bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 181: Biological and clinical relevance of quantitative global methylation in repetitive DNA sequences in B-cell chronic lymphocytic leukemia
Authors: Bollati Valentina , Fabris Sonia , Morabito Fortunato , Agnelli Luca , Motta Valeria , Cutrona Giovanna , Gentile Massimo , Deliliers Giorgio Lambertenghi , Bertazzi Pier Alberto , Ferrarini Manlio , Neri Antonino , Baccarelli Andrea
Published: February 2011

Background: B-cell chronic lymphocytic leukemia (B-CLL) is characterized by highly clinical heterogeneity; the identification of reliable prognostic factors useful in predicting patient outcome and planning therapeutic strategies represent a crucial task. Global DNA hypomethylation affecting repeat sequences, such as long interspersed nuclear elements-1 (LINE-1), Alu and satellite α DNA (SAT-α DNA), has been reported in different cancer types and associated with chromosomal instability.

Aim: In order to investigate the role of global DNA methylation in B-CLL we quantified the methylation levels of Alu, LINE-1 and SAT-α repetitive in B-CLL patients and correlated them with the major cytogenetic and molecular features and clinical relevance in predicting therapy-free survival (TFS).

Patients and methods: A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu, LINE-1, and SAT-α in a panel of highly purified (>90%) peripheral mononuclear CD19+ cells from 7 healthy donors and 77 B-CLL untreated well-characterized patients in early stage disease (Binet stage A).

Results: Forty-eight patients had unmutated IgVH genes; ZAP-70 and CD38 were positive in 28 and 35 cases, respectively; 13q14.3 deletion was present as a sole abnormality in 21/33 patients while in the remaining cases it was combined with 17p13.1 (4 pts) or 11q22.3 deletions (7 pts) or both (1 pt). The 11q22.3 and 17p13.1 deletions were detected as sole abnormality in 6 and 7 patients, respectively. Trisomy 12 occurred in 17 patients, as a sole abnormality in all cases.

Methylation levels (median %5mC) were lower in B-CLLs compared with controls (21.4 vs. 25.9; 66.8 vs. 85.7; and 84.0, vs. 88.2; for Alu, LINE-1 and SAT-α, respectively). A significant association was observed with 17p13.1 deletion (15.4 vs. 22.4; 42.9 vs. 68.5; 32.7 vs. 85.0, for Alu, LINE-1 and SAT-α) but not with other major genetic lesions, IgVH mutation status, CD38 or ZAP-70 expression. Notably, lower SAT-α methylation levels appeared to be an independent prognostic marker significantly associated with a shorter TFS.

Conclusion: Our study extended limited evidence in methylation of repetitive sequences in B-CLL suggesting an important biological and clinical relevance in the disease.

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 181.
Abstract 1814: Waldenström macroglobulinemia and lymphoplasmacytic lymphoma: incidence and demographic patterns in the United States, 1988 – 2006
Authors: McMaster Mary L. , Rosenberg Phillip
Published: February 2011

Background: Waldenström macroglobulinemia (WM) is a clinicopathological syndrome that typically presents with bone marrow involvement by a lymphoproliferative process that produces monoclonal IgM. WM shares clinicopathological features with lymphoplasmacytic lymphoma (LPL) and has been characterized as a bone marrow-based subset of LPL to define specific patient populations for inclusion in clinical trials. However, previous epidemiologic studies of WM did not include LPL, and the extent to which the two disorders overlap is unknown. Methods: We estimated age-adjusted incidence rates (IRs) of WM and LPL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyze patterns of WM and LPL separately and jointly by age, gender, and race. We applied generalized linear regression models to test for interaction between the age-specific curves for each disorder. Results: Overall standardized IRs were 3.22 per 1 000 000 person-years for WM (n = 2 230) and 2.21 for extra-medullary LPL (EM-LPL; n = 1 547) during 1988 – 2006. Incidence of WM/LPL combined was 65% higher among males compared to females, and the male: female IR ratio was significantly higher for WM (2.20) than for EM-LPL (1.50). WM/LPL IRs were 40% lower among blacks compared to whites; this difference was due to a black: white IR ratio that was significantly decreased for WM (0.39), but not for EM-LPL (0.94). Racial differences could not be explained solely by covariates reflecting differential access to care. WM and EM-LPL had significantly different age-at-onset curves after adjusting for period effects, and IRs increased with age in both disorders. Conclusions: Epidemiological patterns for WM and EM-LPL appear to suggest disease heterogeneity. Future studies should include assessment of disease classification in reporting to cancer registries; exploration of race, gender, and age effects, with application of additional area-level measures associated with access to care, in epidemiological studies; and clinical and genetic studies to identify unique pathobiological determinants underlying each disease.

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 1814.
Abstract 1816: Attributable risks for hepatocellular carcinoma in the United States
Authors: McGlynn Katherine A. , Quraishi Sabah , Welzel Tania M. , Davila Jessica A. , El-Serag Hashem B. , Graubard Barry I.
Published: February 2011

In the United States, known risk factors for hepatocellular carcinoma (HCC) include infection with the hepatitis B virus (HBV), infection with the hepatitis C virus (HCV), excess alcohol consumption, diabetes, obesity and several rare metabolic disorders (hemochromatosis, α-1 antitrypsin deficiency, porphyrias). The proportion of risk in the U.S. attributable to each factor separately, and to all factors together, however, is not well understood. To better quantify the risk attributable to these factors, logistic regression analysis was conducted using data from the SEER-Medicare linked database. All persons diagnosed with HCC (n=5,607), with at least 3 pre-diagnostic years of Medicare coverage between 1994 and 2005, were included as cases. A 5% random sample of persons residing in SEER locations (n=190,782) were included as controls. For each risk factor, odds ratios (OR) with their 95% confidence intervals (95%CI), and attributable risks (AR) with their 95%CI were calculated. In addition to calculating overall risks, risks were calculated after stratifying on race/ethnicity, gender and time period of HCC diagnosis. Among all individuals, the AR of all factors together was 63.3%. The AR among males, however, was higher than the AR among females (64.6% vs. 60.7%, respectively). By race/ethnicity, the AR of all factors together was highest among Asians (67.9%). This AR was followed by that among Hispanics (64.9%), then whites (63.3%) and finally, blacks (53.0%). Among specific factors, diabetes had the greatest AR at 34%, followed by alcohol-related conditions at 24.0%, HCV at 20.7%, HBV at 5.7%, metabolic disorders at 3.1% and obesity at 2.0%. These findings differed by gender and race/ethnicity, however. While diabetes had the highest AR among both males and females, the factor with the second highest AR among males was alcohol-related diseases, while among females; the factor with the second highest AR was HCV. The factors with the highest AR among each race/ethnic group were: whites - diabetes (36.4%) and alcohol-related disease (23.5%), blacks - HCV (31.9%) and alcohol-related disease (20.3%), Hispanics - alcohol-related disease (29.9%) and diabetes (28.0%), and Asians - HCV (31.7%) and diabetes (26.5%). These findings indicate that the current increase in incidence of HCC in the U.S. may be fueled by different factors in different racial/ethnic and gender groups. Overall, controlling diabetes might have a greater impact than any other single factor on reducing the incidence of HCC in the U.S.

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 1816.
Abstract 1817: Sex disparities in colorectal cancer incidence by anatomic subsite, race and age
Authors: Murphy Gwen A. , Devesa Susan S. , Inskip Peter D. , McGlynn Katherine A. , Cook Michael B.
Published: February 2011

Background: Colorectal cancer remains the fourth most common cancer diagnosed and the second most common cause of cancer death in the United States. Though incidence and mortality rates have declined in recent years, the burden of disease is disproportionate; rates are higher in men than women and the male-to-female incidence rate ratio (MF IRR) increases progressively across the colon from the cecum to the rectum. Rates among races/ethnicities other than whites or blacks have not been frequently reported.

Methods: To examine colorectal cancer rates by sex across anatomic subsite, age, and racial/ethnic groups, we used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for cases diagnosed among residents of 13 registries during 1992-2006. Incidence rates were expressed per 100,000 person-years and age-adjusted to the 2000 US Standard Population; male-to-female incidence rate ratios (MF IRR) and 95% confidence intervals were also calculated.

Results: Among both males and females, total colorectal cancer rates were highest among Blacks (71.0 and 54.8 per 100,000 person-years, respectively) and lowest among Hispanics (47.8 and 32.4). Rates of proximal colorectal cancer were higher than distal and rectal sites for all race/ethnicities. Among each racial/ethnic group, the MF IRR increased fairly monotonically from close to unity for cecal cancers to 1.81 (Hispanics) for rectal cancers. MF IRRs increased with age most rapidly for distal colon cancers from <1.0 at ages <50 years to 1.4-1.9 at older ages. The MF IRR for rectal cancers also rose with age from about 1.0 to 2.0. For proximal cancer, the MF IRR was consistently <1.5 and varied little with age; among American Indian/Alaska Natives it was <1.0 across all ages.

Conclusion: The MF IRR for colorectal cancer varies markedly according to subsite and age but less by racial/ethnic group. These findings may reflect differing exposure to, or metabolism of, hormonal or environmental elements and may have consequences for screening messages.

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 1817.
Abstract 1824: Sun exposure and the risk of malignant lymphoma in an Asian population: The Singapore Lymphoma Study
Authors: Wong Kin-Yoke , Chia Sin-Eng , Kuperan Ponnudurai , Lee Khai-Mun , Lim Soon-Thye , Loong Susan , Mow Benjamin , Ng Siok-Bian , Tan Suat-Hoon , Tan Leonard , Tan Soo-Yong , Tao Miriam , Wong Alvin , Wong Gee-Chuan , Seow Adeline
Published: February 2011

INTRODUCTION

Recent epidemiological studies have reported an inverse association between sun exposure and Non-Hodgkin lymphoma (NHL) which may be related to vitamin D or other factors, but these studies have been conducted almost exclusively in the Western countries, and in temperate locations.

METHODS

The Singapore Lymphoma Study is a hospital-based, case-control study conducted in Singapore between Feb 2005 and Dec 2008. Singapore residents (men and women, ethnic Chinese/Malays/Indians) aged 18 to 90 formed the study population. Detailed information on outdoor activities under sun (for recreational or occupational purposes) during childhood and in adulthood, skin colour and sun sensitivity, and other information on other possible risk factors were collected in personal interviews.

A total of 543 incident malignant lymphomas including 74 Hodgkin's lymphoma (HL), 403 B-cell and 61 T and NK-cell NHL and 5 others, and 830 controls were recruited. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression analysis, adjusted for age, gender, ethnicity, and housing types as surrogate for social economic status.

RESULTS

Skin colour and sun sensitivity did not show any association with risk of malignant lymphoma, after adjusting for ethnicity. We observed a reduced overall risk of NHL (but not HL) among subjects who reported spending time outdoors regularly, especially on weekends/rest days.

A lower risk of NHL was associated with recreational sun exposure in childhood non-school days (OR 0.7, 95% CI 0.5-0.9) and in adulthood weekends/rest days (OR 0.8, 95%CI 0.6-1.0), and the observed association was significant in females when stratified by gender. In addition, occupational sun exposure in males was inversely associated with the risk of NHL (OR 0.7, 95%CI 0.5-1.0). Cumulative working time outside under sun appeared unrelated to NHL overall. The associations were more consistently observed in B-cell NHL subtypes (OR 0.6, 95%CI 0.5-0.8), in diffuse large B-cell lymphoma (OR 0.6, 95%CI 0.5-0.9) and mucosal-associated lymphoid tissue lymphoma (OR 0.5, 95%CI 0.2-1.0), than in T-cell NHL.

CONCLUSION As the first case-control lymphoma study in Asia, our data are consistent with an inverse association between intermittent sun exposure and NHL in this study population.

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 1824.
Abstract 1826: Anthropometric characteristics, physical activity and risk of lymphoid neoplasms in a large US cohort
Authors: Patel Alpa V. , Diver William Ryan , Birmann Brenda M. , Gapstur Susan M.
Published: February 2011

Body size, height, and physical inactivity are known to alter immune function and have been hypothesized to increase risk of non-Hodgkin lymphoma (NHL). However, results of other studies are inconsistent and whether these relationships vary by histologic subtypes of NHL is not well-documented. Therefore, we examined measures of body size (BMI, adult weight gain, and BMI at age 18), height, physical activity, and sitting time in relation to risk of NHL overall and within the major subtypes (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and multiple myeloma (MM)) in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a prospective study of cancer incidence and mortality, using information obtained at baseline in 1992. From 1992-2007, 2000 incident NHL cases were identified among 150,189 men and women who were cancer-free at enrollment. Cox proportional hazards modeling was used to compute hazard rate ratios (RR) while adjusting for potential confounders. Obese men and women (BMI > 30) had a 20% higher incidence of all NHL (95% confidence interval (CI) 1.05-1.37) compared to normal weight individuals (BMI 18.5-<25). BMI at age 18 and BMI measured 10-years prior to baseline (in 1982) were also associated with NHL risk (trend p=0.008 and p=0.0003, respectively) in men and women, even after adjustment for baseline BMI. Height was positively associated with overall risk (RR=1.25, 95% CI 1.10-1.43 for sex-specific quintile 5 vs. 1). Associations were similar across all subtypes of NHL examined. Measures of physical activity and sitting time were not associated with risk of NHL or within any specific subtype. These findings suggest that obesity throughout adulthood and greater height may play a role in the etiology of NHL. While more recent obesity may impact immune function or levels of various hormones, height and BMI at age 18 may reflect early-life consequences of nutrition or exposure to growth hormones.

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 1826.
Abstract 1827: Ethnic differences in the association between body mass and risk of colorectal cancer in the multiethnic cohort
Authors: Lim Unhee , Nomura Abraham M. Y. , Wilkens Lynne R. , Marchand Loic Le , Monroe Kristine R. , Murphy Suzanne P. , Albright Cheryl L. , Henderson Brian E. , Kolonel Laurence N.
Published: February 2011

Introduction. Higher body mass has been associated with elevated risk of developing colorectal cancer. However, limited prospective data are available as to whether the association differs among ethnic groups with varying degrees of susceptibility for central obesity and obesity-related metabolic diseases. We investigated potential ethnic heterogeneity in the body mass-colorectal cancer association in the Multiethnic Cohort.

Methods. Baseline self-reported data were obtained on height, weight, physical activity, diet, and other risk factors from a population-based sample of over 96,810 men and 118,441 women in Hawaii and Los Angeles who were of Caucasian, African, Japanese, Latino, and Native Hawaiian ancestry and were 45-75 years old in 1993. By December 2006, 1,575 male and 1,316 female incident colorectal cancer cases were ascertained from linkage with SEER registries. The associations of interest were estimated by multivariable-adjusted Cox proportional hazards models with age as the time metric.

Results. Prevalence of obesity at baseline (body mass index (BMI) ≥ 30) ranged from 8% in Japanese to 36% in Native Hawaiian men and from 6% in Japanese to 35-37% in African American and Native Hawaiian women. Baseline BMI was positively associated with colorectal cancer risk in men (hazard ratio (HR) for BMI ≥ 30 compared with 18.5-22.9 = 1.50 (95% confidence interval: 1.32, 1.70)) and women (HR = 1.50 (1.33, 1.70)). When examined by sex and ethnicity, men of Caucasian (HR = 1.80 (1.36, 2.39)), African (HR = 2.17 (1.48, 3.16)), and Japanese (HR = 1.80 (1.44, 2.25)) ancestry showed a positive association, whereas Latino and Native Hawaiian men showed a null association (p-interaction = 0.11). In women, the association was strongest among Native Hawaiians (HR = 2.39 (1.24, 4.60)) and Japanese Americans (HR = 2.21 (1.75, 2.79)), followed by Latinas (HR = 1.67 (1.15, 2.41)) and Caucasians (HR = 1.38 (1.07, 1.77)), while it was null among African Americans (p-interaction = 0.12).

Conclusions. These findings from a large follow-up study of diverse ethnic make-up suggest sex- and ethnicity-related heterogeneity in the body mass-colorectal cancer association, which would be important to consider for understanding the etiology and identifying higher-risk groups for intervention.

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 1827.
Abstract 1835: Life Raft Group registry: An observational registry of gastrointestinal stromal tumor (GIST) patients
Authors: Call Jerry W. , Josephy P. D. , Eickhoff Jens , Pazmino Roberto , Sarnas Magda , Scherzer Norman J.
Published: February 2011

We report on an international observational registry of patients with Gastrointestinal Stromal Tumors (GIST). The Life Raft Group (LRG) registry contains information provided by its members since May 8, 2000. As participation is primarily via the internet some selection bias may occur, e.g., participation by younger patients may be higher. The median current age is 56.2 for females and 57.8 for males. The registry includes 1106 GIST patients, 536 females and 570 males. Mutational status was reported by 268 patients as follows. KIT: exon 11 = 156 pts (58%), exon 9 = 37 pts (14%), exon 13 = 4 (1.5%), unspecified exon = 2 (.7%); PDGFRA: unspecified exon = 1 (.4%), exon 12 = 2 (.7%), exon 14 = 1 (.4%); exon 18 = 12 (4.5%); wild-type = 49 (18%); SDH mutations = 4 (1.5%). Pediatric patients represented 2.6% of the registry. Wild-type patients had a lower median age at diagnosis (29.5 years) than other types, representing a high percentage of pediatric-type GIST patients in this series. Overall, 74% (199) of patients had a KIT mutation, 6% (16) had a PDGFRA mutation, 18% (49) were wild-type and 1.5% (4) had SDH mutations. The age at diagnosis distribution was different between males and females with a higher ratio of females to males diagnosed prior to age 35 (2.02 to 1), a lower ratio between age 35 to 70 (0.81 to 1) and about the same ratio in older patients, 70 and older (1.09 to 1). Overall, the ratio of females to males was 0.94 to 1. The median overall survival for all patients was 14.5 years for females and 8.8 years for males. A multivariate Cox proportional hazard model was used to evaluate the association between gender and overall survival. Age was included as a covariate. For age at diagnosis, the hazard ratio was 1.025 (P = <0.001); for gender, the hazard ratio was 0.642 (P = <0.001). In this observational registry, significant differences were noted between females and males; the ratio of females to males varied with age at diagnosis category and females had a significantly longer overall survival than males.Age at diagnosisAge CategoryFMGrand TotalF/M Ratio5-15166222.6715-20115162.2020-25136192.1725-302412362.0030-353118491.7235-403339720.8540-4552681200.7645-5070751450.9350-5576951710.8055-6069791480.8760-6547721190.6565-703947860.8370-751917361.1275-80811190.7380-856392.0085-90101 90-951121.00Unknown2016361.25Grand Total53657011060.94

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 1835.
Abstract 1840: P53 codon 72 SNP (R72P) and prostate cancer risk
Authors: Rogler Anja , Rogenhofer Michael , Tannapfel Andrea , Borchardt Albert , Lunz Jens-Claudio , Hofstädter Ferdinand , Hartmann Arndt , Stoehr Robert
Published: February 2011

Aims: The tumor suppressor p53 plays a major role in stress responses of the cell and modulates cell cycle arrest and apoptosis. The p53 R72P SNP (G/C) was found to be associated with increased risk of various malignancies. However, for prostate cancer only limited data are available, especially in Caucasian population. We therefore analysed the distribution of the R72P SNP in male Caucasian prostate cancer patients and a healthy control group.

Methods: Peripheral blood or normal prostate tissue from formalin-fixed, paraffin-embedded tissue sections were used for DNA isolation. Allelic variants of p53 Codon 72 SNP were determined using RFLP analysis. Overall, 194 male patients without any malignancy (mean age 67,3 ±10,6, range 34-88) and 118 male consecutive prostate cancer patients (mean age 64,2 ±6,0, range 46-74) were investigated.

Results: The distribution of the p53 R72P SNP did not differ significantly between prostate cancer patients and the control group (Cases GG 55.1%, GC 37.3%, CC 7.6%; Controls GG 53.6%, GC 40.7%, CC 5.7%). There was also no association between the allelic variants and Gleason score (Gleason sum < 7 GG 61.2%, GC 32.7%, CC 6.1%; Gleason sum ≥ 7 GG 53.3%, GC 38.3%, CC 8.3%). Significant difference in the distribution of the R72P SNP regarding onset of the disease was found (p=0,035), showing increased frequency of the proline variant in younger patients (Age ≤ 60 GG 37%, GC 3.7%, CC 59.3%; Age > 60 GG 60.7%, GC 8.3%, CC 31%). Regarding recurrence, a trend towards increase of the G-allele was found in patients with early recurrence (Cases with recurrence GG 81.3%, GC + CC 18.7%, Cases with recurrence GG 50%, GC + CC 50%, p=0.039).

Conclusions: The overall risk of prostate cancer is not associated with R72P SNP. However, disease onset might be modulated by the p53 variant allele suggesting an important role of apoptosis regulation in prostate carcinogenesis.

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 1840.
Abstract 1842: Familial demonstration of the involvement of E-cadherine germ-line mutation in inherited invasive lobular breast carcinomas
Authors: Zeming Xie , Zeming Xie , Uhrhammer Nancy , Bignon Yves Jean
Published: February 2011

Introduction

Germline mutations of the CDH1 (epithelial cadherin, OMIM 192090) gene have been extensively studied in hereditary diffuse gastric cancer (HDGC) families. Carriers of CDH1 germline mutations have a cumulative gastric cancer risk of 40-67% for men and 63-83% for women. Putative associated risk of lobular breast cancer(LBC) has also been documented in some HDGC families. Here we report a 86 members family, with a deleterious CDH1 germline mutation identified in 3 LBC affected members on 2 successive generations, 2 of them being bilateral LBC cases. It is noteworthy that no DGC was observed in this family.

Subjects and Methods

The family is of Caucasian origin, with 5 women affected by breast cancers. The proband is a female diagnosed with ILBC at the age of 60, her daughter was diagnosed with bilateral ILBC at the age of 42, one of her sisters died of breast cancer diagnosed at the age of 53, histological type was unknown. Two of her cousins were also diagnosed with breast cancer at the age of 63 and 54 respectively (one is a bilateral ILBC, another unknown). There is no confirmed diffused gastric cancer diagnosis in the history of this family. The affected members, their offspring, and siblings were recruited for genetic consultation. Two independent blood samples were tested after signing informed consent for each family member. Complete screening of CDH1, BRCA1 and BRCA2 genes was performed on 7 cases by sequencing exons and intron-exon boundaries.

Results

No BRCA1 and BRCA2 mutations were found in the family. A CDH1 Q95X germ-line mutation was found in all the 3 living women with invasive lobular breast cancers (2 of them developed bilateral ILBCs) and a 71-year-old healthy male member (one of the brothers of the proband). The mutation is also present in an obligatory carrier woman who developed a pancreatic cancer at the age of 56. Gastrointestinal endoscopy was recommended for indicative living individuals during genetic consultations, when they harbored the CDH1 mutations. No suspected gastric lesion was found.

Conclusion

Our report demonstrates the first clear example of the involvement of a deleterious E-cadherine germ-line mutation in inherited invasive lobular breast carcinoma. Screening for CDH1 mutation should be considered in families with multiple ILBC cases, even in the absence of DGC cases; ILBC risk should be considered for female carriers during consultations; prophylactic gastrectomy may not be regularly recommended in CDH1 mutations carriers without family histories of DGC.

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 1842.
Abstract 1846: Identification of a germline mutation in PMS2, a DNA mismatch repair gene, in a large consanguineous family with a history of Pediatric GBMs
Authors: Killela Patrick J. , Rasheed Ahmed B. , Yan Hai
Published: February 2011

Glioblastoma multiforme (GBM) is the most frequent and malignant human brain tumor. It is widely accepted that human cancer is a genetic disease caused by sequential accumulation of cancer gene mutations. Specifically, the gene or genes which initiate GBM formation has yet to be identified. Through collaboration with the Pakistani National Genetic Institute we have identified a consanguineous family presenting with a history of Pediatric GBMs to conduct comprehensive genomic analysis in hopes of identifying this “gatekeeper” gene. In this pedigree four children are deceased from GBM while an additional five infants have died within 4 days of birth without diagnosis. GBM has been the only diagnosed cancer in this family, indicating the existence of a GBM-specific germline mutation as a causative agent for the GBM clinical phenotype. Comprehensive genomic analysis has been conducted to elucidate a genetic aberration which is inherited and can be attributed to the GBM presenting clinical phenotype. We have collected blood and tumor DNAs for this family and performed sequencing on numerous genes including TP53, APC, IDH1, IDH2, PMS2, MLH1, MSH2, and, MSH6. Sequencing has successfully identified a germline frame shift mutation (p.Y181X) in PMS2. All affected patients have a homozygous mutation while their parents are both heterozygous carriers, suggesting the homozygous inheritance of this mutation is a causative agent for the GBM clinical phenotype. Our study suggests that the PMS2 inherited homozygous mutation could be a critical event in GBM formation.

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 1846.
Abstract 185: Protein expression of DNMT1, DNMT3a, and DNMT3b in human hepatocellular carcinoma
Authors: Endo Kanenori , Miyake Takanori , Honjo Soichiro , Tsujitani Shunichi , Hirooka Yasuaki , Ikeguchi Masahide
Published: February 2011

Background/Aims: DNA methylation plays an important roles in the regulation of gene expression. Gene silencing by aberrant hypermethylation of CpG islands in gene promoter regions in frequently found in human cancers. By the assistance of DNA methyltransferases (DNMTs), methyl groups are transferred to promoter CpG islands, many tumor suppressor gene can be silenced by promoter CpG islands methylation. However, studies on DNMTs in hepatocellular carcinoma (HCC) are rare, and there are no immunohistochemical studies on the correlations with these expressions and HCC patient's suvival.

Methods : We immunohistochemically examined the expression of DNMT1, DNMT3a and DNMT3b and the relationships between these expressions and histological grade, clinicopathological parameters and patient's survival in 95 patients with HCC.

Results : DNMT1, DNMT3a and DNMT3b immunoreactivities were presented in nuclei of HCC cells. In the tumorous lesion, the number of positive immunoreactivities was 95/95 (100%) for DNMT1, 87/95 (92%) for DNMT3a and 81/95 (85%) for DNMT3b. The degree of each protein expression significantly correlated with tumor differentiation and intrahepatic metastasis, and only DNMT3a protein expression significantly correlated with portal vein imvolvement of tumor. Though there were no relations between the DNMTs expression and tumor size, over-expressions of DNMT3a and 3b proteins were associated with poor prognosis of HCC's patients. Moreover, the overall survival rate of patients group that showed over-expression of three DNMTs in tumorous lesion was significantly lower than it of other patients groups.

Conclusion : DNMTs are involved in HCC progression, and their overexpression is associated with poor prognosis.

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 185.
Abstract 1851: Investigation of the Birt-Hogg-Dubé tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer
Authors: Nahorski Michael S. , Lim Derek Hk , Martin Lynn , Gille Johan JP , Mckay Kirstin , Rehal Pauline K. , Ploeger Martijn , van Steensel Maurice , Tomlinson Ian P. , Latif Farida , Menko Fred H. , Maher Eamonn R.
Published: February 2011

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant multisystem disorder with skin (fibrofolliculomas or trichodiscomas), lung (cysts and pneumothorax) and kidney (renal cell carcinoma) tumours. Although colorectal neoplasia was reported initially to be part of the BHD phenotype, some recent studies have not confirmed this association. We undertook a series of clinical and laboratory studies to investigate possible relationships between colorectal neoplasia and the BHD gene (FLCN). Thus we investigated whether individuals with familial colorectal cancer of unknown cause might have unsuspected germline FLCN mutations, looked for somatic FLCN C8 tract mutations in microsatellite unstable sporadic colorectal cancers and assessed the risk of colorectal neoplasia and possible genotype-phenotype correlations in BHD patients. Although we found previously that germline FLCN mutations can be detected in ∼5% of patients with familial renal cell carcinoma, we did not detect germline FLCN mutations in 50 patients with familial non-syndromic colorectal cancer. Analysis of genotype-phenotype correlations for two recurrent FLCN mutations identified in a subset of 51 families with BHD demonstrated a significantly higher risk of colorectal neoplasia in c.1285dupC mutation (within the exon 11 C8 mononucleotide tract) carriers than in c.610delGCinsTA mutation carriers (χ2=5.78 P=0.016). Somatic frameshift mutations in the FLCN exon 11 C8 mononucleotide tract were detected in 23% of sporadic colorectal cancers with microsatellite instability suggesting that FLCN inactivation might contribute to colorectal tumourigenesis. Our findings suggest that the previously reported clinical heterogeneity for colorectal neoplasia may reflect allelic heterogeneity and the risk of colorectal neoplasia in BHD syndrome requires further investigation.

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 1851.
Abstract 1853: Monoclonal B-cell Lymphocytosis (MBL) has increased incidence in non-Hodgkin lymphoma (NHL) Families
Authors: Slager Susan L. , Rabe Kari G. , Achenbach Sara J. , Call Timothy G. , Vachon Celine M. , Habermann Thomas M. , Kay Neil E. , Ansell Stephen M. , Shanafelt Tait D. , Cerhan James R. , Hanson Curtis A.
Published: February 2011

Background. MBL is defined as a monoclonal expansion of B lymphocytes (< 5 × 109/L) in the blood without associated lymphadenopathy or organomegaly; MBLs with a chronic lymphocytic leukemia (CLL) immunophenotype have been termed as CLL-like MBL. The prevalence of CLL-like MBL in the general population is 3.5-12% but increases with age; however, the frequency is even higher (∼13-18%) among unaffected relatives from CLL families (i.e., families with two or more CLL members). We and others have found that a small proportion of individuals with CLL-like MBL individuals and lymphocytosis will progress to CLL requiring treatment (∼1.1% per year). Because CLL and NHL have been shown to aggregate together within families, suggesting a shared pathogenesis, we evaluated the frequency of MBL in NHL families.

Methods. Individuals were obtained from an ongoing study of NHL families (i.e., families with 2 or more NHL members). However, we limited to NHL families with at most 1 individual with CLL due to the known increased frequency of MBL in CLL families. Multi-color flow cytometry was performed on fresh peripheral blood samples. A CBC and differential count was simultaneously obtained using an automated blood cell counter. Five possible flow diagnoses were defined as: CLL-like MBL (CD5+CD20dim), atypical MBL (CD5+CD20bright), non-CLL like MBL (CD5−), and normal immunophenotype (NIPT). Medical records of NHL cases were reviewed to confirm disease.

Results. A total of 30 individuals from 16 NHL families had available flow cytometry results. The mean age at flow analysis was 56 years (range 37− 83 years). We identified 5 individuals with MBL from 4 families: 3 of the 6 had CLL-like MBL, 1 had atypical MBL, and 1 had non-CLL like MBL. The remaining 25 individuals had a NIPT. Thus, the MBL rate in NHL families is 17% (5/30). Among the CD5+ MBL (both CLL-like and atypical MBL) individuals, all were female and the mean absolute lymphocyte count was 1.4 × 109/L. Of interest, 1 of the CLL-like MBL individuals is from a family where two members had monoclonal gammopathy of uncertain significance (MGUS).

Conclusion: Our data show that MBLs of various phenotypes can be found at a higher prevalence in NHL families than that of the general population. Further, the frequency of MBL in NHL families is comparable to that of CLL families. Although more work is needed, our results suggest that MBL may be clustering within NHL families, and thus support a possible common inherited predisposition of NHL and CLL, with MBL signifying a shared early pathogenetic step.

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 1853.
Abstract 186: Methyl binding domain protien 2 (MBD2) promotes epithelial dedifferentiation in breast cancer
Authors: Mian Omar , Ginder Gordon
Published: February 2011

Purpose: Methyl-CpG Binding Proteins (MCBPs) are thought to function as the interpreters of epigenetic information encoded in cytosine methylation. Their ability to translate DNA methylation into local transcriptional repression has sparked interest in the role MCBPs play in cancer. We have studied the function of Methyl-Binding Domain Proteins (MBDs) in human mammary epithelial cancers, where repatterning of CpG methylation is common.

Results: We find Methyl Binding Domain Protein 2 (MBD2) promotes the abnormal multi-cellular morphology characteristic of tumor cells. Stable MBD2 knockdown in MCF7 cells leads to an increased proportion of differentiated epithelial structures (e.g. acinii, 70%, [CI=0.55-0.83]) in 3D culture when compared to untransfected (46%, [CI=0.39-0.53], p ≤ 0.038) or control shRNA transfected (37%, [CI=0.29-0.45], p ≤ 0.012) populations. To identify the genes underlying this MBD2 dependant phenotype, high throughput quantitative PCR data were probed using self organizing map (SOM) analysis. We found only a small subset of the breast cancer specific tumor suppressors known to be silenced by promoter hypermethylation were regulated by MBD2 alone (n=7, 15%). Several genes previously shown (by us and others) to be MBD2 bound by chromatin immunoprecipitation (ChIP) were not induced by MBD2 knockdown, suggesting MBD2 exhibits tumor and tissue-type specificity. Moreover, gene sets activated by the DNA methylation inhibitor, 2-deoxy-5-aza-cytidine (4uM, n=30, 67%), and MBD2 knockdown (n=18, 40%) were different, suggesting pleiotropic activity; for example at loci that exhibit additive induction (n=11, 24%) and those that do not. MBD2 dependant genes were rapidly re-suppressed upon rescue with a shRNA binding site variant MBD2 and ChIP studies confirmed binding of MBD2 at all genes examined within the MBD2 dependant cluster. Transient siRNA mediated knockdown of individual MBD2 dependant genes did not restore the dedifferentiated phenotype, suggesting coordinate regulation by multiple downstream targets of MBD2.

Conclusion: Our studies show MBD2 promotes tumor suppressor silencing and dedifferentiation in breast cancer and intimate a role for MBD2 in fine-tuning mammary epithelial gene expression patterns.

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 186.
Abstract 1860: Association of esophageal cancer risk with genetic polymorphisms of xenobiotic metabolizing genes, DNA repair genes, and inflammation-regulating genes in Huaian, China
Authors: Xu Li , Wang Zemin , Tang Lili , Wang Shaokang , Hu Xu , Sun Guiju , Wang Jia-Sheng
Published: February 2011

Accumulating evidences suggest that both exposure to environmental carcinogens and individual susceptibility factors contribute to the formation of esophageal cancer. Huaian City is one of the highest risk areas of esophageal cancer in China with the annual incidence over 100/100,000 people. To explore etiological risk factors contributing to the high rate of esophageal cancer, a population-based case-control study was conducted in 185 esophageal squamous cell carcinoma (ESCC) cases and 515 age-, gender-, and residency-matched healthy controls in Huaian. Our previous study found an association between dietary fumonisin exposure and ESCC risk in this population. In the present study, we further investigated the association between ESCC and polymorphic genes involving in xenobiotic metabolizing activities, DNA repair, and inflammation regulation including GSTM1, GSTT1, XPD (Lys751Gln), hOGG1 (Ser326Cys), TNF-α (G308A), NF-κB (−94ins/delATTG), COX-2 (G765C), and iNOS (Ser608Leu). Genetic polymorphisms of GSTM1 and GSTT1 were determined by multiplex PCR and other polymorphisms were determined by PCR-restriction fragment length polymorphism (RFLP) analysis using genomic DNA samples obtained from lymphocytes of study subjects. The prevalence of GSTT1 null genotype was significantly higher in cases (53.51%) than in controls (41.94%) (p=0.0067), with an age- and gender-adjusted odds ratio (OR) of 1.68 and 95% confidence interval (CI) of 1.18 − 2.39. After stratifying by gender, GSTT1 null type was found more prevalent in male cases (57.14%) than in male controls (42.64%) (p=0.0117). XPD Lys751Gln polymorphism was associated with increased ESCC risk (age- and gender-adjusted OR=1.74, 95% CI: 1.11-2.74). XPD heterozygous and mutant genotypes (Lys/Gln+Gln/Gln) were more prevalent in cases (20.54%) than in controls (14.26%) (p=0.0453), and in female cases (24.32%) than in female controls (13.01%) (p=0.0187). Heterozygous genotype of TNF-α was found in 12.97% of cases and 7.65% of controls, showing a marginal increased risk of ESCC (adjusted OR=1.68, 95% CI: 0.95-2.98). These results suggest that polymorphisms of GSTT1, XPD and TNF-α gene may contribute to ESCC risk in this high-risk population. (Supported by NIH/NCI grants, CA94683 and CA90997).

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 1860.
Abstract 1866: Polymorphisms in DNA double-strand break repair genes and end-joining capacity from sisters discordant for breast cancer from the New York site of the BCFR
Authors: Wu Hui-Chen , Machella Nicola , Wang Qiao , Senie Ruby T. , Santella Regina M. , Terry Mary Beth
Published: February 2011

Dysfunction in DNA double strand break (DSB) repair increases breast cancer risk. Genetic variation could be an important factor in determining DSB capacity. However, data on the association of single nucleotide polymorphisms (SNPs) of DSB repair genes with phenotype and with breast cancer risk are limited. We determined genotypes for 25 DSB repair SNPs in a total of 298 families with discordant sisters for breast cancer, including 85 families with end-joining (EJ) capacity data available from the New York site of the Breast Cancer Family Registry (BCFR). We observed that XRCC4 variant (rs1056503) was associated with increased breast cancer risk with age-adjusted odds ratios (OR) of 1.67 (95% confidence interval (CI)=1.02-2.74) and a significant inverse effect of an XRCC5 variant (rs1051677) with an age-adjusted OR of 0.07 (95% CI=0.009-0.58). EJ capacities differed by different genotypes of BRCA1 among controls, and different genotypes of XRCC5 among cases and controls. However, in a final multivariable conditional logistic model, including RAD52 (rs11226), XRCC4 (rs1056503) and XRCC5 (rs3834), we did not observed any statistically significant genetic effect of DSB repair genes on breast cancer risk. Although these findings suggest that selected polymorphisms of DSB pathway genes were associated with EJ capacity, there were no main associations with breast cancer suggesting that DSB phenotype rather than genotype may be more important in predicting breast 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 1866.
Abstract 1867: DNA repair gene polymorphisms and tobacco smoking and the risk of colorectal adenoma
Authors: Gao Ying , Hayes Richard , Huang Wen-Yi , Caporaso Neil , Burdett Laurie , Yeager Meredith , Chanock Stephen , Berndt Sonja
Published: February 2011

Genetic variants of DNA repair genes may contribute to their altered capacity to repair endogenous and exogenous DNA damage. Although rare mutations in mismatch repair genes are known to lead to hereditary non-polyposis colorectal cancer, to date studies investigating common single nucleotide polymorphisms (SNPs) in DNA repair genes and colorectal cancer or adenoma risk have only examined a small number of variants in a limited number of genes. We conducted a comprehensive analysis of DNA repair gene polymorphisms and colorectal adenoma risk using a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Effect modification by smoking, which is a known risk factor for adenoma, was also explored. A total of 1,338 advanced, left-sided colorectal adenoma cases and 1,503 frequency-matched controls without evidence of a left-sided polyp on sigmoidoscopy were included in the current study. Using DNA extracted from blood specimens, 3,401 tag SNPs in 153 DNA repair genes were genotyped. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between genetic variants and adenoma risk assuming a log-additive model for the genotype. Among Caucasians, 30 SNPs were associated with adenoma risk at p<0.01. The most significant finding was for a non-synonymous SNP in EXO1 (rs9350), which was predicted to be deleterious using the SIFT and PolyPhen databases. The C allele at EXO1 rs9350 was associated with a 1.30-fold increased risk (95% CI=1.11-1.51, P=0.001). The association appeared to be limited to smokers (OR=1.54, 95% CI=1.26-1.89) with the strongest risk for current smokers (OR=2.15, 95% CI=1.27-3.65), and an intermediate risk for former smokers (OR=1.45, 95% CI=1.14-1.82), compared to never smokers (OR=0.98, 95% CI=0.76-1.25) that exhibited no increased risk (Pinteraction=0.002). Among the top findings, a SNP (rs17503908) in ATM with an overall OR of 0.75 (95% CI=0.63-0.91) was also modified by smoking (Pinteraction=0.006); the T allele at ATM rs17503908 was protective among never smokers (OR=0.55, 95% CI=0.40-0.76) but not among smokers (OR=0.89, 95% CI=0.70-1.13). The study suggests that polymorphisms in EXO1 and ATM may be associated with risk of advanced colorectal adenoma with the effects modified by tobacco smoking status. Our findings warrant extended investigations of these associations for colorectal cancer risk.

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 1867.