutic drugs. Understanding the mechanisms of deregulation of apoptosis related genes would enable targeted treatment methods to improve the efficacy of chemotherapy. Growth Arrest and DNA Damage inducible, alpha (GADD45a) mediates cytotoxicity of docetaxel chemotherapy. We examined the mechanism of regulation of GADD45a in prostate cancer cells and the effect of its upregulation on sensitivity to docetaxel chemotherapy. Methods: Levels of GADD45a in Du145, LNCaP and PC3 were analyzed by real time reverse transcriptase PCR and western blotting. DNA methylation was studied by bisulfite sequencing. Chromatin immunoprecipitation was used to study interaction of methyl binding proteins to GADD45 5’ sequence. Cytotoxicity after drug treatment was measured by MTT cell proliferation assay. Apoptosis assays were done by Annexin V/propidium iodide staining followed by flow cytometry. Results: Levels of expression of GADD45a in Du145 and LNCaP cells were lower than that in PC3. A 4 CpG region upstream of the proximal promoter region was methylated in Du145 and LNCaP cells. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyl transferase (DNMT) inhibitors such as 5- Azacytidine or 5- Aza deoxycytidine leading to reactivation of GADD45a expression in these cells. This region was also frequently methylated in prostate cancer tissues. Methyl binding protein, MeCP2 was associated with the methylated 4 CpGs in Du145 and knock down of MeCP2 by transfection of MeCP2 siRNA vector in Du145 cells (Du145-MeCP2-ve) led to increased expression of GADD45a, without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by upregulation of GADD45a in Du145 cells by (a) recombinant expression of GADD45a (b) downregulation of MeCP2 and (c) pretreatment with 5-Azacytidine. Conclusions: GADD45a is frequently deregulated in prostate cancer by methylation of 5’ 4 CpG region and is a potential therapeutic target for treatment of prostate cancer. [Table: see text]
Chromosomal alterations in oligodendroglial tumors over multiple surgeries: Is progression associated with change in 1p/19q status?
Authors: Campbell B. , Horsman D. , Maguire J. , Young S. , Curman D. , Ma R. , Thiessen B. 
Published: March 2020

10577 Background: There is morphologic and genotypic heterogeneity of oligodendroglial neoplasms. Tumors with loss of heterozygosity (LOH) of 1p and/or 19q are associated with increased chemo-sensitivity and survival. Despite treatment, rates of recurrence and malignant transformation are high. The pathogenesis of treatment-resistance is unknown. We aim to determine if tumour progression is associated with a proliferation of clonagens with retention of heterozygosity (ROH) of 1p, or if progressing tumours remain 1p/19q LOH. Methods: Between 1/1/2001 and 7/31/2006, 24 patients with oligodendroglial neoplasms, and possessing serial biopsies taken at diagnosis and at progression, were identified. Using PCR amplification of multiple microsatellite markers, a total of 53 tumour specimens were available for LOH analysis of 1p and 19q; 40 were also tested for 9p and 10q. Results: At diagnosis, the median age was 34 (24–66) years and 14 were male. Using the WHO criteria, 19 tumors were Grade II oligodendrogliomas or oligoastrocytomas, and 5 were high grade. The most common genomic status was 19q LOH (88%); 54% had 1p LOH. Of the 13 primary biopsies with 1p LOH, 11 had 19q LOH, 1 had 19q ROH, and 1 was 19q non-informative. A further 2 primaries were mixed 1p LOH/ROH, and 9 were 1p ROH. At progression, 10 of 11 patients with 1p/19q LOH had persistent co-deletion. The patient with 1p LOH and 19q ROH at diagnosis, had 1p/19q LOH at progression. Of the mixed 1p primaries, 1 was 1p ROH, and the other remained mixed LOH/ROH at progression. 8 of 9 primaries with 1p ROH remained 1p ROH. There was also little heterogeneity of 9p and 10q between primary and progressive tumours. Using Kaplain-Meier analysis, mean overall survival (OS) for the group was 102 (95% CI: 77–127) months. Mean progression-free survival was 52 (95% CI: 33–72) months. OS was not statistically significant between patients with 1p LOH and 1p ROH primary tumours. Conclusions: 91% of repeat biopsies of oligodendroglial tumors, demonstrated persistent 1p/19q LOH. Therefore, progression of 1p/19q LOH primary tumours is not due to a proliferating sub-group of chemo-resistant, 1p ROH clonagens. We propose that additional mutations contribute to this aggressive phenotype. No significant financial relationships to disclose.
Prognostic role of the extent of peritumoral vascular invasion in operable breast cancer
Authors: Colleoni M. , Rotmensz N. , Andrighetto S. , Maisonneuve P. , Sonzogni A. , Pruneri G. , Casadio C. , Goldhirsch A. , Viale G. 
Published: March 2020

10586 Background: Peritumoral vascular invasion (PVI) has been recently recognized as a significant prognostic indicator for women with operable breast cancer, yet the clinical relevance of the degree of PVI in patients with no or limited involvement of the axillary nodes is unknown. Methods: 2606 consecutive patients with pT1–3, pN0 (1586)-1a (1020), and M0, operated and counseled for medical therapy from 1/2000 to 12/2002 were prospectively classified according to the degree of PVI: absent (2017, 77.4%), focal (368, 14.1%), moderate (51, 2.0%) and extensive (170, 6.5%). The median follow-up was 3.8 years for disease-free survival (DFS) and 4.3 years for overall survival (OS). Results: Patients with extensive PVI were more likely be younger, to have larger tumors, high tumor grade, axillary positive nodes, high Ki-67 expression, and HER2/neu over-expression if compared with patients having less amount if PVI (p for trend, <.0001). Patients with diffuse PVI were prescribed significantly more frequently anthracycline containing chemotherapy and less endocrine therapy alone (p for trend, <.0001). In patients with node negative disease a statistically significant difference in DFS, risk of distant metastases and OS was observed at the multivariate analysis for diffuse PVI versus no PVI (Hazard Ratios: 2.11, 95% CI, 1.02 to 4.34, P<.0001 for DFS; 4.51, 95% CI, 1.96 to 10.4, P<.0001 for distant metastases; 3.55, 95% CI, 1.24 to 10.1, P=.02 for OS). Conclusions: Extensive peritumoral vascular invasion has a prognostic role in patients with axillary lymph node negative breast cancer. The extent of vascular invasion should be considered in the therapeutic algorithm in order to proper select targeted adjuvant treatment. No significant financial relationships to disclose.
Gamma-Secretase, ErbB4 nuclear localization and neuregulin expression correlates with prostate cancer patient clinical outcome
Authors: Koumakpayi I. , Le Page C. , Karakiewicz P. I. , Diallo J. , Lessard L. , Mes-Masson A. , Saad F. 
Published: March 2020

10587 Background: Membrane protein ErbB4 is a member of ErbB growth factor receptor family, which can be activated by neuregulins (NRG). Upon neuregulin activation, ErbB4 is cleaved within its transmembrane domain by presenilin γ-secratase (PSN) to release an intracellular domain that translocates into the nucleus. Although, ErbB4 ligand-dependant translocation of ErbB4 to the nucleus and its nuclear activity has been reported in breast cancer cell lines, there are few reports concerning ErbB4 nuclear localization and its clinical relevance. Here, we report for the first time the clinical relevance of ErbB4 nuclear localization, NRG, and PSN expression in prostate cancer tissues. Methods: Immunostaining using anti-ErbB4, anti-PSN2 and anti-neuregulin antibodies was done on a set of tissue microarrays (TMA) from 140 patients. The TMAs contained, 92 cores of normal prostate tissue obtained from 46 autopsy specimens from young males, 373 tumor and normal adjacent cores from 63 hormone sensitive PCa (HSPCa) patients, and 146 cores from 31 hormone refractory PCa (HRPCa) patients. Results: We found a statistically significant increase (p<0.01) in the percentage of ErbB4 nuclear localization (68.7% vs 53.2%), NRG expression (2.06 vs 1.41) and PSN2 expression (2.14 vs 1.53) when comparing cancerous tissues to normal tissue adjacent to cancer. Interestingly, a similar statistically significant increase in nuclear ErbB4 and NRG expression was observed when comparing HRPCa to HSPCa (p<0.001). In cancerous tissues, a strong correlation was found between nuclear ErbB4 and NRG expression (r=0.672), between nuclear ErbB4 and PSN2 expression (r=0.51), and between PSN2 and NRG expression (r=0.71). Nuclear ErbB4 and PSN2 inversely correlated with tumor stage and lymph node invasion. Kaplan Meier analysis of nuclear ErbB4 (p=0.030) and PSN2 expression (p=0.018) showed an inverse association with biochemical recurrence (BCR) of PCa. In multivariate analyses including these three markers and clinical parameters, only nuclear ErbB4 retained an independent prognosis value. Conclusion: Our results suggest that high nuclear ErbB4 along with increased PSN2 expression have a protective effect against prostate cancer progression and BCR. No significant financial relationships to disclose.