bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18: Targeted epidermal ablation of EGFR causes local and systemic inflammation
Authors: Mascia Francesca , Lam Gary , Threadgill David , Yuspa Stuart H.
Published: February 2011

EGFR is overexpressed or mutated in a variety of malignancies, and it plays a fundamental role in tumor development and progression, in the angiogenetic process and in the metastatic spread of tumors. As a result investigators have developed approaches to inhibit EGFR activation, with the aim of blocking tumor growth and invasion. The most common adverse effect seen with EGFR inhibition therapy is a pronounced skin inflammatory response (papulopustular rash) that can affect different areas of the body with variable severity. Interestingly, in vitro and in vivo experiments demonstrate that the pharmacological blockade of EGFR or ERK1/2, induces chemokine expression in epidermal keratinocytes and in turn leads to worsening of skin inflammatory conditions. Recent findings suggest a link between chemokine expression and EGFR status in the skin lesions of patients undergoing EGFR therapy and during tumor progression in BCC (basal cell carcinoma) and SCC (squamous cell carcinoma) skin lesions. Given these previous findings we believe that the study of the regulatory functions of the EGFR-ERK1/2 pathway on skin inflammatory mediators will help in understanding not only the adverse effect of this broad class of antitumor drugs but will possibly help to understand if and how they can modify the tumor microenvironment. In this study a mouse model was developed to better characterize the role of EGFR in the control of skin inflammation. By crossing Keratin 5 driven Cre recombinase transgenics with EGFR floxed mice, EGFR was ablated in the epidermis. During the first week of life, double transgenics started to display a strong skin phenotype with aberrant hair growth. During the following weeks the skin of these mice became progressively more inflamed with abundant neutrophilic infiltrate, scaly, dry and less elastic and underwent cycles of hair growth and hair loss. Double transgenic mice experienced a strong pruritus through their entire life, and their scratching behavior caused skin erosions. Tissue samples isolated from skin of adult double transgenics contained high levels of CD45 antigen and increased mRNA levels of a subset of inflammatory mediators namely CCL17, CCL20, CCL2, TNF-α, IL-6, IL-17, IL-18, and G-CSF. Targeted knockout mice also displayed hematological abnormalities with a higher number of circulating CD11b/Gr1 positive cells, extramedullary hematopoiesis and higher plasma levels of G-CSF, IL-1ra, IL-17, IL-6 and CCL2. These data indicate that the local absence of EGFR triggers local and systemic inflammatory responses. Therefore, this model represents a valuable tool to further investigate the control of EGFR in the maintenance of a balanced immuno-homeostasis of the skin.

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 18.
Abstract 1801: Predictive diagnostics for the PI3 kinase inhibitor GDC-0941 in breast and ovarian cancer
Authors: O'Brien Carol , Spoerke Jill , Mohan Sankar , Pandita Ajay , Sampath Deepak , Wallin Jeffrey , Lackner Mark
Published: February 2011

The class I phosphatidylinositol 3’ kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting the PI3K pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. GDC-0941 is a pan-inhibitor of all 4 isoforms of class 1 PI3K that is currently undergoing testing in the clinic. The PI3 kinase pathway is generally regarded as the most frequently altered pathway in cancer, and an attractive hypothesis is that these alterations will help identify tumors where the pathway is particularly active and hence patients who are likely to receive benefit from treatment with a PI3 kinase inhibitor.

We used a large panel of breast and ovarian cancer cell lines as well as in vivo xenograft models to evaluate candidate predictive biomarkers for GDC-0941. The approach involved pharmacogenomic profiling as well as analysis of gene expression datasets from tumor cells profiled at baseline or after GDC-0941 treatment. We found that models harboring key pathway alterations were generally sensitive to the anti-tumor effects of GDC-0941. We found that a number of models that do not harbor these alterations also showed sensitivity, suggesting alternative explanations for sensitivity and thus a need to identify additional diagnostic hypotheses. Gene expression studies identified a small number of genes whose expression appears to be intimately linked to pathway activation that may also be useful diagnostic markers.

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 1801.
Abstract 1808: Modulation of the immune cell repertoire and immunogenicity of tumor cells by sorafenib
Authors: Seliger Barbara , Giersberg Corinna , Mueller Anja
Published: February 2011

Recently, tyrosine kinase inhibitors have been successfully implemented in frontline therapy for the treatment of malignant tumors including renal cell carcinoma (RCC). These different substances provide significant objective clinical responses and a longer progression-free survival of patients. This is mainly caused by the inhibition of cell growth, angiogenesis and induction of apoptosis. In addition, an effect of sorafenib on the frequency and function of T subpopulations, dendritic cells as well as myeloid-suppressor cells has been postulated. The aim of this study was to determine the effect of sorafenib on cell growth, apoptosis and immunogenic properties of RCC cells as well as on the composition of immune subpopulations of peripheral blood mononuclear cells and subsequently immune responses. A direct effect of sorafenib on the expression pattern of a number of immune modulatory components including HLA class I antigens and members of the B7-H family as well as on the proliferation of RCC cell lines was detected. In addition, the frequency and function of different immune cell populations, such as regulatory T cells and myeloid-derived suppressor cells, was altered upon sorafenib treatment. These data suggest a novel activity of sorafenib in tumor patients by extending its activity beyond the tumor endothelium as its major target to the modulation of immune cell function and the immunogenicity of RCC cells.

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 1808.
Abstract 1809: Reversal of Taxol resistance in ovarian cancer cell lines by IGF pathway inhibition
Authors: Brouwer-Visser Jurriaan , Horwitz Susan Band , Huang Gloria S.
Published: February 2011

Our group recently reported increased insulin-like growth factor 2 (IGF2) expression and AKT activation in ovarian cancer cells following treatment with the microtubule-stabilizing agent Taxol. We hypothesized that IGF2 is a modulator of Taxol resistance. Therefore, we developed cell line models of Taxol-resistance in A2780 and HEY, two ovarian cell lines, by repeated treatment with increasing Taxol concentrations, with or without concurrent verapamil, a p-glycoprotein inhibitor. The involvement of IGF2 in drug resistance was evaluated by real time PCR, immunoblotting, siRNA knockdown of IGF2, and small-molecule inhibition of the IGF1 Receptor (IGF1R; which is the major receptor for IGF2). In both of the resistant cell lines (A2780-Tx8Vp, 3-fold Taxol-resistance; and HEY-T30, 40-fold Taxol-resistance), IGF2 mRNA expression, measured by real time PCR, was significantly elevated compared with the parental cell lines, while IGF1R expression, assessed by immunoblotting, was mildly decreased. IGF1R inhibition by the small molecule NVP-AEW541 dramatically re-sensitized both resistant cell lines to Taxol, and cell cycle analysis demonstrated that concurrent NVP-AEW541 and Taxol significantly enhanced G2/M arrest, compared with Taxol alone. While A2780-Tx8Vp cells did not express detectable mdr1/abcb1 (encoding p-glycoprotein), HEY-T30 cells did over-express mdr1 (and were sensitized to Taxol treatment by verapamil). To exclude a possible interaction with p-glycoprotein, we evaluated IGF2 siRNA as an alternate, more specific approach of targeting the IGF pathway in HEY-T30 cells. It was found that IGF2 depletion by siRNA significantly enhanced the antiproliferative effect of Taxol in these cells. In summary, IGF2 modulates Taxol resistance in these ovarian cancer cell lines. IGF pathway inhibition, by IGF2 depletion or by inhibition of its major receptor IGF1R, reverses Taxol resistance in these cells. Such novel findings suggest that IGF2 could be a therapeutic target for ovarian cancer, particularly in the setting of Taxol resistance.

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 1809.
Abstract 1811: Breaking scaffolds: Targeting paxillin in ovarian cancer
Authors: Carroll Amy , Kim Seung Wook , Nick Alpa M. , Stone Rebecca L. , Spannuth Whitney A. , Armaiz-Pena Guillermo N. , Matsuo Koji , Vivas-Mejia Pablo E. , Mangala Selanere , Mora Edna M. , Shahzad Mian , Lopez-Berestein Gabriel , Sood Anil K.
Published: February 2011

Background

Paxillin is a mediator of many cellular processes important for cancer progression. Here, we characterize the clinical and biologic significance of paxillin in epithelial ovarian cancer.

Methods

Paxillin and phospho-paxillin expression was determined in 93 human epithelial ovarian cancer specimens. Clinical data were extracted and associations tested using univariate and multivariate analyses. The effect of paxillin silencing on ovarian cancer cell migration and invasion was evaluated in vitro. In vivo paxillin silencing was achieved with siRNA incorporated into DOPC nanoliposomes and its effect on tumor growth, angiogenesis, and proliferation were examined.

Results

Examination of 93 epithelial ovarian cancers revealed moderate to high paxillin expression in 84% and high phospho-paxillin expression in 63% of tumors. High paxillin expression correlated with high tumor grade (p=0.02) and advanced stage (p=0.03). Phospho-paxillin expression was associated with high tumor grade (p=0.01), suboptimal cytoreduction (p=0.01), and decreased overall survival (p<0.001). Compared to non-transformed ovarian epithelial cells (HIO-180), paxillin expression was increased in chemosensitive (HeyA8, SKOV3) and chemoresistant (HeyA8-MDR, SKOV3-TR) ovarian cancer cell lines. Paxillin siRNA resulted in >85% reduction in protein expression in these cell lines. In vitro paxillin silencing decreased HeyA8 and HeyA8-MDR cell migration (60% and 75%) and invasion (55% and 47%). In orthotopic mouse models, paxillin siRNA treatment reduced tumor growth in HeyA8 and HeyA8-MDR by 49% and 31%, respectively, compared to non-targeting siRNA controls. The greatest efficacy was observed by combining paxillin siRNA with docetaxel, resulting in a >90% and 45% reduction in tumor burden over non-targeting siRNA in HeyA8 and HeyA8-MDR tumors, respectively. The dramatic in vivo effects of paxillin silencing are due, in part, to its activation of multiple signaling cascades once localized to the focal adhesion complex. Protein complex immunoprecipitation confirms interactions with Src, FAK, and EphA2 tyrosine kinases as well as effector molecules such as Crk. Paxillin silencing resulted in decreased proliferation by 57%, decreased microvessel density by 72%, and increased apoptosis by 140% in HeyA8 tumors.

Conclusion

Paxillin is overexpressed in epithelial ovarian cancer. Paxillin influences several pathways important to cancer progression and represents a novel and attractive treatment target in ovarian cancer.

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 1811.
Abstract 1818: Space-time analysis of racial disparities in advanced-stage prostate cancer incidence across Florida
Authors: Goovaerts Pierre , Xiao Hong
Published: February 2011

Prostate cancer is the most frequently diagnosed non-skin cancer and the second leading cause of cancer-related death for American men. Florida ranks second behind California for both incidence and mortality from prostate cancer in 2008. With the wide spread use of prostate specific antigen (PSA) and digital rectal examination (DRE), a larger proportion of prostate cancer cases is now diagnosed at early stages. Yet, striking racial/ethnic differences in incidence and mortality still persist in the United States and Florida. Eliminating such disparities requires a better understanding of factors responsible for the geographic and ethnic differences in prostate cancer late stage incidence and mortality over time.

Percentages of advanced-stage prostate cancer diagnosis were analyzed yearly from 1981 through 2005 for each county of Florida and three ethnic subgroups (white, black, Hispanic). All three ethnic groups experienced a 50% decline in the state-average proportion of late-stage diagnosis. This drop, which started in the early 1990s when PSA became widely available, was the most pronounced for Hispanics whose rates is now similar to white non-Hispanics; black non-Hispanics still have a 25% larger rate compared to the two other ethnic groups. Interestingly, the total number of diagnosed cases kept increasing for black and Hispanics, while it started declining slowly for white in the early 1990s. These temporal trends are however not uniform across Florida; cluster and boundary analysis revealed geographical disparities that were substantial for all ethnic groups before the mid 1990s. The gap among Florida counties is narrowing with time as the percentage of late-stage diagnosis is decreasing. One outlier is the Big Bend region of Florida where the decline in late-stage diagnosis has been the slowest in all Florida for both white and black males.

While this paper focused on the geographic distribution of race-based disparities in advanced-stage prostate cancer diagnosis in Florida, the approach can be easily generalized to other states and cancer sites, with clear applications in (a) monitoring and surveillance of cancer incidence and mortality, (b) the generation of hypotheses for in depth individual studies of risk factors that are causal, or impact survival; and (c) establishing the rationale for targeted cancer control interventions, including consideration of health services needs, and resource allocation for screening and diagnostic testing.

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 1818.
Abstract 1820: Patterns of hematopoietic cancers in Egypt from a population-based registry
Authors: Herzog Catherine M. , Soliman Amr S. , Eldein Ibrahim A. Seif , Hablas Ahmed , Ramadan Mohamed , Wilson Mark
Published: February 2011

Objectives: Rates of lymphoma are rising by 4% annually in the United States. Globally, lymphoma incidence rates are also on the rise with about 342,000 new cases per year. Egypt, where hematopoietic (blood and lymphatic) cancer is considered common, has one of the highest age-standardized incidence rates of lymphoma in the world (16.3/100,000), greater than that of the United States (15.3/100,000). Risk factors for hematopoietic cancers include radiation, viral and bacterial infections, occupational and environmental exposures, family history, and genetic mutations. We evaluated the incidence of these cancers in Egypt and analyzed them in relation to select risk factors to better understand their etiology.

Methods: Hematopoietic cancer case data for 1999-2005 from the Gharbiah Population-Based Cancer Registry in Tanta, Egypt, the only population-based registry in Egypt, were analyzed. Crude and age- and gender-specific rates were calculated for 4,260 cases, and evaluated by REAL Malignancy type, morphology, topology, and stage. Potential risk factor variables included age, gender, date of diagnosis, and district of residence, and urban/rural setting. Descriptive and multivariable statistics were calculated and space-time patterns were investigated.

Results: Overall, incidence was greater among males and among residents of urban areas. More than half of cases were diagnosed at Stage III or IV. Leukemia and Hodgkin lymphoma predominated in cases under 18 years of age whereas mature B-cell neoplasms were the most common in those older than 18. Average annual crude incidence varied by district, ranging from 10.21 to 20.34 per 100,000, and generally rose during the seven year period. This rise was most prominent in the crude incidence of mature B cell neoplasms, mostly due to diffuse B cell lymphoma.

Conclusions: This study provides numerical evidence of the impact of hematopoietic cancer, especially Non-Hodgkin lymphoma, on the Egyptian population. It also appears to follow the rising trend in Non-Hodgkin lymphoma cases seen worldwide. Further comparison of the distribution of incidence and alternative risk factors may lead to a novel understanding of the etiology of hematopoietic cancers and improvements in current treatment.

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 1820.
Abstract 1822: Age-period-cohort (APC) analysis of primary bone cancer incidence rates in the United States (1976 – 2005)
Authors: Anfinsen Kristin P. , Bray Freddie I. , Troisi Rebecca , Jonasdottir Thora J. , Bruland Oyvind S. , Devesa Susan S. , Grotmol Tom
Published: February 2011

BACKGROUND: Primary bone cancer comprises three major histological subtypes: osteosarcoma (OS), Ewing sarcoma (ES) and chondrosarcoma (CS). The most frequent subtype, OS, primarily occurs in adolescence, but has a second peak at the oldest ages, usually attributed to late effects of radiotherapy and chemotherapy, and Paget's disease. The adolescent age distribution of ES resembles that of OS, suggesting a link between the onset of puberty and these subtypes of bone cancer. CS is rare in childhood, and incidence rates, unlike those of OS and ES, increase fairly uniformly with age. Given the limited knowledge about the etiology of primary bone cancer, and the unusual age-incidence distribution for OS and ES, we undertook an APC analysis to determine whether incidence varied by birth cohort or calendar period. For other cancers, such as testis and breast, the identification of cohort patterns has generated new hypotheses regarding environmental risk factors. METHODS: We fit an APC model to incidence data among U.S. whites for OS, ES and CS obtained from nine registries of the Surveillance, Epidemiology, and End Results (SEER) program, which covers about 10% of the U.S. population, 1976-2005. The purpose was to examine the temporal development of each bone cancer subtype, with an aim to providing etiologic clues as to the role of birth cohort-related changes. RESULTS: Incidence of OS decreased between 1976 and 2005 among those 60 years and older, and rates declined among cohorts born 1905-34. The risk of CS doubled among females 20-69 years, with rates increasing among consecutive birth cohorts born 1925-54, whereas those of males were unaltered. For both sexes, ES incidence rates tended to be stable. CONCLUSIONS: The risk reduction in OS at older ages was most likely due to improved radiotherapy and more effective chemotherapy. The CS risk increase in females corresponds to birth cohorts who were increasingly exposed to estrogens, both in terms of contraceptives (from 1960 onwards), and hormone replacement therapy (from 1950 onwards). In support of our hypothesis that estrogens are involved in the increase in CS among women over time, in vitro studies show that the estrogen signaling pathway stimulates proliferation of both normal and malignant chondrocytes. Further studies are warranted to pursue the possible etiological significance of estrogen exposure in CS risk.

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 1822.
Abstract 1825: Maternal alcohol consumption and childhood acute myeloid leukemia risk
Authors: Song Minkyo , Lee Kyoung-Mu , Han Sohee , Park Sue K. , Ahn Hyo Seop , Shin Hee Young , Kang Hyoung Jin , Koo Hong Hoe , Seo Jong Jin , Choi Ji Eun , Ahn Yoon-Ok , Kang Daehee
Published: February 2011

Background: Leukemia is the most common malignancy in children. The etiology of childhood leukemia is mostly unknown, although some environmental factors such as ionizing radiation and parental alcohol and tobacco use may play a causative role in leukemia.

Methods: To investigate the association between parental alcohol consumption and childhood leukemia in a hospital-based case-control study in Korea, histologically-confirmed incident childhood leukemia cases (n=365) aged 0-18 years old were recruited from three teaching hospitals located in Seoul, Korea, between May 2003 and August 2008. Non-cancer controls (n=558) aged 0-18 years old without medical history of childhood cancer were recruited from the Department of Pediatrics of the same hospitals. Controls were frequency-matched to cases by 5-year age intervals and sex (cases: controls=1:1). Leukemia risks were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis adjusted for age, sex, parent's education, and birth weight (<3.25, 3.25-3.70, ≥3.70 kg). In addition to conducting analyses of all childhood leukemia, we calculated histologic subtype-specific ORs for acute lymphoblastic leukemia (ALL; n=200) and acute myeloid leukemia (AML; n=88).

Results: Among general characteristics, higher birth weight and parental education were associated with childhood leukemia risk (P<0.05). The proportion of drinking mothers was significantly higher among all leukemia cases than controls (58% vs. 49%: OR=1.4, 95% CI=1.00-1.83), whereas no association was observed for paternal alcohol consumption (87% vs. 83%). When the analysis was restricted to AML cases, the association between maternal drinking and cancer risk became stronger (OR=1.8, 95% CI=1.06-2.90). Drinking frequency of the mothers was also associated with the increased risk. (≥1/month vs. <1/month; OR=1.7, 95% CI=1.10-2.28). Also, drinking duration of more than one year before pregnancy increased the risk of AML (OR=1.7, 95% CI= 1.00-2.85). No association was found between parental alcohol consumption and ALL risk.

Conclusion: Our results suggest that maternal alcohol consumption is associated with AML among Korean children. However, larger studies need to be conducted to replicate our findings.

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 1825.
Abstract 1837: Exposure to Aristolochic Acid is associated with endemic (Balkan) nephropathy
Authors: Edwards Karen L. , Wang Jia Yin , Snappin Katherine , Sonicki Zdenko , Miletic-Medved Marcia , Grollman Arthur P. , Jelakovic Bojan
Published: February 2011

Endemic (Balkan) Nephropathy (EN) is a rare, chronic tubulointerstitial nephritis that gradually progresses to end state renal disease. EN is also associated with development of urothelial cancer. EN has been the subject of many epidemiologic investigations during the past 50 years and is now thought to occur more broadly than just the endemic Balkan regions. Numerous hypotheses have been investigated but no causal factor has been identified. Exposure to Aristolochic Acid (AA) was proposed 30 years ago as a potential cause of EN, but was dismissed. The most likely route of human exposure to AA is via ingestion of home-baked bread prepared from flour contaminated by seeds of Aristolochia clematitis.

Methods: Studies are underway in Croatia in collaboration with US investigators to evaluate this hypothesis. Data for this study comes from a population-based survey conducted in 2005 that includes 1081 subjects from 3 endemic and 1 nonendemic village. Logistic regression was used to evaluate the association between exposure to AA and EN.

Results: Exposure to Aristolochic Acid (AA) from bread consumption is associated with a nearly 2 fold increase in risk of EN (OR=1.7; 95%CI: 1.07,2.98), growing wheat for flour is associated with a 3 fold increase risk (OR=3.5; 1.27, 10.1)), and recalling the AA containing weed in the wheat field was also significant (OR=2.4; 1.32, 4.62). Adjustment for covariates reduced the significance, but the elevated risk was still observed. A larger population-based assessment of several new villages in Croatia was recently completed.

Conclusion: Understanding the etiology of this debilitating disease is the first step in developing an effective prevention strategy. Next steps will include evaluating specific genetic components and their interactions with exposure to AA.

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 1837.
Abstract 1845: Genetic analyses of MGMT in familial gliomas and colorectal cancer
Authors: Moutinho Cátia , Blanco Ignacio , Martinez Ramon , Esteller Manel
Published: February 2011

DNA repair is an important area of research in cancer biology. The O6-methylguanine DNA methyltransferase (MGMT) enzyme is one of the key players in this area. When deregulated affects DNA repair capacity and it is involved in cancer formation. In eukaryotes the MGMT enzyme is the first line of defense against the adverse effects of DNA alkyl-lesions that are potent mutagenic and cytotoxic lesions. Evidence for MGMT suppressing cancer susceptibility in humans include the loss of expression by epigenetic silencing in a variety of human cancers, including > 30% of colorectal, brain, lung, lymphoma, head and neck cancers. Moreover, these cancers frequently show higher incidence of G to A transitions mutations in oncogene v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and in the tumour suppressor gene tumour protein p53 (TP53) compared to tumours with normal MGMT expression. A single report has described somatic mutations in MGMT gene. However, there are several reports of individual differences in MGMT activity. A few germline variants affecting this gene have been described, but the functional relevance of these nucleotides changes is unclear. There are many familial colorectal cancers (CCR) and familial gliomas for which it has not been described an associated germline mutation. In order to see if MGMT tumour suppressor gene could be genetically involved on that, we did a germline screening of 78 CCR probands and 8 gliomas probands from familial cases. As control we also did the screening of 80 normal DNAs lymphocytes from healthy volunteers. For that we performed direct sequencing of all MGMT exons. We found polymorphisms (SNPs) already described, where are included the three common non-synonymous SNPs Leu84Phe, Ile143Val and Lys178Arg. The frequency of SNPs in probands lymphocytes was the same as in normal DNA lymphocytes. The study is ongoing and further extensive research is warranted.

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 1845.
Abstract 1848: Folliculin (FLCN) sequence variants involved in Birt-Hogg-Dube syndrome
Authors: Lim Derek HK , Rehal Pauline K. , Nahorski Michael S. , Macdonald Fiona , Claessens Tijs , Geel Michel Van , Gijezen Lieke , Gille Johan JP , Giraud Sophie , Richard Stephane , Steensel Maurice Van , Menko Fred , Maher Eamonn
Published: February 2011

Background:

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominantly inherited familial cancer syndrome characterized most commonly by the development of facial fibrofolliculomas, pulmonary cysts (predisposing to spontaneous pneumothorax) and renal cancer. Germline mutations in FLCN on 17p11.2 have been reported in patients with BHD and also in patients with isolated familial primary spontaneous pneumothorax and familial clear cell renal cell carcinoma without other features of BHD. The function of the FLCN gene product, folliculin, is not well characterized but recent studies have suggested that it may be implicated in the regulation of several key signalling pathways including the AMPK-mTOR route.

Methods:

We previously established an online locus-specific database (LSDB) for FLCN sequence variants at www.lovd.nl/flcn. Variants in the database have been curated from the published literature and novel unpublished sequence variants submitted to the database from diagnostic and research laboratories working on BHD syndrome. The entries in the database were analyzed looking at the variant type and distribution and associated phenotype.

Results:

The database currently contains a total of 115 unique sequence variants (including 70 pathogenic, 7 probably pathogenic, 1 variant of unknown significance and 37 single nucleotide polymorphisms) in FLCN. The majority of pathogenic mutations results in protein truncation whilst a minority are splice-site alterations. An up to date summary of the variants and their associated phenotype will be presented.

Conclusion:

Pathogenic mutations are found throughout the coding regions (exons 4-14) and there are no apparent genotype-phenotype correlations. The FLCN mutation database available at www.lovd.nl/flcn offers a valuable resource and tool for clinicians involved in the management of BHD patients, clinical geneticists and researchers. Researchers can directly submit new sequence variants online to the database or by e-mailing the author.

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 1848.
Abstract 1857: 3p12.3 and 7q36.3 harbor genes associated with hereditary breast and colorectal carcinomas
Authors: Abreu Francine B. , Santos Erika M.M. , Rossi Benedito M. , Kowalski Luiz P. , Brentani Ricardo R. , Rogatto Silvia R.
Published: February 2011

Lynch syndrome (LS) is the most common hereditary syndrome that predisposes to colorectal cancer (CRC). LS is associated with susceptibility to proximal colon cancer, multiple primary (CRC) and extra-colonic tumors. According to Registration of Hereditary Colorectal Cancer (RHCC) of AC Camargo Hospital of Brazil, breast cancer is the most frequent extra-colonic tumor among women with suspicion of hereditary CRC, suggesting the possibility of a new syndrome known as Hereditary Breast and Colorectal Cancer (HBCC). Array comparative genomic hybridization (array CGH) is the high-resolution laboratory technique of choice for the detection of chromosomal DNA copy number alterations on a genome-wide scale. The aim of the present study was to identify copy number alterations in genes related to predisposition in HBCC syndrome. Array comparative genomic hybridization was performed using Human 4 × 180K Oligoarrays (G4449A, Agilent) in 47 individuals from families showing HBCC phenotype. For each sample, 800 ng of DNA were fragmented by a double enzymatic digestion (AluI + RsaI). DNA from peripheral blood leukocytes and control DNA from Promega (Human Genomic DNA Female G1521) were labeled with CY3-dCTP and CY5-dCTPs, respectively, and hybridized at 65°C for 17 h. The chips were scanned on an Agilent DNA Microarray Scanner and image analysis was done using the Feature-Extraction version 10.1.1.1 software (Agilent Technologies). Raw copy number ratio data were transferred to the Agilent Genomic Workbench Software (version 5.0.14) for further analysis. It was detected copy number variations involving 36 regions previously described in genome databases. Furthermore, it was observed loss at 3p12.3 in two individuals. One patient presented breast cancer and CCR while the other one had breast carcinoma. Both of them had breast cancer around the 50 years. In both families, their relatives had CCR, breast cancer and endometrial cancer, which is another extra-colonic tumor found among patients with LS. In a third women with breast and colorectal carcinomas was detected deletion at 7q36.3. Germline copy number alterations may indicate new genes associated with cancer predisposition. Our results suggest that 3p12.3 and 7q36.3 harbor genes associated with hereditary breast and colorectal carcinomas. Additional members of these families are being evaluated to confirm the involvement of these regions as candidate genes. Financial Support: FAPESP (2008/57887-9) and CNPq (57589/2008-9).

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 1857.
Abstract 1859: Breast cancer risk:tp53 genotyping in a Nigerian population
Authors: Kasvosve Nancy N. , Fackenthal Jim , Zhang Jing , Olopade Olufunmilayo
Published: February 2011

Background: Women of African descent have a lower incidence of breast cancer than other ethnicities but higher mortality rates. Their tumors are characterized by an earlier age of onset, aggressive behavior, poor prognosis, and molecular characteristics of “triple negative” status (i.e. lacking detectable ER, PR, and HER2/neu expression). These characteristics are also typical of tumors carrying somatic TP53 mutations. Experimental evidence has shown that somatic inactivation of the TP53 pathway is necessary for tumor development. Null or strongly hypomorphic TP53 mutations inherited through the germline are associated with a high likelihood of tumorigenesis. Studies on different ethnic populations show inheritance of TP53 variants, especially the R72P polymorphism, to be associated with risk of tumor formation in breast and other tissues. These observations suggest that TP53 gene activity plays a significant role in promoting tumor development in tissues.

Hypothesis: As the TP53 R72P polymorphism has been associated with cancer risk in non-African populations, and patients of African ancestry frequently have tumors with TP53 mutation-like characteristics, we hypothesize the R72P variant may be associated with low-penetrance breast cancer risk in a Nigerian/Yoruba population. In addition, this variant may be associated with the triple negative tumor subtype.

Methods: The study is a case-control analysis using 213 breast cancer patients and 213 unaffected controls from the University Hospital in Ibadan, Nigeria. The TP53 R72P genotype was determined by direct sequencing of TP53 exon 4, amplified by PCR from peripheral genomic DNA. Chi-square statistical analysis was used to compare frequencies of individual alleles and genotypes in between cases and controls.

Results and Conclusions: 130 cases and 207 controls have been genotyped so far. Genotype frequencies for G/G, G/C, and C/C were 21%, 38%, and 41% in cases and 12%, 46% and 42% in the controls, respectively with a p value of 0.11 and an odds ratio of 1.24 at 95% CL. Preliminary results indicate a trend toward risk associated with the G/G genotype, though these results do not yet reach statistical significance. This analysis may provide important clues to the genetic basis of cancer risk and tumor etiology in patients of African ancestry.

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 1859.
Abstract 1865: ERCC2 polymorphisms, smoking, and risk of breast cancer
Authors: Conlon Michael S. , Bewick Mary A.
Published: February 2011

The nucleotide excision repair (NER) pathway is important in the repair of bulky DNA lesions, including those that may be induced by cigarette smoking. Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 2 (ERCC2) is an important gene in the NER pathway. Previous research suggests that polymorphisms in this gene may be associated with altered DNA repair capacity, cancer risk and treatment outcome. This study investigated whether two common single nucleotide polymorphisms (SNPs) in ERCC2 (ERCC2 Asp312Gln and ERCC2 Lys751Gln) were associated with risk of breast cancer, or modified a breast cancer risk associated with smoking. We used data previously collected from a primarily Caucasian population in northeastern Ontario Canada of 347 women diagnosed (2002-2004) with breast cancer and 775 population-based controls. The mailed study package contained a questionnaire that provided information on known breast cancer risk factors and lifetime residential and occupational history of exposure to passive and active smoking, and a buccal swab for genetic analyses. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression, and used a refined referent group that excluded women with substantial exposure to passive smoke and who were never active smokers. Both SNPs were in Hardy-Weinburg Equilibrium (HWE) in controls. Overall, there was no significant association with either SNP and risk of breast cancer. Women who were active smokers of long duration (> 29 years), or high (>20) pack-years, were at significantly increased risk of breast cancer if they carried the G allele of ERCC2Asp312Gln, with ORs of 1.72 (95% CI 1.10-2.68) and 1.68 (95% CI 1.09-2.61) and p=0.03 and 0.007 for trend, respectively. Similar significantly increased risks were observed in women who carried the A allele of ERCC2 Lys751Gln, with ORs of 1.77 (95% CI 1.14-2.76) and 1.67 (95% CI 1.08-2.58) and p=0.02 and 0.01 for trend, respectively. In conclusion, our data suggest that polymorphisms in the NER pathway may modify a smoking-breast cancer relationship.

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 1865.
Abstract 1887: Distinct molecular targets of blueberry and black raspberry in breast cancer prevention
Authors: Ravoori Srivani , Kausar Hina , Aqil Farrukh , Gupta Ramesh C.
Published: February 2011

We previously demonstrated protection with berries in diet, against estrogen-induced ACI rat mammary tumorigenesis, by inhibition of proliferation as early as 3 weeks of estrogen administration. In this study, blueberry (BB) and black raspberry (BRB) were administered in diet at 5% 2 weeks prior to implantation with 1.2 cm silastic implants containing 9 mg 17β-estradiol. Rats were killed at 3 weeks, 3 months and ∼7 months, when the tumor incidence in control group reached 80%. Analysis revealed significant reduction (p<0.05) in tumor volume (Control: 801.2±105.3 mm3; BB: 395±97.9 mm3; BRB: 461±109.8 mm3) and tumor multiplicity (Control: 6.9±0.9; BB: 4.4±0.6; BRB: 4.3±0.6) by the berry diets. Most important finding is that while BB was more effective in reducing the tumor volume, BRB was more efficient in delaying the first tumor incidence, by 5 weeks (p<0.05). We also investigated the key molecules of cell-cycle regulation, cell proliferation and transcription. The cell-cycle regulatory molecule cyclin D1 which was up-regulated by 3-4-fold in mammary tissues with estrogen treatment, was significantly down-regulated by BB diet as early as 3 weeks and remained down-regulated during the entire tumorigenesis period (p<0.05), as detected by western blot. BRB diet did not show any significant down-regulation of cyclin D1. Estrogen receptor α, on the other hand, which was significantly overexpressed with estrogen treatment at all the three time points, was significantly offset by BRB diet, but it was not well pronounced with BB diet. Molecules downstream of these effector proteins are currently being explored. While BB contains five distinct anthocyanidins (delphinidin, cyanidin, malvidin, peonidin, and petunidin) and insignificant levels of ellagic acid, BRB contains chiefly cyanidin and high levels of ellagic acid. Thus, the distinct and specific molecular targets and pathways involved in the protective actions of the two berries corroborate their distinct phytochemical signatures. (Supported by CA-118114 and Agnes Brown Duggan Endowment).

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 1887.
Abstract 1891: Tanshinone IIA is a novel agent for melanoma prevention and therapy
Authors: Wang Zhibo , Cui Naiqiang , Ferrone Soldano , Wu Xianzhong , Herberman Ronald , Wang Wenjun
Published: February 2011

Background: Tanshinone IIA (TIIA) is a non-toxic natural compound isolated from traditional Chinese herb, Salvia Miltiorrhiza that has been used for prevention and therapy of a wide array of diseases such as vascular diseases and cancers in other countries. It has been documented outside the United States that TIIA has the biological functions of being pro-differentiation, anti-oxidant, anti-inflammation, anti-carcinogenesis and anti-tumor. However, TIIA has not been studied for melanoma prevention and therapy up to date.

Methods: Purified standard substance of TIIA has been use for this pilot study. Human adult epidermal melanocyte HEMa-LP and primary human melanoma cell MEL526 were used. Western blot, flow cytometry, ELISA and immunofluorescence techniques were employed to probe the biomarkers interested pre and post treatment of TIIA.

Results: TIIA inhibited MEL526 proliferation and induced MEL526 apoptosis at 20 µM that is below far away from TIIA plasma therapeutic concentrations in vivo. TIIA inhibited MEL526 cell motility at concentrations of 2.5µM or 5µM. TIIA (1.25 µM, 2.5 µM and 5 µM) prevented melanocyte epigenetic transdifferentiation to malignant melanoma cell induced by MEL526 conditioned cell culture medium, while TIIA is not toxic to normal melanocytes at those concentrations. TIIA induced transformed-HEMa-LP cell apoptosis at the above concentrations addressed. TIIA consistently down-regulated, at various ratios of drug concentration/cell density, the expression of melanoma stem cell biomarker CD133, and the expression of chondroitin sulfate proteoglycan 4 that is associated positively with melanocytic malignant transformation/progression and melanoma stem cell biomarker expression. STAT5-mediated up-regulation of Foxp3 has been documented in regulatory T cell differentiation and function, but not in melanocyte; and the higher expression level of STAT5a predicts the lower degree of atypia of nevi. In this study it was fund that TIIA increased the expression of STAT5a in MEL526 while the expression of Foxp3, a cancer suppressor gene, was up-regulated. TIIA inhibited the activation EFGR, which activation promotes carcinogenesis and progression of skin cancers. It was not found that TIIA regulated other biomarkers tested such as HLA Class I and B7H1 antigens. In addition, it was found that TIIA promoted human PBMC to produce IFNγ.

Conclusion: TIIA is a potential novel agent used for melanoma prevention and therapy. However, further studies of TIIA are needed to prove the biological function and mechanisms in vivo.

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 1891.
Abstract 1893: Soy consumption and colorectal cancer risk in humans: a meta-analysis
Authors: Yan Lin , Spitznagel Edward L. , Bosland Maarten C.
Published: February 2011

The purpose of the present study was to determine the relationship between soy consumption and colorectal cancer risk in humans by conducting a meta-analysis of available epidemiologic studies. We systematically reviewed publications obtained through a Medline literature search and identified four cohort and seven case-control studies on soy and colorectal cancer risk that met the inclusion criteria. We extracted the risk estimate (hazard ratio, relative risk or odds ratio) of the highest and the lowest reported categories of intake from each study and conducted this analysis using a random-effects model. Our analysis did not find that soy consumption was associated with colorectal cancer risk (combined risk estimate: 0.90, 95% CI: 0.79, 1.03) nor the separate analyses on colon cancer (combined risk estimate: 0.88, 95% CI: 0.74, 1.06) and rectal cancer (combined risk estimate: 0.88, 95% CI: 0.67, 1.14). However, when separately analyzed on the basis of gender, we found soy was associated with an approximately 21% reduction in colorectal cancer risk in women (combined risk estimate: 0.79, 95% CI: 0.65, 0.97; P = 0.026), but not in men (combined risk estimate: 1.10, 95% CI: 0.90, 1.33). Thus, consumption of soy foods may be associated with a reduction in colorectal cancer risk in women, but not in men.

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 1893.