Kelly J. Yu

Pancreatic Cancer Risk and ABO Blood Group Alleles: Results from the Pancreatic Cancer Cohort Consortium

A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with risk of pancreatic cancer, but the influence of specific ABO genotypes remains unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, and BB) in 1,534 cases and 1,583 controls from 12 prospective cohorts in PanScan, grouping participants by genotype-derived serologic blood type (O, A, AB, and B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared with blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 [95% confidence interval (95% CI), 1.18-1.62], 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5 cases per 100,000 subjects per year. An increase in risk was noted with the addition of each non-O allele. Compared with OO genotype, subjects with AO and AA genotype had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), whereas subjects with BO and BB genotypes had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54) compared with nonsmokers of blood type O. We concluded that ABO genotypes were significantly associated with pancreatic cancer risk.A recent genome-wide association study (PanScan) identified significant associations at the ABO gene locus with pancreatic cancer risk; however, the mechanisms underlying these associations and the influence of specific ABO genotypes remain unknown. We determined ABO genotypes (OO, AO, AA, AB, BO, BB) in 1534 cases and 1583 controls from 12 prospective cohort studies participating in PanScan. We also grouped participants by genotype-derived serologic blood type (O, A, AB, B). Adjusted odds ratios (ORs) for pancreatic cancer by ABO alleles were calculated using logistic regression. Compared to blood type O, the ORs for pancreatic cancer in subjects with types A, AB, and B were 1.38 (95% confidence interval [CI], 1.18-1.62), 1.47 (95% CI, 1.07-2.02), and 1.53 (95% CI, 1.21-1.92), respectively. The incidence rates (cases per 100,000 subjects per year) for blood types O, A, AB, and B were 28.9, 39.9, 41.8, and 44.5. An increase in risk was noted with the addition of each non-O allele. Compared to OO, subjects with AO and AA had ORs of 1.33 (95% CI, 1.13-1.58) and 1.61 (95% CI, 1.22-2.18), while subjects with BO and BB had ORs of 1.45 (95% CI, 1.14-1.85) and 2.42 (1.28-4.57). The population attributable fraction for non-O blood type was 19.5%. In a joint model with smoking, current smokers with non-O blood type had an adjusted OR of 2.68 (95% CI, 2.03-3.54), compared with non-smokers with blood type O. Among participants in a large prospective cohort consortium, ABO genotypes were significantly associated with pancreatic cancer risk.

The extent of genetic diversity of Epstein-Barr virus and its geographic and disease patterns: a need for reappraisal.

Epstein-Barr virus (EBV) is a ubiquitous, gamma-1 lymphotrophic virus etiologically linked to nasopharyngeal carcinoma (NPC), endemic to Southern China, and Burkitt lymphoma (BL), endemic to equatorial Africa, both of which are rare elsewhere in the world. Why EBV is associated with different malignancies in different geographic regions remains puzzling and may be related to EBV genotypic variability through specific disease and geographic associations. We review the literature on sequence variation in EBV genes, focusing on LMP-1, EBNA-1, and BZLF-1 and their distribution by geography and disease. Given the limitations of current studies, definitive conclusions regarding the link between EBV genotypes, disease and geography are not possible. We suggest that the true extent of EBV diversity is likely to be greater than is currently recognized. Additional studies conducted in carefully selected populations, that are sufficiently powered to provide robust estimates, and that utilize testing approaches that permit full characterization of viral diversity are needed to further our understanding of patterns of EBV genetic variation and their association with malignancies in different regions.

Identification of several human homologs of hamster DNA damage-inducible transcripts. Cloning and characterization of a novel UV-inducible cDNA that codes for a putative RNA-binding protein.

Low ratio hybridization subtraction technique was previously used in this laboratory to enrich and isolate a number of low abundance UV-inducible hamster transcripts (Fornace, A. J., Jr., Alamo, I. J., and Hollander, M. C. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 8800–8804) that led to the identification and cloning of five important hamster and humanGADD genes (Fornace, A. J., Jr., Nebert, D. W., Hollander, M. C., Luethy, J. D., Papathanasiou, M., Fargnoli, J., and Holbrook, N. J. (1989) Mol. Cell. Biol.9, 4196–4203). In this study we have characterized the remaining DNA damage-inducible (DDI) transcripts. Of the 24 DDI clones, 3 clones (A13, A20, and A113) representing different regions of the same hamster cDNA exhibited near perfect homology to human p21 WAF1/CIP1 cDNA. The DDI clones A26, A88, and A99 displayed very high sequence homologies with the human proliferating nuclear antigen, rat translation initiation factor-5 (eIF-5), and human thrombomodulin, respectively, whereas clones A29 and A121 matched with express sequence tagged sequences of unknown identity. The DDI clones A18, 106, and A107 were different isolates of the same hamster cDNA (hereafter referred to as A18) and displayed high sequence homology with the members in the heterogeneous ribonucleoprotein (hnRNP) family. Using the hamster A18 partial-length cDNA as a probe, we screened human fibroblast cDNA library and isolated the corresponding full-length human cDNA. The deduced amino acid sequence revealed that the putative protein contains all the canonical features of a novel glycine-rich hnRNP. The A18 mRNA levels were specifically increased in response to DNA damage induced by UV irradiation or UV mimetic agents. Thus the putative A18 hnRNP is the first hnRNP whose mRNA is specifically regulated in response to UV-induced DNA damage; accordingly, it may play some role in repair of UV-type DNA damage.

Inhibitory effect of Bcl-2 on p53-mediated transactivation following genotoxic stress

In the cellular response to genotoxic stress, cell cycle checkpoint and apoptosis are considered to be two of the major biological events in maintaining genomic stability. The tumor suppressor p53 has been shown to play critical roles in these stress-induced cellular responses at least in part through the activation of its down-stream genes, such as p21CIP1/WAF1, GADD45 and BAX. In addition, p53 has been found to down-regulate the expression of BCL-2, which is able to block apoptosis induced by both p53-dependent and independent signaling events. In this report, we have found that increased expression of Bcl-2 protein in the human Burkitts lymphoma WMN cell line suppressed apoptosis induced by different DNA-damaging agents. The induction of p53-regulated genes including GADD45, p21CIP1/WAF1 and BAX by genotoxic stress was substantially reduced in cells expressing high levels of Bcl-2 protein. Furthermore, Bcl-2 protein was shown to specifically suppress the p53-mediated transactivation of p21CIP1/WAF1 and PG13-CAT, which is a typical p53-binding-site reporter construct. Similarly, the inhibitory effect of Bcl-2 protein was seen in a GADD45 promoter reporter construct after treatment with methylmethane sulfonate or UV-radiation. These results indicate that in addition to its apoptosis-suppressing activity, Bcl-2 protein is able to inhibit transactivation of p53-regulated genes, which function in multiple important cellular responses to genotoxic stress, including the control of cell cycle checkpoints, cell growth suppression and DNA repair.

Extended mortality results for prostate cancer screening in the PLCO trial with median follow‐up of 15 years

Two large‐scale prostate cancer screening trials using prostate‐specific antigen (PSA) have given conflicting results in terms of the efficacy of such screening. One of those trials, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, previously reported outcomes with 13 years of follow‐up. This study presents updated findings from the PLCO trial.

Prognostic utility of anti-EBV antibody testing for defining NPC risk among individuals from high-risk NPC families.

Purpose: Epstein–Barr virus (EBV) infection and a family history of nasopharyngeal carcinoma (NPC) are associated with NPC risk. We examined the risk associated with EBV markers and their clinical utility to identify NPC susceptibles within high-risk NPC families. Experimental Design: We evaluated antibody titers against viral capsid antigen (VCA) IgA, EBV nuclear antigen-1 (EBNA1) IgA, and DNase among unaffected relatives of NPC cases from 358 multiplex families in Taiwan. Incident NPC cases were identified via linkage to the National Cancer Registry. Clinical examinations of 924 individuals were also done to identify occult, asymptomatic NPC. Baseline EBV serology was used to estimate NPC risk using rate ratios with 95% CI. Associated sensitivity/specificity and receiver operating characteristic (ROC) curves were calculated. Results: A total of 2,444 unaffected individuals with 15,519 person-years (6.5 years median follow-up) yielded 14 incident NPC cases (nearly 11 times the general population rate). The absolute rate of NPC among anti-EBV EBNA1 IgA seropositives using a standard positivity cutoff versus an optimized cutoff point defined by ROC analyses was 265/100,000 person-years with a 4.7-fold increased risk of NPC (95% CI: 1.4–16) and 166/100,000 person-years with a 6.6-fold increase (95% CI: 1.5–61), respectively. Sensitivity and specificity using the optimized positivity cutoff points were 85.7% and 51.2%, respectively. It is estimated that active evaluation of 49% of individuals from high-risk NPC families seropositive for this marker could lead to earlier detection of up to 86% of NPC cases. Risks associated with the other three EBV markers were weaker. Conclusions: Future efforts are needed to identify susceptibility markers among high-risk NPC families that maximize both sensitivity and specificity. Clin Cancer Res; 17(7); 1906–14. ©2011 AACR.

Familial Tendency and Risk of Nasopharyngeal Carcinoma in Taiwan: Effects of Covariates on Risk

In the present study, the authors compared the long-term risk of nasopharyngeal carcinoma (NPC) of male participants in an NPC multiplex family cohort with that of controls in a community cohort in Taiwan after adjustment for anti-Epstein-Barr virus (EBV) seromarkers and cigarette smoking. A total of 43 incident NPC cases were identified from the 1,019 males in the NPC multiplex family cohort and the 9,622 males in the community cohort, for a total of 8,061 person-years and 185,587 person-years, respectively. The adjusted hazard ratio was 6.8 (95% confidence interval (CI): 2.3, 20.1) for the multiplex family cohort compared with the community cohort. In the evaluation of anti-EBV viral capsid antigen immunoglobulin A and anti-EBV deoxyribonuclease, the adjusted hazard ratios were 2.8 (95% CI: 1.3, 6.0) and 15.1 (95% CI: 4.2, 54.1) for those positive for 1 EBV seromarker and positive for both seromarkers, respectively, compared with those negative for both EBV seromarkers. The adjusted hazard ratio was 31.0 (95% CI: 9.7, 98.7) for participants who reported a family history of NPC and who were anti-EBV-seropositive compared with individuals without such a history who were anti-EBV-seronegative. The findings suggest that both family history of NPC and anti-EBV seropositivity are important determinants of subsequent NPC risk and that the effect of family history on NPC risk cannot be fully explained by mediation through EBV serologic responses.

Cancer patterns in nasopharyngeal carcinoma multiplex families in Taiwan

Genetic and environmental factors have been implicated in the etiology of nasopharyngeal carcinoma (NPC), a tumor known to be closely associated with Epstein‐Barr virus (EBV) infection. Studies have reported familial aggregation of NPC and have suggested the possible aggregation of NPC and other cancers. We evaluated familial aggregation of cancer in 358 high‐risk families with two or more NPC cases enrolled in a NPC genetics study in Taiwan. Participants were linked to the Taiwan National Cancer Registry to identify incident cancers diagnosed after study enrollment (started in 1996) and before December 31, 2005, or death. In total, 2,870 individuals from the NPC Multiplex Family Study contributed 15,151 person‐years over an average of 5.3 years of follow‐up. One hundred ten incident cancers were identified. Multiple‐primary standardized incidence ratios (MP‐SIRs) were computed to evaluate overall cancer risk associated with infectious agents and with other tumors. The overall MP‐SIR was 1.3 (95% CI: 1.1–1.6), which was largely explained by an excess in NPC (MP‐SIR = 15; 95% CI: 10–23). Exclusion of incident NPC diagnoses led to an overall MP‐SIR of 1.0 (95% CI: 0.83–1.3). Similarly, the observed excess risk of cancers associated with infectious agents (MP‐SIR = 2.0; 95% CI: 1.5–2.6) was driven by the excess in NPC; exclusion of NPC cases led to a reduced MP‐SIR that did not differ from 1.0. Analysis of the largest NPC multiplex family study to date confirms the presence of coaggregation of NPC within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors.

The familial aggregation of cannabis use disorders.

AIMS The aim of this paper is to examine the familial aggregation of cannabis use disorders and other psychiatric conditions among first-degree relatives and spouses of probands with a cannabis use disorder. DESIGN Controlled family study methods. SETTING Out-patient psychiatric clinics and the local community (same geographic area). PARTICIPANTS Two hundred and sixty-two probands with a life-time history of cannabis use disorder, alcohol dependence, anxiety disorders or no history of any disorder, and their first-degree relatives and spouses. MEASUREMENTS Cannabis use disorders and other DSM-III-R disorders in the relatives and spouses using the Schedule for Affective Disorders and Schizophrenia. FINDINGS Results reveal an elevated risk of life-time history of cannabis use disorders among siblings [odds ratio (OR: 3.6), adult offspring (OR): 6.9], and spouses (OR: 4.4) of probands with cannabis use disorders. There is a latent familial factor underlying cannabis use disorders that was shared partially with alcohol abuse/dependence. Comorbid mood and anxiety disorders aggregated independently from cannabis use disorders in families. Equal elevation in the magnitude of the association among the first-degree adult relatives and spouses of probands with a cannabis use disorder suggests the probable contribution of both environmental and genetic factors. CONCLUSIONS These findings support a family-based approach to drug abuse intervention and the importance of future research concerning environmental mediators of familial transmission of drug abuse.

Extended mortality results for ovarian cancer screening in the PLCO trial with median 15 years follow-up

BACKGROUND The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial originally reported no mortality benefit of ovarian cancer screening after a median of 12.4years of follow-up. The UKCTOCS screening trial failed to show a statistically significant mortality reduction in the primary analysis but reported an apparent increased mortality benefit in trial years 7-14 compared to 0-7. Here we report an updated analysis of PLCO with extended mortality follow-up. METHODS Participants were randomized from 1993 to 2001 at ten U.S. centers to an intervention or usual care arm. Intervention arm women were screened for ovarian cancer with annual trans-vaginal ultrasound (TVU) (4years) and CA-125 (6years), with a fixed cutoff at 35U/mL for CA-125. The original follow-up period was for up to 13years (median follow-up 12.4years); in this analysis follow-up for mortality was extended by up to 6years. RESULTS 39,105 (intervention) and 39,111 (usual care) women were randomized, of which 34,253 and 34,304, respectively, had at least one ovary at baseline. Median follow-up was 14.7years in each arm and maximum follow-up 19.2years in each arm. A total of 187 (intervention) and 176 (usual care) deaths from ovarian cancer were observed, for a risk-ratio of 1.06 (95% CI: 0.87-1.30). Risk-ratios were similar for study years 0-7 (RR=1.04), 7-14 (RR=1.06) and 14+ (RR=1.09). The risk ratio for all-cause mortality was 1.01 (95% CI: 0.97-1.05). Ovarian cancer specific survival was not significantly different across trial arms (p=0.16). CONCLUSION Extended follow-up of PLCO indicated no mortality benefit from screening for ovarian cancer with CA-125 and TVU.