Publications by authors named "Kelly J Yu"

42 Publications

Pancreatic cancer among solid organ transplant recipients in the United States.

J Cancer Res Clin Oncol 2022 Aug 6. Epub 2022 Aug 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Introduction: Pancreatic cancer (PC) in solid organ transplant (SOT) recipients is not well studied. Some PC cases may be incidentally detected during hepatobiliary imaging.

Methods: We evaluated PC among 374,106 SOT recipients during 1995-2017 in the United States using linked data from the national transplant registry and multiple state/regional cancer registries. Standardized incidence ratios (SIRs) were used to compare PC risk in recipients to the general population. We used multivariate Poisson regression to identify independent risk factors for PC. We assessed survival after PC diagnosis using Kaplan-Meier curves and log-rank tests.

Results: SOT recipients had elevated incidence for PC compared with the general population (SIR 1.40, 95% CI 1.29-1.52), and this increase was strongest in liver recipients (1.65, 1.41-1.92). Among all recipients, PC incidence was especially increased for cases arising in the head of the pancreas (SIR 1.50, 95% CI 1.34-1.68) and for cases diagnosed at localized stage (1.85, 1.37-2.44). Among SOT recipients, factors independently associated with increased incidence were consistent with those in general population including male sex, older age, non-O blood type, and history of diabetes. Additionally, compared to other organ recipients, liver transplant recipients had higher PC incidence (adjusted incidence rate ratio 1.28; 95% CI 1.06-1.54). Overall survival after PC diagnosis was poor (median 4 months) and similar between liver and other organ transplant recipients (p = 0.08).

Conclusions: PC incidence is elevated among SOT recipients, and more commonly diagnosed in liver transplant recipients perhaps related to incidental detection. However, survival is poor even in liver recipients, arguing against routine PC screening.
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http://dx.doi.org/10.1007/s00432-022-04227-3DOI Listing
August 2022

Cancer risk in living kidney donors.

Am J Transplant 2022 08 24;22(8):2006-2015. Epub 2022 May 24.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Living kidney donors are screened for transmissible diseases including cancer. Outcomes following donation are excellent, but concern exists regarding development of chronic kidney disease, and cancer risk is unknown. We used linked transplant and cancer registry data to identify incident cancers among 84,357 kidney donors in the United States (1995-2017). We compared risk with the general population using standardized incidence ratios (SIRs). For selected cancers, we used Poisson regression to compare donors with 47,451 Adventist Health Study 2 (AHS-2) participants, who typically have healthy lifestyles. During follow-up, 2843 cancers were diagnosed in donors, representing an overall deficit (SIR 0.79, 95%CI 0.76-0.82). None of 46 specified cancer sites occurred in excess relative to the general population, and 15 showed significant deficits (SIR < 1.00). Compared with AHS-2 participants, donors had similar incidence of liver cancer, melanoma, breast cancer, and non-Hodgkin lymphoma but, starting 7 years after donation, elevated incidence of colorectal cancer (adjusted incidence rate ratio 2.07, 95%CI 1.54-2.79) and kidney cancer (2.97, 1.58-5.58, accounting for the presence of a single kidney in donors). Elevated kidney cancer incidence may reflect adverse processes in donors' remaining kidney. Nonetheless, cancer risk is lower than in the general population, suggesting that enhanced screening is unnecessary.
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http://dx.doi.org/10.1111/ajt.17082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9357116PMC
August 2022

Utility of Epstein-Barr Virus DNA in Nasopharynx Swabs as a Reflex Test to Triage Seropositive Individuals in Nasopharyngeal Carcinoma Screening Programs.

Clin Chem 2022 07;68(7):953-962

Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Epstein-Barr virus (EBV) DNA detection in the nasopharynx is considered a biomarker for nasopharyngeal carcinoma (NPC). We evaluated its performance as a reflex test to triage EBV seropositives within an NPC screening program in China.

Methods: The study population was embedded within an ongoing NPC screening trial and included 1111 participants who screened positive for anti-EBV VCA (antibodies against EBV capsid antigens)/EBNA1 (EBV nuclear antigen1)-IgA antibodies (of 18 237 screened). Nasopharynx swabs were collected/tested for EBNA1 gene EBV DNA load. We evaluated performance of EBV DNA in the nasopharynx swab as a reflex test to triage EBV serological high-risk (those referred to endoscopy/MRI) and medium-risk (those referred to accelerated screening) individuals.

Results: By the end of 2019, we detected 20 NPC cases from 317 serological high-risk individuals and 4 NPC cases from 794 medium-risk individuals. When used to triage serological high-risk individuals, nasopharynx swab EBV DNA was detected in 19/20 cases (positivity rate among cases: 95.0%; 95% CI, 75.1%-99.9%), with a referral rate of 63.4% (201/317, 95% CI, 57.8%-68.7%) and NPC detection rate among positives of 9.5% (19/201, 95% CI, 5.8%-14.4%). The performance of an algorithm that combined serology with triage of serology high-risk individuals using EBV DNA testing yielded a sensitivity of 72.4% (95% CI, 3.0%-81.4%) and specificity of 97.6% (95% CI, 97.2%-97.9%). When used to triage EBV serological medium-risk individuals, the positivity rate among cases was 75.0% (95% CI, 19.4%-99.4%), with a referral rate of 61.8% (95% CI, 58.4%-65.2%) and NPC detection rate among positives of 0.6% (95% CI, 0.1%-1.8%).

Conclusions: Nasopharynx swab EBV DNA showed promise as a reflex test to triage serology high-risk individuals, reducing referral by ca. 40% with little reduction in sensitivity compared to a serology-only screening program.
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http://dx.doi.org/10.1093/clinchem/hvac032DOI Listing
July 2022

Spectrum of Nonkeratinocyte Skin Cancer Risk Among Solid Organ Transplant Recipients in the US.

JAMA Dermatol 2022 04;158(4):414-425

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Importance: Nonkeratinocyte skin cancers are an important cause of morbidity and mortality for immunosuppressed solid organ transplant recipients (SOTRs), but the spectrum of disease and risk factor characteristics are unknown.

Objective: To characterize the spectrum of disease and risk factors for common and rare nonkeratinocyte skin cancers in SOTRs.

Design, Setting, And Participants: This population-based cohort study included 444 497 SOTRs who underwent a transplant in the US between January 1, 1987, and December 31, 2017, using linked data from the national transplant registry and 32 cancer registries. Data analysis was conducted from April 1, 2021, to September 30, 2021.

Main Outcomes And Measures: Standardized incidence ratios (SIRs) were used to assess risk relative to the general population, and Poisson regression was used to evaluate risk factors.

Results: A total of 2380 nonkeratinocyte skin cancers were identified among 444 497 SOTRs (median age at transplant, 50 years; range, 0-96 years; 274 276 [61.7%] male; 272 241 [61.2%] non-Hispanic White). Melanoma was the most common cancer (1471 [61.8%]), followed by Merkel cell carcinoma (334 [14.0%]), Kaposi sarcoma (186 [7.8%]), sebaceous carcinoma (170 [7.1%]), and cutaneous lymphomas (108 [4.5%]). Risks were most strongly elevated for cancers associated with viruses, including Kaposi sarcoma (SIR, 20.5; 95% CI, 17.7-23.7), Merkel cell carcinoma (SIR, 16.2; 95% CI, 14.5-18.1), and extranodal natural killer/T-cell lymphoma (SIR, 44.3; 95% CI, 5.37-160). Risks were also significantly elevated for sebaceous carcinoma (SIR, 15.2; 95% CI, 13.0-17.7), anaplastic large cell lymphoma (SIR, 6.82; 95% CI, 4.53-9.85), and diffuse large B-cell lymphoma (SIR, 5.17; 95% CI, 3.28-7.76). Several characteristics were independently associated with greater risk for multiple skin cancer types, including male sex, older age at transplant, factors associated with UV radiation exposure (non-Hispanic White race and ethnicity, living in an area with higher UV radiation exposure, and posttransplant diagnosis of keratinocyte carcinoma), and increasing time since transplantation. Treatment with mammalian target of rapamycin inhibitors was associated with reduced melanoma incidence (incidence rate ratio, 0.75; 95% CI, 0.57-0.98). A total of 847 skin cancers (39.4%) occurred on the head and neck.

Conclusions And Relevance: The findings of this cohort study suggest that viruses, UV radiation exposure, and immunosuppression are associated with the development of skin cancer in SOTRs. Certain high-risk subgroups may benefit from increased skin surveillance, and treatment with mammalian target of rapamycin inhibitors could be effective for melanoma chemoprevention in the transplant population.
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http://dx.doi.org/10.1001/jamadermatol.2022.0036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908231PMC
April 2022

Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma.

Sci Rep 2021 12 8;11(1):23664. Epub 2021 Dec 8.

Division of Cancer Epidemiology and Genetics, 9609 Medical Center Drive, National Cancer Institute, Rockville, MD, 20850, USA.

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case-control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORs > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin.
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http://dx.doi.org/10.1038/s41598-021-02788-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655014PMC
December 2021

Identifying Epstein-Barr virus peptide sequences associated with differential IgG antibody response.

Int J Infect Dis 2022 Jan 30;114:65-71. Epub 2021 Oct 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Background: Epstein-Barr virus (EBV) infection contributes to cancers in a fraction of seropositive individuals, but much remains to be learned about variation in EBV-directed humoral immunity in cancer-free adults.

Methods: A protein microarray was used to probe serum from 175 Taiwanese and 141 Northern European adults for immunoglobulin G (IgG) antibody responses to 115 different peptide sequences, representing protein segments or protein variants, from 45 EBV proteins. It was posited that this antibody-based approach could identify EBV peptide sequences representing immunodominant regions relevant for B-cell immunity.

Results: Analyses of 45 EBV proteins with multiple protein segments or variants printed on the array identified eight EBV peptide sequences that appear to play a role in immunogenicity. This included: (1) three proteins with segments/regions associated with IgG reactivity (BALF5, LMP1, LMP2A); and (2) five proteins with sequence variants/amino acid changes associated with IgG reactivity (BDLF4, EBNA3A, EBNA3B, EBNA-LP, LF1).

Conclusion: This examination of IgG antibody responses against 115 EBV peptide sequences in 316 cancer-free adults represents an important step toward identifying specific EBV protein sequences that play a role in generating B-cell immunity in humans.
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http://dx.doi.org/10.1016/j.ijid.2021.10.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724419PMC
January 2022

Predicted Cure and Survival Among Transplant Recipients With a Previous Cancer Diagnosis.

J Clin Oncol 2021 12 22;39(36):4039-4048. Epub 2021 Oct 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Purpose: A previous cancer diagnosis is a negative consideration in evaluating patients for possible solid organ transplantation. Statistical models may improve selection of patients with cancer evaluated for transplantation.

Methods: We fitted statistical cure models for patients with cancer in the US general population using data from 13 cancer registries. Patients subsequently undergoing solid organ transplantation were identified through the Scientific Registry of Transplant Recipients. We estimated cure probabilities at diagnosis (for all patients with cancer) and transplantation (transplanted patients). We used Cox regression to assess associations of cure probability at transplantation with subsequent cancer-specific mortality.

Results: Among 10,524,326 patients with 17 cancer types in the general population, the median cure probability at diagnosis was 62%. Of these patients, 5,425 (0.05%) subsequently underwent solid organ transplantation and their median cure probability at transplantation was 94% (interquartile range, 86%-98%). Compared with the tertile of transplanted patients with highest cure probability, those in the lowest tertile more frequently had lung or breast cancers and less frequently colorectal, testicular, or thyroid cancers; more frequently had advanced-stage cancer; were older (median 57 51 years); and were transplanted sooner after cancer diagnosis (median 3.6 8.6 years). Patients in the low-cure probability tertile had increased cancer-specific mortality after transplantation (adjusted hazard ratio, 2.08; 95% CI, 1.48 to 2.93; the high tertile), whereas those in the middle tertile did not differ.

Conclusion: Patients with cancer who underwent solid organ transplantation exhibited high cure probabilities, reflecting selection on the basis of existing guidelines and clinical judgment. Nonetheless, there was a range of cure probabilities among transplanted patients and low probability predicted increased cancer-specific mortality after transplantation. Cure probabilities may facilitate guideline development and evaluating individual patients for transplantation.
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http://dx.doi.org/10.1200/JCO.21.01195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677988PMC
December 2021

Cancer patterns in nasopharyngeal carcinoma multiplex families over 15 years.

Cancer 2021 11 29;127(22):4171-4176. Epub 2021 Jul 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Background: Genetic and environmental factors are important determinants of nasopharyngeal carcinoma (NPC). NPC is associated with Epstein-Barr virus (EBV) infection. Studies have reported familial aggregation of NPC, but evidence has been mixed for elevated rates of cancers other than NPC.

Methods: The authors reassessed their previous evaluation of familial aggregation of cancer in 348 high-risk Taiwanese multiplex families with 2 or more NPC cases enrolled between 1980 and 2003. Participants were linked to the Taiwan National Cancer Registry and National Death Registry to identify cancers.

Results: In all, 2590 individuals contributed 37,959 person-years over an average of 15 years of follow-up; 314 incident cancers were identified. The authors computed multiple primary standardized incidence ratios (MP-SIRs) to evaluate the overall risk and the risk of infection-associated, EBV-associated, and individual cancers. The overall MP-SIR was 1.24 (95% confidence interval [CI], 1.10-1.38). The exclusion of excess NPC risk led to an overall MP-SIR of 1.11 (95% CI, 0.98-1.25). Similarly, the risk of cancers associated with infectious agents was driven by the excess in NPC, and its exclusion led to an MP-SIR of 1.22 (95% CI, 0.99-1.48) for infection-associated cancers and to an MP-SIR of 1.18 (95% CI, 0.72-1.82) for EBV-associated cancers. The authors observed a significant excess of second cancers among NPC cases (oral cancer, mouth cancer, tongue cancer, gum cancer, nasal cavity cancer, bone cancer, and non-Hodgkin lymphoma).

Conclusions: This reassessment of the largest NPC multiplex family study confirms the presence of NPC coaggregation within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors. Among NPC cases, elevated rates of secondary cancers, mostly at the, head and neck and hematopoietic cancers suggest radiation treatment effects on subsequent cancer risk.
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http://dx.doi.org/10.1002/cncr.33799DOI Listing
November 2021

Comparison of new magnetic resonance imaging grading system with conventional endoscopy for the early detection of nasopharyngeal carcinoma.

Cancer 2021 09 7;127(18):3403-3412. Epub 2021 Jul 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Background: Although stratifying individuals with respect to nasopharyngeal carcinoma (NPC) risk with Epstein-Barr virus-based markers is possible, the performance of diagnostic methods for detecting lesions among screen-positive individuals is poorly understood.

Methods: The authors prospectively evaluated 882 participants aged 30 to 70 years who were enrolled between October 2014 and November 2018 in an ongoing, population-based NPC screening program and had an elevated NPC risk. Participants were offered endoscopy and magnetic resonance imaging (MRI), and lesions were identified either by biopsy at a follow-up endoscopy or further contact and linkage to the local cancer registry through December 31, 2019. The diagnostic performance characteristics of endoscopy and MRI for NPC detection were investigated.

Results: Eighteen of 28 identified NPC cases were detected by both methods, 1 was detected by endoscopy alone, and 9 were detected by MRI alone. MRI had significantly higher sensitivity than endoscopy for NPC detection overall (96.4% vs 67.9%; P = .021) and for early-stage NPC (95.2% vs 57.1%; P = .021). The sensitivity of endoscopy was suggestively lower among participants who had previously been screened in comparison with those undergoing an initial screening (50.0% vs 81.2%; P = .11). The authors observed a higher overall referral rate by MRI versus endoscopy (17.3% vs 9.1%; P < .001). Cases missed by endoscopy had early-stage disease and were more commonly observed for tumors originating from the pharyngeal recess.

Conclusions: MRI was more sensitive than endoscopy for NPC detection in the context of population screening but required the referral of a higher proportion of screen-positive individuals. The sensitivity of endoscopy was particularly low for individuals who had previously been screened.
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http://dx.doi.org/10.1002/cncr.33552DOI Listing
September 2021

Solid Organ Transplantation and Survival among Individuals with a History of Cancer.

Cancer Epidemiol Biomarkers Prev 2021 07 29;30(7):1312-1319. Epub 2021 Apr 29.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Background: The success of immunotherapy highlights a possible role for immunity in controlling cancer during remission for patients with cancer in the general population. A prior cancer diagnosis is common among solid organ transplant candidates, and immunosuppressive medications administered to transplant recipients may increase recurrence risk.

Methods: Using linked data from the United States solid organ transplant registry and 13 cancer registries, we compared overall and cancer-specific survival among patients with cancer who did versus did not receive subsequent transplantation. We used Cox regression in cohort and matched analyses, controlling for demographic factors, cancer stage, and time since cancer diagnosis.

Results: The study included 10,524,326 patients with cancer, with 17 cancer types; 5,425 (0.05%) subsequently underwent solid organ transplantation. The median time from cancer diagnosis to transplantation was 5.7 years. Transplantation was associated with reduced overall survival for most cancers, especially cervical, testicular, and thyroid cancers [adjusted hazard ratios (aHR) for overall mortality, 3.43-4.88]. In contrast, transplantation was not associated with decreased cancer-specific survival for any cancer site, and we observed inverse associations for patients with breast cancer (aHRs for cancer-specific mortality, 0.65-0.67), non-Hodgkin lymphoma (0.50-0.51), and myeloma (0.39-0.42).

Conclusions: Among U.S. patients with cancer, subsequent organ transplantation was associated with reduced overall survival, likely due to end-stage organ disease and transplant-related complications. However, we did not observe adverse associations with cancer-specific survival, partly reflecting careful candidate selection.

Impact: These results do not demonstrate a detrimental effect of immunosuppression on cancer-specific survival and support current management strategies for transplant candidates with previous cancer diagnoses.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254777PMC
July 2021

HLA zygosity increases risk of hepatitis B virus-associated hepatocellular carcinoma.

J Infect Dis 2021 Apr 14. Epub 2021 Apr 14.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: Diversity in the human leukocyte antigen (HLA) genes might be associated with disease outcomes - the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).

Methods: We utilized DNA from >10,000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the two HLA alleles at that locus.

Results: Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend=1.18×10 -7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend=0.031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio=1.40, 95% confidence interval=1.06-1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control.

Conclusions: Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC.
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http://dx.doi.org/10.1093/infdis/jiab207DOI Listing
April 2021

Patterns of Human Leukocyte Antigen Class I and Class II Associations and Cancer.

Cancer Res 2021 02 3;81(4):1148-1152. Epub 2020 Dec 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case-control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4 T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis. SIGNIFICANCE: GWAS of >71,000 individuals across 27 cancer types suggest that patterns of HLA Class I and Class II associations may provide etiologic insights for cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2292DOI Listing
February 2021

Epstein-Barr Virus-Based Nasopharyngeal Carcinoma (NPC) Risk Prediction Scores Are Elevated in NPC Multiplex Family Members in Taiwan.

J Infect Dis 2021 02;223(3):441-444

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Nasopharyngeal carcinoma (NPC) is caused by Epstein-Barr virus (EBV) and is more likely to occur in susceptible families. Whether genetic susceptibility operates through altered EBV control is incompletely understood. We used a NPC risk prediction model based on 14 EBV markers to compare risk score distribution in unaffected members from multiplex families with that in population-based controls. Despite the absence of NPC at the time of antibody measurement, we observed an upward shift in risk score among multiplex family members compared to the general population, consistent with the possibility that genetic factors affect NPC risk through alterations in EBV control.
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http://dx.doi.org/10.1093/infdis/jiaa385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982447PMC
February 2021

Validation of an Epstein-Barr Virus Antibody Risk Stratification Signature for Nasopharyngeal Carcinoma by Use of Multiplex Serology.

J Clin Microbiol 2020 04 23;58(5). Epub 2020 Apr 23.

Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Serological testing for nasopharyngeal carcinoma (NPC) has recently been reinvigorated by the implementation of novel Epstein-Barr virus (EBV)-specific IgA and IgG antibodies from a proteome array. Although proteome arrays are well suited for comprehensive antigen selection, they are not applicable for large-scale studies. We adapted a 13-marker EBV antigen signature for NPC risk identified by proteome arrays to multiplex serology to establish an assay for large-scale studies. Taiwanese NPC cases ( = 175) and matched controls ( = 175) were used for assay validation. Spearman's correlation was calculated, and the diagnostic value of all multiplex markers was assessed independently using the area under the receiver operating characteristic curve (AUC). Two refined signatures were identified using stepwise logistic regression and internally validated with 10-fold cross validation. Array and multiplex serology showed strong correlation for each individual EBV marker, as well as for a 13-marker combined model on continuous data. Two refined signatures with either four (LF2 and BGLF2 IgG, LF2 and BMRF1 IgA) or two (LF2 and BGLF2 IgG) antibodies on dichotomous data were identified as the most parsimonious set of serological markers able to distinguish NPC cases from controls with AUCs of 0.992 (95% confidence interval [CI], 0.983 to 1.000) and 0.984 (95% CI, 0.971 to 0.997), respectively. Neither differed significantly from the 13-marker model (AUC, 0.992; 95% CI, 0.982 to 1.000). All models were internally validated. Multiplex serology successfully validated the original EBV proteome microarray data. Two refined signatures of four and two antibodies were capable of detecting NPC with 99.2% and 98.4% accuracy.
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http://dx.doi.org/10.1128/JCM.00077-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180240PMC
April 2020

Cigarette smoking increases the risk of nasopharyngeal carcinoma through the elevated level of IgA antibody against Epstein-Barr virus capsid antigen: A mediation analysis.

Cancer Med 2020 03 10;9(5):1867-1876. Epub 2020 Jan 10.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: The study aims are to evaluate the associations between nasopharyngeal carcinoma (NPC) risk and cigarette smoking and to explore the effects of cigarette smoking on Epstein-Barr virus (EBV) infection for NPC risk.

Methods: 1235 male NPC cases and 1262 hospital-based male controls matched to cases were recruited across six collaborative hospitals between 2010 and 2014. Using a standardized questionnaire, information on cigarette smoking and other potential risk factors for NPC was obtained. Blood was collected and used for anti-EBV VCA IgA and anti-EBV EA-EBNA1 IgA testing using standard methods. Unconditional logistic regression analysis was used to estimate odds ratio (OR) with 95% confidence interval (CI) for each risk factor after adjusting for confounders.

Results: 63.6% of cases and 44.0% of controls reported ever smoking cigarettes. After full adjustment, current smokers had a significant 1.60-fold (95% CI = 1.30-1.97) and former smokers a borderline significant 1.27-fold (95% CI = 1.00-1.60) increased NPC risk compared to never smokers. NPC risk increased with increasing duration, intensity, and pack-years of cigarette smoking but not with age at smoking initiation. Among controls, anti-EBV VCA IgA seropositivity rate was higher in current smokers than never smokers (14.0% vs 8.4%; OR = 1.82; 95% CI = 1.19-2.79). Mediation analyses showed that more than 90% of the cigarette smoking effect on NPC risk is mediated through anti-EBV VCA IgA.

Conclusion: This study confirms the association between long-term cigarette smoking and NPC and demonstrates that current smoking is associated with seropositivity of anti-EBV VCA IgA antibodies.
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http://dx.doi.org/10.1002/cam4.2832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050088PMC
March 2020

Evaluation of the antibody response to the EBV proteome in EBV-associated classical Hodgkin lymphoma.

Int J Cancer 2020 08 14;147(3):608-618. Epub 2019 Nov 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

The humoral immune response to Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV-positive cHL cases, 70 EBV-negative cHL cases and 141 population-based controls frequency matched to EBV-positive cHL cases on sex and age by area (UK, Denmark and Sweden). We leveraged existing data on the proportion of circulating B-cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV-positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratios observed for the following EBV proteins: LMP1 (oncogene), BcLF1 (VCAp160, two variants) and BBLF1 (two variants). Our cHL IgG signature correlated with the proportion of circulating EBV-infected B-cells, but not serum CCL17 levels. We observed no differences in the anti-EBV antibody profile between EBV-negative cHL cases and controls. BdRF1(VCAp40)-IgG and BZLF1(Zta)-IgG were identified as the serological markers best able to distinguish EBV-positive from EBV-negative cHL tumors. Our results support the hypothesis that differences in the EBV antibody profile are specific to patients with EBV-positive cHL and are not universally observed as part of a systematically dysregulated immune response present in all cHL cases.
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http://dx.doi.org/10.1002/ijc.32741DOI Listing
August 2020

Multilaboratory Assessment of Epstein-Barr Virus Serologic Assays: the Case for Standardization.

J Clin Microbiol 2019 11 23;57(11). Epub 2019 Oct 23.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

IgA antibodies targeting Epstein-Barr virus (EBV) have been proposed for screening for nasopharyngeal carcinoma (NPC). However, methods differ, and the antigens used in these assays differ considerably between laboratories. To enable formal comparisons across a range of established EBV serology assays, we created a panel of 66 pooled serum samples and 66 pooled plasma samples generated from individuals with a broad range of IgA antibody levels. Aliquots from these panels were distributed to six laboratories and were tested by 26 assays measuring antibodies against VCA, EBNA1, EA-EBNA1, Zta, or EAd antigens. We estimated the correlation between assay pairs using Spearman coefficients (continuous measures) and percentages of agreement (positive versus negative, using predefined positivity cutoffs by each assay developer/manufacturer). While strong correlations were observed between some assays, considerable differences were also noted, even for assays that targeted the same protein. For VCA-IgA assays in serum, two distinct clusters were identified, with a median Spearman coefficient of 0.41 (range, 0.20 to 0.66) across these two clusters. EBNA1-IgA assays in serum grouped into a single cluster with a median Spearman coefficient of 0.79 (range, 0.71 to 0.89). Percentages of agreement differed broadly for both VCA-IgA (12% to 98%) and EBNA1-IgA (29% to 95%) assays in serum. Moderate-to-strong correlations were observed across assays in serum that targeted other proteins (correlations ranged from 0.44 to 0.76). Similar results were noted for plasma. We conclude that standardization of EBV serology assays is needed to allow for comparability of results obtained in different translational research studies across laboratories and populations.
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http://dx.doi.org/10.1128/JCM.01107-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813000PMC
November 2019

Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma.

Sci Rep 2019 07 9;9(1):9916. Epub 2019 Jul 9.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA, 20892.

Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwan (205 affected, 21 obligate carriers, and 25 unaffected) using SeqCap EZ Human Exome Library v3.0 and Illumina HiSeq. Aligned sequences were filtered to identify likely-to-be-functional deleterious variants that co-segregated with disease. Ingenuity Pathway analysis was performed. Circulating magnesium levels were measured in 13 individuals in 2 families with NIPAL1 mutations and in 197 sporadic NPC cases and 237 controls. We identified variants in 12 genes likely involved in cancer pathogenesis, viral infection or immune responses to infection. These included genes postulated to be involved in magnesium transport (NIPAL1), EBV cell entry (ITGB6), modulation of EBV infection (BCL2L12, NEDD4L), telomere biology (CLPTM1L, BRD2, HNRNPU), modulation of cAMP signaling (RAPGEF3), DNA repair (PRKDC, MLH1), and Notch signaling (NOTCH1, DLL3). Pathway based analysis demonstrated enrichment for Notch signaling genes (p-value = 0.0006). Evaluation of individuals within NIPAL1 families suggested lower serum magnesium in NPC compared to unaffected members. A significant reduction in serum magnesium levels was observed among sporadic NPC cases compared to controls (7.1% NPC/1.7% controls below normal range; OR = 4.5; 95% CI = 1.4,14) and is consistent with findings demonstrating a role for magnesium channeling in T-cell responses to EBV. We identified novel genes associated with NPC that point to new areas of inquiry to better understand genetic factors that determine the fate of viral infections and/or otherwise predisposes to NPC.
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http://dx.doi.org/10.1038/s41598-019-46137-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617453PMC
July 2019

Evaluation of Rare and Common Variants from Suspected Familial or Sporadic Nasopharyngeal Carcinoma (NPC) Susceptibility Genes in Sporadic NPC.

Cancer Epidemiol Biomarkers Prev 2019 10 3;28(10):1682-1686. Epub 2019 Jul 3.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC.

Methods: We conducted targeted gene sequencing of 20 genes [16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies] among 819 NPC cases and 938 controls from two case-control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted.

Results: We found that NPC was associated with combined common and rare variants in ( = 1.3 × 10), ( = 1.6 × 10), ( = 4.0 × 10), and ( = 5.4 × 10). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of = 4.6 × 10; for rare variants, = 0.04). We also observed a suggestive association with rare variants in ( = 3.8 × 10) for NPC risk. In addition, we validated four previously reported NPC risk-associated SNPs.

Conclusions: Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC.

Impact: NPC-associated genes, including , and , suggest a role for telomere length maintenance in NPC etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774819PMC
October 2019

Elevated antibodies against Epstein-Barr virus among individuals predicted to carry nasopharyngeal carcinoma susceptibility variants.

J Gen Virol 2018 09 5;99(9):1268-1273. Epub 2018 Jul 5.

1​Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Epstein-Barr virus (EBV) is an obligatory factor in the development of nasopharyngeal carcinoma (NPC), and anti-EBV IgA antibodies are elevated many years prior to the development of NPC. Nearly all adults are infected with EBV, but only a few develop cancer, suggesting that additional co-factors, including genetic susceptibility, must be required for the disease to manifest. Individuals were selected from the Taiwan Family Study, a cohort of 3389 individuals from NPC multiplex families. Primary analyses were conducted among 671 individuals from 69 pedigrees with the strongest family history of disease (>3 NPC-affected family members). The likelihood that a given family member carried a NPC susceptibility variant was estimated using Mendelian segregation rules, assuming a dominant mode of inheritance. We compared anti-EBV IgA antibody seropositivity between family members predicted to be carriers of NPC-linked genetic variants and those with a lower likelihood of carrying such variants. Obligate carriers of NPC susceptibility variants (100 % predicted probability of harbouring the genetic mutation) were nine-fold more likely to be anti-EBV IgA positive compared to family members predicted not to carry disease-causing variants (OR=9.2; P-trend<0.001). This elevated risk was confirmed in analyses restricted to both unaffected individuals and pedigrees with EBV-related pathway variants identified through exome sequencing. Our data indicate that family members who are more likely to carry NPC susceptibility variants are also more likely to be anti-EBNA1 IgA seropositive. Genetic susceptibility associated with control over this common herpes virus is likely a co-factor in determining which EBV-infected adults develop NPC.
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http://dx.doi.org/10.1099/jgv.0.001115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230770PMC
September 2018

Evaluation of Total and IgA-Specific Antibody Targeting Epstein-Barr Virus Glycoprotein 350 and Nasopharyngeal Carcinoma Risk.

J Infect Dis 2018 08;218(6):886-891

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Background: We previously reported that higher levels of antibody targeting Epstein-Barr virus (EBV) glycoprotein350 (gp350), an EBV vaccine candidate, were protective against nasopharyngeal carcinoma (NPC) in genetically high-risk families from Taiwan. The current study attempted to extend this association to a general population cohort.

Methods: We compared total and IgA-specific gp350 antibody levels in 35 incident NPC cases and 81 disease-free controls from the Cancer Screening Program in Taiwan (23943 individuals recruited 1991-1992). Luciferase immunoprecipitation assays quantified gp350 antibody.

Results: Total EBVgp350 antibody levels were not higher in individuals who remained disease free compared to those who developed NPC (P = .11). This lack of a protective gp350 association persisted for cases diagnosed ≥5 years (odds ratio [OR] = 1.05; P = .91) and <5 years (OR = 1.85; P = .40) after blood draw. IgA-specific gp350 antibody levels were higher in cases than controls (OR = 7.03; P = .001). This increased risk was most pronounced for cases diagnosed <5 years after blood draw (OR = 11.7; P = .004).

Conclusion: Unlike our prior findings in those with a strong family history of NPC, total gp350 antibody levels were not protective against NPC development in this general population setting.
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http://dx.doi.org/10.1093/infdis/jiy250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093398PMC
August 2018

Patterns of Interindividual Variability in the Antibody Repertoire Targeting Proteins Across the Epstein-Barr Virus Proteome.

J Infect Dis 2018 05;217(12):1923-1931

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Background: Little is known about variation in antibody responses targeting the full spectrum of Epstein-Barr virus (EBV) proteins and how such patterns inform disease risk.

Methods: We used a microarray to measure immunoglobulin G (IgG) and immunoglobulin A (IgA) antibody responses against 199 EBV protein sequences from 5 EBV strains recovered from 289 healthy adults from Taiwan. We described positivity patterns, estimated the correlation between antibodies, and investigated the associations between environmental and genetic risk factors and variations in antibody responses.

Results: Healthy adults were more likely to mount IgG antibody responses to EBV proteins (median positivity frequency, 46.5% for IgG and 17.3% for IgA; P = 1.6 × 10-46, by the Wilcoxon rank sum test). Responses against glycoproteins were particularly prevalent. The correlations between antibody responses of the same class were higher than correlations across classes. The mucosal exposure to proteins involved in EBV reactivation (as determined by the IgA response) was associated with smoking (P = .002, by the sequence kernel association test-combined), and approximately one quarter of adults displayed antibody responses associated with EBV-related cancer risk.

Conclusions: These data comprehensively define the variability in human IgG and IgA antibody responses to the EBV proteome. Patterns observed can serve as the foundation for elucidating which individuals are at highest risk of EBV-associated clinical conditions and for identifying targets for effective immunodiagnostic tests.
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http://dx.doi.org/10.1093/infdis/jiy122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279144PMC
May 2018

Identification of a Novel, EBV-Based Antibody Risk Stratification Signature for Early Detection of Nasopharyngeal Carcinoma in Taiwan.

Clin Cancer Res 2018 03 4;24(6):1305-1314. Epub 2018 Jan 4.

Queensland Institute of Medical Research, Brisbane, Australia.

Epstein-Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, approximately 90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy [area under the curve (AUC)] of this risk score, and its performance relative to currently used biomarkers, was evaluated in two independent Taiwanese cohorts. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between stage I/IIa NPC cases and controls ( < 0.0002). Risk prediction analyses identified antibody targets that best discriminated NPC status-BXLF1, LF2,BZLF1, BRLF1, EAd, BGLF2, BPLF1, BFRF1, and BORF1. When combined with currently used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95% CI, 87%-98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%; 95% CI, 75%-90%, ≤ 0.01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%; 95% CI, 82%-96%) compared with current biomarkers (78%; 95% CI, 66%-90%, ≤ 0.03). We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856605PMC
March 2018

Evaluation of nasal and nasopharyngeal swab collection for the detection of Epstein-Barr virus in nasopharyngeal carcinoma.

J Med Virol 2018 01 11;90(1):191-195. Epub 2017 Sep 11.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Epstein-Barr virus detection using nasopharyngeal swabs has been suggested as a potential screening test that could improve the specificity of current EBV-based serological assays. However, application requires insertion of the swab deep into the nasopharynx, a procedure not amenable to non-clinic screening. We reasoned that swabbing the more easily accessible nasal cavity might provide an appealing alternative for NPC detection. Patients > 18 years of age diagnosed with histologically confirmed NPC were recruited from the Otolaryngology Department at the National Taiwan University Hospital. ENT clinicians collected both nasal and nasopharyngeal swabs. EBV DNA and cellular beta-globulin DNA were quantified using quantitative PCR targeting a highly-conserved region of the BKRF1 gene. EBV DNA was detectable (non-zero) in all 34 nasopharyngeal swabs and above the positivity threshold of 1666 EBV copies in 30 (88.2%) patients. EBV DNA was detectable in 50% of 34 nasal swabs and above the positivity threshold in four (11.8%) patients. Average EBV DNA levels were >3-fold higher (P < 0.001) in nasopharyngeal compared to nasal swabs. Among the 17 NPC patients with detectable EBV DNA in both swab types, we observed correlation (P < 0.01) between EBV DNA measurements. Our data represent the first evaluation of EBV DNA collected from nasal swabs. Given current EBV DNA amplification techniques, nasopharyngeal swabs remain more sensitive than nasal swabs for NPC detection.
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http://dx.doi.org/10.1002/jmv.24918DOI Listing
January 2018

The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial Pathology Tissue Resource.

Cancer Epidemiol Biomarkers Prev 2016 12 15;25(12):1635-1642. Epub 2016 Sep 15.

Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.

Background: Pathology tissue specimens with associated epidemiologic and clinical data are valuable for cancer research. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial undertook a large-scale effort to create a public resource of pathology tissues from PLCO participants who developed a cancer during the trial.

Methods: Formalin-fixed paraffin-embedded tissue blocks were obtained from pathology laboratories on a loan basis for central processing of tissue microarrays, with additional free-standing tissue cores collected for nucleic acid extraction.

Results: Pathology tissue specimens were obtained for prostate cancer (n = 1,052), lung cancer (n = 434), colorectal cancer (n = 675) and adenoma (n = 658), ovarian cancer and borderline tumors (n = 212), breast cancer (n = 870), and bladder cancer (n = 204). The process of creating this resource was complex, involving multidisciplinary teams with expertise in pathology, epidemiology, information technology, project management, and specialized laboratories.

Conclusions: Creating the PLCO tissue resource required a multistep process, including obtaining medical records and contacting pathology departments where pathology materials were stored after obtaining necessary patient consent and authorization. The potential to link tissue biomarkers to prospectively collected epidemiologic information, screening and clinical data, and matched blood or buccal samples offers valuable opportunities to study etiologic heterogeneity, mechanisms of carcinogenesis, and biomarkers for early detection and prognosis.

Impact: The methods and protocols developed for this effort, and the detailed description of this resource provided here, will be useful for those seeking to use PLCO pathology tissue specimens for their research and may also inform future tissue collection efforts in other settings. Cancer Epidemiol Biomarkers Prev; 25(12); 1635-42. ©2016 AACR.
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http://dx.doi.org/10.1158/1055-9965.EPI-16-0506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135604PMC
December 2016

Birth order and risk of nasopharyngeal carcinoma in multiplex families from Taiwan.

Int J Cancer 2016 12 30;139(11):2467-73. Epub 2016 Aug 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, Maryland.

A small proportion of individuals infected with Epstein-Barr virus (EBV) develop nasopharyngeal carcinoma (NPC). Timing of initial exposure could alter immunological responses to primary EBV infection and explain variation in cancer risk later in life. We measured early life family structure as a proxy for the timing of primary EBV infection to examine whether earlier age at infection alters NPC risk. We utilized data from 480 NPC cases and 1,291 unaffected siblings from Taiwanese NPC multiplex families (≥ 2 family members with NPC, N = 2,921). Information on birth order within the family was derived from questionnaires. We utilized logistic regression models to examine the association between birth order and NPC, accounting for correlations between relatives. Within these high-risk families, older siblings had an elevated risk of NPC. Compared with being a first-born child, the risk (95% CIs) of NPC associated with a birth order of two, three, four and five or more was 1.00 (0.71, 1.40), 0.88 (0.62, 1.24), 0.74 (0.53, 1.05) and 0.60 (0.43, 0.82), respectively (P for trend = 0.002). We observed no associations between NPC risk and the number of younger siblings or cumulative infant-years exposure. These associations were not modified by underlying genetic predisposition or family size. We observed that early life family structure was important for NPC risk in NPC multiplex families, with older siblings having a greater risk of disease. Future studies focusing on more direct measures of the immune response to EBV in early childhood could elucidate the underlying mechanisms.
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http://dx.doi.org/10.1002/ijc.30390DOI Listing
December 2016

High Levels of Antibody that Neutralize B-cell Infection of Epstein-Barr Virus and that Bind EBV gp350 Are Associated with a Lower Risk of Nasopharyngeal Carcinoma.

Clin Cancer Res 2016 07 26;22(14):3451-7. Epub 2016 Feb 26.

Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.

Purpose: Elevated IgA antibodies indicative of ongoing exposure to Epstein-Barr virus (EBV) are high-risk biomarkers for nasopharyngeal carcinoma (NPC), an EBV-related epithelial tumor. However, protective biomarkers that limit exposure to the virus have not been defined. We evaluated whether antibodies that can neutralize EBV infection by targeting glycoproteins involved in viral cell entry, including EBV vaccine candidate glycoprotein 350 (gp350), were associated with lower NPC risk.

Experimental Design: In a prospective cohort of 2,557 individuals from 358 high-risk NPC multiplex families in Taiwan, we identified 21 incident NPC cases and 50 disease-free controls. To complement data from high-risk families, we further identified 30 prevalent NPC cases and 50 healthy controls from the general Taiwanese population. We quantified EBV-neutralizing antibody, antibodies against EBV glycoproteins involved in B-cell and epithelial cell entry, and anti-EBNA1 IgA, a high-risk NPC biomarker.

Results: EBV-neutralizing antibodies blocking B-cell infection and anti-gp350 antibodies were present at significantly higher levels in disease-free controls compared with incident NPC cases (P < 0.03). Family members with both low EBV-neutralizing potential and elevated EBNA1 IgA had a 7-fold increased risk of NPC (95% CI, 1.9-28.7). Neutralizing antibodies against epithelial cell infection did not differ between incident cases and disease-free controls. Anti-glycoprotein antibody levels measured at diagnosis (prevalent NPC) were significantly higher than levels measured prior to diagnosis (P < 0.01).

Conclusions: Elevated titers of EBV-neutralizing antibody and anti-gp350 antibody were low-risk biomarkers for NPC. These data suggest that a vaccine that induces potent EBV gp350 and B-cell-neutralizing antibodies could reduce the risk of EBV-related cancers such as NPC. Clin Cancer Res; 22(14); 3451-7. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947430PMC
July 2016

Incidence and mortality of colorectal cancer in individuals with a family history of colorectal cancer.

Gastroenterology 2015 Nov 5;149(6):1438-1445.e1. Epub 2015 Aug 5.

Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.

Background & Aims: Little is known about the change in risk conferred by family history of colorectal cancer (CRC) as a person ages. We evaluated the effect of family history on CRC incidence and mortality after 55 years of age, when the risk of early onset cancer had passed.

Methods: We collected data from participants in the randomized, controlled Prostate, Lung, Colorectal and Ovarian cancer screening trial of flexible sigmoidoscopy versus usual care (55-74 years old, no history of CRC), performed at 10 US centers from 1993 to 2001. A detailed family history of colorectal cancer was obtained at enrollment, and subjects were followed for CRC incidence and mortality for up to 13 years.

Results: Among 144,768 participants, 14,961 subjects (10.3%) reported a family of CRC. Of 2090 incident cases, 273 cases (13.1%) had a family history of CRC; among 538 deaths from CRC, 71 (13.2%) had a family history of CRC. Overall, family history of CRC was associated with an increased risk of CRC incidence (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10-1.50; P<.0001) and increased mortality (HR, 1.31; 95% CI, 1.02-1.69; P = .03). Subjects with 1 first degree relative (FDR) with CRC (n = 238; HR, 1.23; 95% CI, 1.07-1.42) or ≥2 FDRs with CRC (n = 35; HR, 2.04; 95% CI, 1.44-2.86) were at increased risk for incident CRC. However, among individuals with 1 FDR with CRC, there were no differences in risk based on age at diagnosis in the FDR (for FDR <60 years of age: HR, 1.27; 95% CI, 0.97-1.63; for FDR 60-70 years of age: HR, 1.33; 95% CI, 1.06-1.62; for FDR >70 years of age: HR, 1.14; 95% CI, 0.93-1.45; P trend = .59).

Conclusions: After 55 years of age, subjects with 1 FDR with CRC had only a modest increase in risk for CRC incidence and death; age of onset in the FDR was not significantly associated with risk. Individuals with ≥2 FDRs with CRC had continued increased risk in older age. Guidelines and clinical practice for subjects with a family history of CRC should be modified to align CRC testing to risk. ClinicalTrials.gov number, NCT00002540.
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http://dx.doi.org/10.1053/j.gastro.2015.07.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628587PMC
November 2015

Risk of follicular lymphoma associated with BCL2 translocations in peripheral blood.

Leuk Lymphoma 2015 17;56(9):2625-9. Epub 2015 Mar 17.

b Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda , MD , USA.

Many adults have circulating lymphocytes with the BCL2 gene translocation characteristic of follicular lymphoma. We therefore conducted a nested case-control study of incident lymphomas with peripheral blood obtained a median 4.9 years pre-diagnosis from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Overall, 13 of 26 cases of lymphoma and 14 of 47 controls had BCL2 major breakpoint region (MBR) translocations in pre-diagnosis blood (odds ratio [OR] = 2.8). Nine cases had BCL2-MBR-positive tumors; eight of these nine had BCL2-MBR translocations in paired blood versus five of the 17 with BCL2-MBR-negative tumors (p = 0.01). Comparing both tumor types to controls, blood BCL2-MBR translocations had a strong, statistically significant association with BCL2-MBR-positive tumors (OR = 26), but not with BCL2-MBR-negative tumors (OR = 0.9). All eight BCL2-MBR-positive tumors with pre-diagnosis BCL2 translocations were clonally related to these circulating cells, based on similarity of recombination sequences. These data indicate that blood BCL2-MBR translocations represent lymphoma precursor clones with malignant potential.
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http://dx.doi.org/10.3109/10428194.2014.999324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819878PMC
August 2016
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