bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table 3 from Lifetime Physical Activity and the Risk of Non-Hodgkin Lymphoma
Authors: Boyle Terry , Gallagher Richard P. , Gascoyne Randy D. , Connors Joseph M. , Le Nhu D. , Spinelli John J.
Published: March 2023

Associations between total, moderate-intensity and vigorous-intensity physical activity performed in specific age-periods and the risk of non-Hodgkin lymphoma in a case-control study conducted in British Columbia, Canada, 2000-2004.
Supplementary Materials and Methods, Supplementary Tables S1-S4 from The Impact of Receiving Predictive Genetic Information about Lynch Syndrome on Individual Colonoscopy and Smoking Behaviors
Authors: Kim Joanne Soo-Min , Coyte Peter C. , Cotterchio Michelle , Keogh Louise A. , Flander Louisa B. , Gaff Clara , Laporte Audrey
Published: March 2023

Table S1. Study participants' smoking status. Table S2. Estimation results of the logit regression models only on the study participants who underwent colonoscopy before baseline. Table S3. Estimation results of the logit regression model only on the study participants who smoked before baseline. Table S4. Estimation results: subgroup analyses only on the study participants with no previous cancer diagnosis at follow-up
Supplementary Table 3 from A Cohort Study of Metformin Exposure and Survival in Patients with Stage I–III Colorectal Cancer
Authors: Spillane Susan , Bennett Kathleen , Sharp Linda , Barron Thomas I.
Published: March 2023

PDF file - 56K, Sensitivity Analysis: Inclusion of stage IV and unspecified stage patients.
Data from CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium
Authors: Travis Ruth C. , Schumacher Fredrick , Hirschhorn Joel N. , Kraft Peter , Allen Naomi E. , Albanes Demetrius , Berglund Goran , Berndt Sonja I. , Boeing Heiner , Bueno-de-Mesquita H. Bas , Calle Eugenia E. , Chanock Stephen , Dunning Alison M. , Hayes Richard , Feigelson Heather Spencer , Gaziano J. Michael , Giovannucci Edward , Haiman Christopher A. , Henderson Brian E. , Kaaks Rudolf , Kolonel Laurence N. , Ma Jing , Rodriguez Laudina , Riboli Elio , Stampfer Meir , Stram Daniel O. , Thun Michael J. , Tjønneland Anne , Trichopoulos Dimitrios , Vineis Paolo , Virtamo Jarmo , Le Marchand Loïc , Hunter David J.
Published: March 2023

Abstract
Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 × 10-5], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2734–44)
Data from Comparative Biomarker Expression and RNA Integrity in Biospecimens Derived from Radical Retropubic and Robot-Assisted Laparoscopic Prostatectomies
Authors: Ricciardelli Carmela , Bianco-Miotto Tina , Jindal Shalini , Dodd Thomas J. , Cohen Penelope A. , Marshall Villis R. , Sutherland Peter D. , Samaratunga Hemamali , Kench James G. , Dong Ying , Wang Hong , Clements Judith A. , Risbridger Gail P. , Sutherland Robert L. , Tilley Wayne D. , Horsfall David J.
Published: March 2023

Abstract
Background: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue sampling, handling, and storage might affect biomarker expression or invalidate tissue samples as analytes for some technologies.

Methods: We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP samples were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores.

Results: No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these samples into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR, ghrelin, Ki67, PCNA, VEGF-C, PAR2, YB1, p63, versican, and chondroitin 0-sulfate) in RALP compared with RRP tissue. No difference in RNA quality or gene expression was detected between RALP and RRP tissue.

Conclusions: Changes in biomarker expression between RALP and RRP tissue exist at the immunoreactive protein level, but the etiology is unclear.

Impact: Future studies should account for changes in biomarker expression when using RALP tissues, and mixed cohorts of RALP and RRP tissue should be avoided. Cancer Epidemiol Biomarkers Prev; 19(7); 1755–65. ©2010 AACR.
Data from Leukocyte Telomere Length in Relation to Pancreatic Cancer Risk: A Prospective Study
Authors: Campa Daniele , Mergarten Björn , De Vivo Immaculata , Boutron-Ruault Marie-Christine , Racine Antoine , Severi Gianluca , Nieters Alexandra , Katzke Verena A. , Trichopoulou Antonia , Yiannakouris Nikos , Trichopoulos Dimitrios , Boeing Heiner , Quirós J. Ramón , Duell Eric J. , Molina-Montes Esther , Huerta José María , Ardanaz Eva , Dorronsoro Miren , Khaw Kay-Tee , Wareham Nicholas , Travis Ruth C. , Palli Domenico , Pala Valeria , Tumino Rosario , Naccarati Alessio , Panico Salvatore , Vineis Paolo , Riboli Elio , Siddiq Afshan , Bueno-de-Mesquita H.B. , Peeters Petra H. , Nilsson Peter M. , Sund Malin , Ye Weimin , Lund Eiliv , Jareid Mie , Weiderpass Elisabete , Duarte-Salles Talita , Kong So Yeon , Stepien Magdalena , Canzian Federico , Kaaks Rudolf
Published: March 2023

Abstract
Background: Several studies have examined leukocyte telomere length (LTL) as a possible predictor for cancer at various organ sites. The hypothesis originally motivating many of these studies was that shorter telomeres would be associated with an increase in cancer risk; the results of epidemiologic studies have been inconsistent, however, and suggested positive, negative, or null associations. Two studies have addressed the association of LTL in relation to pancreatic cancer risk and the results are contrasting.

Methods: We measured LTL in a prospective study of 331 pancreatic cancer cases and 331 controls in the context of the European Prospective Investigation into Cancer and Nutrition (EPIC).

Results: We observed that the mean LTL was higher in cases (0.59 ± 0.20) than in controls (0.57 ± 0.17), although this difference was not statistically significant (P = 0.07), and a basic logistic regression model showed no association of LTL with pancreas cancer risk. When adjusting for levels of HbA1c and C-peptide, however, there was a weakly positive association between longer LTL and pancreatic cancer risk [OR, 1.13; 95% confidence interval (CI), 1.01–1.27]. Additional analyses by cubic spline regression suggested a possible nonlinear relationship between LTL and pancreatic cancer risk (P = 0.022), with a statistically nonsignificant increase in risk at very low LTL, as well as a significant increase at high LTL.

Conclusion: Taken together, the results from our study do not support LTL as a uniform and strong predictor of pancreatic cancer.

Impact: The results of this article can provide insights into telomere dynamics and highlight the complex relationship between LTL and pancreatic cancer risk. Cancer Epidemiol Biomarkers Prev; 23(11); 2447–54. ©2014 AACR.
Data from Body Mass Index, Hormone Replacement Therapy, and Endometrial Cancer Risk: A Meta-Analysis
Authors: Crosbie Emma J. , Zwahlen Marcel , Kitchener Henry C. , Egger Matthias , Renehan Andrew G.
Published: March 2023

Abstract
Background: Body mass index (BMI) is a risk factor for endometrial cancer. We quantified the risk and investigated whether the association differed by use of hormone replacement therapy (HRT), menopausal status, and histologic type.

Methods: We searched MEDLINE and EMBASE (1966 to December 2009) to identify prospective studies of BMI and incident endometrial cancer. We did random-effects meta-analyses, meta-regressions, and generalized least square regressions for trend estimations assuming linear, and piecewise linear, relationships.

Results: Twenty-four studies (17,710 cases) were analyzed; 9 studies contributed to analyses by HRT, menopausal status, or histologic type, all published since 2003. In the linear model, the overall risk ratio (RR) per 5 kg/m2 increase in BMI was 1.60 (95% CI, 1.52–1.68), P < 0.0001. In the piecewise model, RRs compared with a normal BMI were 1.22 (1.19–1.24), 2.09 (1.94–2.26), 4.36 (3.75–5.10), and 9.11 (7.26–11.51) for BMIs of 27, 32, 37, and 42 kg/m2, respectively. The association was stronger in never HRT users than in ever users: RRs were 1.90 (1.57–2.31) and 1.18 (95% CI, 1.06–1.31) with P for interaction = 0.003. In the piecewise model, the RR in never users was 20.70 (8.28–51.84) at BMI 42 kg/m2, compared with never users at normal BMI. The association was not affected by menopausal status (P = 0.34) or histologic type (P = 0.26).

Conclusions: HRT use modifies the BMI-endometrial cancer risk association.

Impact: These findings support the hypothesis that hyperestrogenia is an important mechanism underlying the BMI-endometrial cancer association, whilst the presence of residual risk in HRT users points to the role of additional systems. Cancer Epidemiol Biomarkers Prev; 19(12); 3119–30. ©2010 AACR.
Data from Circulation of Progenitor Cells in Obese and Lean Colorectal Cancer Patients
Authors: Bellows Charles F. , Zhang Yan , Chen Jinyun , Frazier Marsha L. , Kolonin Mikhail G.
Published: March 2023

Abstract
Background: Colorectal cancer (CRC) is a common life-threatening malignancy; risk and progression are elevated in obesity. The purpose of this study was to measure the frequency of circulating CD34-positive endothelial and progenitor cells in the circulation and evaluate their potential values as CRC biomarkers.

Methods: Blood was collected from 45 patients with CRC and compared with cancer-free control donors. Detection and enumeration of cells was carried out by flow cytometry on the basis of immunophenotypes established for the cell populations of interest: hematopoietic and endothelial circulating progenitor cells, endothelial cells, mesenchymal stromal cells (MSC), and CD34bright leukocytes (CD34b LC). Groups were compared using multivariate regression analysis. Receiver-operating characteristic (ROC) curve analysis was used to evaluate the diagnostic values.

Results: After adjusting for age and body mass index (BMI), the mean frequencies of MSCs and CD34b LCs were significantly higher in the circulation of patients with CRC than in controls. The areas under the ROC curve were 0.77 and 0.82 for MSCs and CD34b LCs, respectively. The frequency of circulating MSCs, but not of the other cell populations, was also found to be significantly higher in the circulation of obese patients with CRC (BMI ≥ 30 kg/m2) than in lean patients with CRC and obese controls.

Conclusions: Increased frequency of MSCs and CD34b LCs in the peripheral blood may represent a new diagnostic marker for CRC.

Impact: BMI-dependent changes in circulating MSCs, potentially mobilized from white adipose tissue may reveal their trafficking to tumors, which could be one of the mechanistic links between obesity and cancer progression. Cancer Epidemiol Biomarkers Prev; 20(11); 2461–8. ©2011 AACR.
Data from Distribution and Hepatocellular Carcinoma–Related Viral Properties of Hepatitis B Virus Genotypes in Mainland China: A Community-Based Study
Authors: Yin Jianhua , Zhang Hongwei , He Yongchao , Xie Jiaxin , Liu Shijian , Chang Wenjun , Tan Xiaojie , Gu Chunying , Lu Wei , Wang Hongyang , Bi Shengli , Cui Fuqiang , Liang Xiaofeng , Schaefer Stephan , Cao Guangwen
Published: March 2023

Abstract
Introduction: Hepatitis B virus (HBV) genotypes, replication status, and mutations have been associated with the risk of hepatocellular carcinoma (HCC). Our aim was to study the distribution and HCC-related viral properties of HBV genotypes/subgenotypes in Mainland China.

Methods: A multistage cluster probability sampling method was applied to select 81,775 participants between 1 and 59 years at 160 national disease surveillance points. We examined hepatitis B surface antigen, HBV genotypes and subgenotypes, hepatitis B e antigen, viral load, and mutations in the PreS and core promoter regions of HBV genome.

Results: HBV subgenotypes B2 (27.3%), C1 (10.7%), and C2 (58.0%) were predominant. Genotype D (D1, 80.8%) was frequent in the Uygur. We identified a new subgenotype, C9, mainly in Tibetans. Compositions of subgenotypes B2 and C1 and genotype mixture increased from the North to Central South, which was consistently associated with the increasing prevalence of hepatitis B surface antigen. Hepatitis B e antigen positivity and viral loads were higher in the young with genotype B and declined more rapidly with increasing age than those with genotype C. In contrast to G1896A, PreS deletion, T31C, T1753V, and A1762T/G1764A were more frequent in subgenotype C2 than in subgenotype B2. A1762T/G1764A, T1753V, C1653T, and G1896A, except PreS deletion, consecutively increased with increasing age.

Conclusion: HBV subgenotypes B2, C1, and C2 are endemic in Mainland China. HBV genotype C exhibits less replication activity in the young and harbors higher frequencies of the HCC-associated mutations than genotype B.

Impact: These basic data could help evaluate the association of HBV variations with HCC. Cancer Epidemiol Biomarkers Prev; 19(3); 777–86
Data from Oral Human Papillomavirus Infection and Its Risk Factors among 5,410 Healthy Adults in China, 2009–2011
Authors: Hang Dong , Liu Fangfang , Liu Mengfei , He Zhonghu , Sun Min , Liu Ying , Li Jingjing , Pan Yaqi , Ning Tao , Guo Chuanhai , Liang Yongmei , Xu Ruiping , Zhang Lixin , Cai Hong , Ke Yang
Published: March 2023

Abstract
Background: Despite the established link between oral human papillomavirus (HPV) infection and a subset of oropharyngeal squamous cell carcinoma (OSCC), little is known about the epidemiology of oral HPV infection among healthy adults in China.

Methods: Oral swab specimens and questionnaires were collected from 5,410 individuals (ages 25–65 years). HPV DNA in oral exfoliated cells was tested by general primer-mediated (SPF1/GP6+) PCR and sequencing. Univariate and multivariate analyses were performed to assess the associations between exposure factors and oral infection.

Results: Alpha mucosal HPV types were detected in 0.67% [95% confidence interval (CI), 0.47%–0.93%] of 5,351 β-globin–positive specimens, and cutaneous HPV in 5.46% (95% CI, 4.86%–6.10%). HPV 16 and 3 were the most prevalent types of α mucosal (0.43%; 95% CI, 0.27%–0.64%) and cutaneous HPV (4.17%; 95% CI, 3.65%–4.74%), respectively. The prevalence of α mucosal HPV decreased with increasing age (25–65 years) from 0.93% to 0.36% (Ptrend = 0.033), and was associated with self-reported history of oral disease [adjusted odds ratio (OR), 4.78; 95% CI, 1.07–21.41]. In 1,614 heterosexual couples, cutaneous HPV in one partner was found to increase the other partner's risk of cutaneous HPV infection (adjusted OR, 2.33; 95% CI, 1.22–4.48).

Conclusions: Oral HPV infection, particularly with α mucosal types, is rare among healthy adults in China. A younger age and a history of oral disease imply higher risk of α mucosal HPV infection.

Impact: This study addresses the paucity of epidemiological data on oral HPV infection among healthy population in China. Cancer Epidemiol Biomarkers Prev; 23(10); 2101–10. ©2014 AACR.
Data from Cumulative Effect of Multiple Loci on Genetic Susceptibility to Familial Lung Cancer
Authors: Liu Pengyuan , Vikis Haris G. , Lu Yan , Wang Yian , Schwartz Ann G. , Pinney Susan M. , Yang Ping , de Andrade Mariza , Gazdar Adi , Gaba Colette , Mandal Diptasri , Lee Juwon , Kupert Elena , Seminara Daniela , Minna John , Bailey-Wilson Joan E. , Amos Christopher I. , Anderson Marshall W. , You Ming
Published: March 2023

Abstract
Background: Genetic factors play important roles in lung cancer susceptibility. In this study, we replicated the association of 5p15.33 and 6p21.33 with familial lung cancer. Taking into account the previously identified genetic susceptibility variants on 6q23-25/RGS17 and 15q24-25.1, we further determined the cumulative association of these four genetic regions and the population attributable risk percent of familial lung cancer they account for.

Methods: One hundred ninety-four case patients and 219 cancer-free control subjects from the Genetic Epidemiology of Lung Cancer Consortium were used for the association analysis. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Single nucleotide polymorphisms (SNP) on chromosomal regions 5p15.33, 6p21.33, 6q23-25/RGS17, and 15q24-25.1 were assessed for their associations with familial lung cancer. The cumulative association of the four chromosomal regions with familial lung cancer was evaluated with the use of a linear logistic model. Population attributable risk percent was calculated for each SNP using risk ratio.

Results: SNP rs31489 showed the strongest evidence of familial lung cancer association on 5p15.33 (P = 2 × 10−4; odds ratio, 0.57; 95% confidence interval, 0.42-0.77), whereas rs3117582 showed a weak association on 6p21.33 (P = 0.09; odds ratio, 1.47; 95% confidence interval, 0.94-2.31). Analysis of a combination of SNPs from the four regions provided a stronger cumulative association with familial lung cancer (P = 6.70 × 10−6) than any individual SNPs. The risk of lung cancer was increased to 3- to 11-fold among those subjects who had at least one copy of risk allele at each region compared with subjects without any of the risk factors. These four genetic regions contribute to a total of 34.6% of familial lung cancer in smokers.

Conclusions: The SNPs in four chromosomal regions have a cumulative and significant association with familial lung cancer and account for about one-third of the population attributable risk for familial lung cancer. Cancer Epidemiol Biomarkers Prev; 19(2); 517–24
Data from Polymorphisms in Telomere Maintenance Genes and Risk of Lung Cancer
Authors: Choi Jin Eun , Kang Hyo-Gyoung , Jang Jin Sung , Choi Yi Young , Kim Min Jung , Kim Jong Sik , Jeon Hyo-Sung , Lee Won Kee , Cha Sung Ick , Kim Chang Ho , Kam Sin , Jung Tae Hoon , Park Jae Yong
Published: March 2023

Abstract
This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C > T and rs2736098 g.G > A, and TNKS1 rs6985140 g.A > G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (Ptrend < 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2773–81)
Data from Ordered Subset Analysis Identifies Loci Influencing Lung Cancer Risk on Chromosomes 6q and 12q
Authors: Fang Shenying , Pinney Susan M. , Bailey-Wilson Joan E. , de Andrade Mariza A. , Li Yafang , Kupert Elena , You Ming , Schwartz Ann G. , Yang Ping , Anderson Marshall W. , Amos Christopher I.
Published: March 2023

Abstract
Background: Genetic susceptibility for cancer can differ substantially among families. We use trait-related covariates to identify a genetically homogeneous subset of families with the best evidence for linkage in the presence of heterogeneity.

Methods: We performed a genome-wide linkage screen in 93 families. Samples and data were collected by the familial lung cancer recruitment sites of the Genetic Epidemiology of Lung Cancer Consortium. We estimated linkage scores for each family by the Markov chain Monte Carlo procedure using SimWalk2 software. We used ordered subset analysis (OSA) to identify genetically homogenous families by ordering families based on a disease-associated covariate. We performed permutation tests to determine the relationship between the trait-related covariate and the evidence for linkage.

Results: A genome-wide screen for lung cancer loci identified strong evidence for linkage to 6q23–25 and suggestive evidence for linkage to 12q24 using OSA, with peak logarithm of odds (LOD) scores of 4.19 and 2.79, respectively. We found other chromosomes also suggestive for linkages, including 5q31–q33, 14q11, and 16q24.

Conclusions: Our OSA results support 6q as a lung cancer susceptibility locus and provide evidence for disease linkage on 12q24. This study further increased our understanding of the inheritability for lung cancer. Validation studies using larger sample size are needed to verify the presence of several other chromosomal regions suggestive of an increased risk for lung cancer and/or other cancers.

Impact: OSA can reduce genetic heterogeneity in linkage study and may assist in revealing novel susceptibility loci. Cancer Epidemiol Biomarkers Prev; 19(12); 3157–66. ©2010 AACR.
Data from Association of Leukocyte Mitochondrial DNA Copy Number with Colorectal Cancer Risk: Results from the Shanghai Women's Health Study
Authors: Huang Bo , Gao Yu-Tang , Shu Xiao-Ou , Wen Wanqing , Yang Gong , Li Guoliang , Courtney Regina , Ji Bu-Tian , Li Hong-Lan , Purdue Mark P. , Zheng Wei , Cai Qiuyin
Published: March 2023

Abstract
Background: Mitochondria play an important role in cellular energy metabolism, free radical production, and apoptosis, and thus may be involved in cancer development.

Methods: We evaluated mitochondrial DNA (mtDNA) copy number in peripheral leukocytes in relation to colorectal cancer risk in a case–control study of 444 colorectal cancer cases and 1,423 controls nested in the Shanghai Women's Health Study, a population-based, prospective cohort study. Relative mtDNA copy number was determined by a quantitative real-time PCR assay using peripheral leukocyte DNA samples collected at the time of study enrollment, before cancer diagnosis.

Results: We found that baseline mtDNA copy number was lower among women who subsequently developed colorectal cancer [geometric mean, 0.277; 95% confidence interval (CI), 0.269–0.285] than among women who remained cancer-free (geometric mean, 0.288; 95% CI, 0.284–0.293; P = 0.0153). Multivariate adjusted ORs were 1.26 (95% CI, 0.93–1.70) and 1.44 (95% CI, 1.06–1.94) for the middle and lower tertiles of mtDNA copy number, respectively, compared with the upper tertile (highest mtDNA copy number; Ptrend = 0.0204). The association varied little by the interval between blood collection and cancer diagnosis.

Conclusions: Our data suggest that mtDNA copy number measured in peripheral leukocytes may be a potential biomarker useful for colorectal cancer risk assessment.

Impact: If confirmed, mtDNA copy number measured in peripheral leukocytes may be a biomarker useful for colorectal cancer risk assessment. Cancer Epidemiol Biomarkers Prev; 23(11); 2357–65. ©2014 AACR.
Data from Association of Common Susceptibility Variants of Pancreatic Cancer in Higher-Risk Patients: A PACGENE Study
Authors: Childs Erica J. , Chaffee Kari G. , Gallinger Steven , Syngal Sapna , Schwartz Ann G. , Cote Michele L. , Bondy Melissa L. , Hruban Ralph H. , Chanock Stephen J. , Hoover Robert N. , Fuchs Charles S. , Rider David N. , Amundadottir Laufey T. , Stolzenberg-Solomon Rachael , Wolpin Brian M. , Risch Harvey A. , Goggins Michael G. , Petersen Gloria M. , Klein Alison P.
Published: March 2023

Abstract
Individuals from pancreatic cancer families are at increased risk, not only of pancreatic cancer, but also of melanoma, breast, ovarian, and colon cancers. While some of the increased risk may be due to mutations in high-penetrance genes (i.e., BRCA2, PALB2, ATM, p16/CDKN2A or DNA mismatch repair genes), common genetic variants may also be involved. In a high-risk population of cases with either a family history of pancreatic cancer or early-onset pancreatic cancer (diagnosis before the age of 50 years), we examined the role of genetic variants previously associated with risk of pancreatic, breast, ovarian, or prostate cancer. We genotyped 985 cases (79 early-onset cases, 906 cases with a family history of pancreatic cancer) and 877 controls for 215,389 SNPs using the iSelect Collaborative Oncological Gene-Environment Study (iCOGS) array with custom content. Logistic regression was performed using a log-linear additive model. We replicated several previously reported pancreatic cancer susceptibility loci, including recently identified variants on 2p13.3 and 7p13 (2p13.3, rs1486134: OR = 1.36; 95% CI, 1.13–1.63; P = 9.29 × 10−4; 7p13, rs17688601: OR = 0.76; 95% CI, 0.63–0.93; P = 6.59 × 10−3). For the replicated loci, the magnitude of association observed in these high-risk patients was similar to that observed in studies of unselected patients. In addition to the established pancreatic cancer loci, we also found suggestive evidence of association (P < 5 × 10−5) to pancreatic cancer for SNPs at HDAC9 (7p21.1) and COL6A2 (21q22.3). Even in high-risk populations, common variants influence pancreatic cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 25(7); 1185–91. ©2016 AACR.
Data from Preoperative Serum Levels of Matrix Metalloproteinase-2 (MMP-2) and Survival of Breast Cancer among Korean Women
Authors: Song Nan , Sung Hyuna , Choi Ji-Yeob , Han Sohee , Jeon Sujee , Song Minkyo , Lee Yunhee , Park Chulbum , Park Sue K. , Lee Kyoung-Mu , Yoo Keun-Young , Noh Dong-Young , Ahn Sei-Hyun , Lee Sang-Ah , Kang Daehee
Published: March 2023

Abstract
Background: Matrix metalloproteinase-2 (MMP-2) has been thought of as a predictor of recurrence or metastasis risk or prognostic markers in cancer. We evaluated whether preoperative serum levels of MMP-2 work as a prognostic biomarker in breast cancer prognosis.

Methods: Preoperative serum levels of MMP-2 were measured with ELISA in 303 patients with histologically confirmed breast cancer. The median follow-up time for all patients was 4.24 years. The relationship of MMP-2 to survival was investigated using Cox proportional hazard regression model adjusted for the tumor–node–metastasis (TNM) stage and estrogen receptor (ER) status.

Results: In the multivariate analysis, disease-free survival (DFS) was worse among patients with the third tertile of MMP-2 level than with the first tertile of MMP-2 level [hazard ratio, 1.80; 95% confidence interval (CI), 1.04–3.11; P = 0.04]. However, when the patients were stratified by age, ER status, histologic grade, and nuclear grade, inverse correlation was shown between serum MMP-2 levels and prognostic factors, and the associations between MMP-2 and DFS were only significant among patients with poor prognostic factors (HR, 2.75; 95% CI, 1.32–5.73 in ER-negative; HR, 2.90; 95% CI, 1.42–5.92 in histologic grade III; and HR, 2.61; 95% CI, 1.26–5.39 in nuclear grade III).

Conclusions: Our results suggest that the preoperative serum levels of MMP-2 were associated with the survival in patients with breast cancer in ER-negative, higher histologic grade, or higher nuclear grade breast cancers.

Impact: Our results indicate that serum levels of MMP-2 may play a role as prognostic biomarker in breast cancer survival. Cancer Epidemiol Biomarkers Prev; 21(8); 1371–80. ©2012 AACR.
Data from Endometrial Cancer Risk Factors, Hormone Receptors, and Mortality Prediction
Authors: Busch Evan L. , Crous-Bou Marta , Prescott Jennifer , Chen Maxine M. , Downing Michael J. , Rosner Bernard A. , Mutter George L. , De Vivo Immaculata
Published: March 2023

Abstract
Background: Endometrial tumors arise from a hormonally responsive tissue. Defining subtypes by hormone receptor expression might better inform etiology and prediction of patient outcomes. We evaluated the potential role of tumor estrogen receptor (ER) and progesterone receptor (PR) expression to define endometrial cancer subtypes.

Methods: We measured semi-continuous ER and PR protein expression in tissue specimens from 360 endometrial primary tumors from the Nurses' Health Study. To explore the impact of different definitions of marker positivity, we dichotomized ER and PR expression at different cut points in increments of 5% positive cells. Logistic regression was used to estimate associations between endometrial cancer risk factors, such as body mass index, with dichotomous ER or PR status. Reclassification statistics were used to assess whether adding dichotomous ER or PR status to standard prognostic factors of stage, grade, and histologic type would improve endometrial cancer-specific mortality prediction.

Results: Compared with not being obese, obesity increased the odds of having an ER-positive tumor at cut points of 0% to 20% [maximum OR, 2.92; 95% confidence interval (CI), 1.34–6.33] as well as the odds of having a PR-positive tumor at cut points of 70% to 90% (maximum OR, 2.53; 95% CI, 1.36–4.68). Adding dichotomous tumor ER or PR status to the panel of standard predictors did not improve both model discrimination and calibration.

Conclusions: Obesity may be associated with greater endometrial tumor expression of ER and PR. Adding either marker does not appear to improve mortality prediction beyond the standard predictors.

Impact: Body mass index might explain some of the biological variation among endometrial tumors. Cancer Epidemiol Biomarkers Prev; 26(5); 727–35. ©2017 AACR.
Data from Prognostic Impact of Cigarette Smoking on the Survival of Patients with Established Nasopharyngeal Carcinoma
Authors: OuYang Pu-Yun , Su Zhen , Mao Yan-Ping , Liang Xue-Xia , Liu Qing , Deng Wuguo , Xie Fang-Yun
Published: March 2023

Abstract
Background: Cigarette smoking is associated with the etiology of nasopharyngeal carcinoma; however, the influence of smoking on survival in patients with established nasopharyngeal carcinoma remains unknown.

Methods: We retrospectively analyzed 1,849 patients with nasopharyngeal carcinoma who were categorized as never, former, and current smokers. Cumulative effect of smoking was defined in terms of pack-years. Associations between cigarette exposure and survival were estimated by Cox proportional hazards model.

Results: The risks of death, progression, locoregional relapse, and distant metastasis were significantly higher for former and current smokers (all P ≤ 0.002) than never smokers. Heavy smokers with high pack-years had HRs for death of 3.31 [95% confidence interval (CI), 2.58–4.26; P < 0.001], for progression of 2.53 (95% CI, 2.03–3.16; P < 0.001), and for distant metastasis of 2.65 (95% CI, 1.89–3.70; P < 0.001). Specifically, in the cohort of 495 patients treated with intensity-modulated radiotherapy/three-dimensional conformal radiotherapy, we obtained similarly significant results. All of the survival outcomes remained significant in multivariate analyses.

Conclusions: Pretreatment cigarette smoking is an independent, poor prognostic factor for patients with nasopharyngeal carcinoma, which is associated with increased risk of death, progression, locoregional relapse, and distant metastasis, with the risk increasing with pack-years.

Impact: It is clear that cigarette smoking not only promotes carcinogenesis in the normal nasopharyngeal epithelium, but also affects the survival of patients with nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev; 22(12); 2285–94. ©2013 AACR.
Data from A Novel Quantitative Multiplex Tissue Immunoblotting for Biomarkers Predicts a Prostate Cancer Aggressive Phenotype
Authors: Zhu Guangjing , Liu Zhi , Epstein Jonathan I. , Davis Christine , Christudass Christhunesa S. , Carter H. Ballentine , Landis Patricia , Zhang Hui , Chung Joon-Yong , Hewitt Stephen M. , Miller M. Craig , Veltri Robert W.
Published: March 2023

Abstract
Background: Early prediction of disease progression in men with very low-risk (VLR) prostate cancer who selected active surveillance (AS) rather than immediate treatment could reduce morbidity associated with overtreatment.

Methods: We evaluated the association of six biomarkers [Periostin, (−5, −7) proPSA, CACNA1D, HER2/neu, EZH2, and Ki-67] with different Gleason scores and biochemical recurrence (BCR) on prostate cancer TMAs of 80 radical prostatectomy (RP) cases. Multiplex tissue immunoblotting (MTI) was used to assess these biomarkers in cancer and adjacent benign areas of 5 μm sections. Multivariate logistic regression (MLR) was applied to model our results.

Results: In the RP cases, CACNA1D, HER2/neu, and Periostin expression were significantly correlated with aggressive phenotype in cancer areas. An MLR model in the cancer area yielded a ROC-AUC = 0.98, whereas in cancer-adjacent benign areas, yielded a ROC-AUC = 0.94. CACNA1D and HER2/neu expression combined with Gleason score in a MLR model yielded a ROC-AUC = 0.79 for BCR prediction. In the small biopsies from an AS cohort of 61 VLR cases, an MLR model for prediction of progressors at diagnosis retained (−5, −7) proPSA and CACNA1D, yielding a ROC-AUC of 0.78, which was improved to 0.82 after adding tPSA into the model.

Conclusions: The molecular profile of biomarkers is capable of accurately predicting aggressive prostate cancer on retrospective RP cases and identifying potential aggressive prostate cancer requiring immediate treatment on the AS diagnostic biopsy but limited in BCR prediction.

Impact: Comprehensive profiling of biomarkers using MTI predicts prostate cancer aggressive phenotype in RP and AS biopsies. Cancer Epidemiol Biomarkers Prev; 24(12); 1864–72. ©2015 AACR.
Data from The Association of Telomere Length in Peripheral Blood Cells with Cancer Risk: A Systematic Review and Meta-analysis of Prospective Studies
Authors: Zhang Xia , Zhao Qian , Zhu Wei , Liu Tao , Xie Shao-Hua , Zhong Li-Xin , Cai Yuan-Yuan , Li Xiao-Na , Liang Mei , Chen Wen , Hu Qian-Sheng , Zhang Bo
Published: March 2023

Abstract
The association between telomere length (TL) in peripheral blood cells and cancer risk remains inconclusive. We carried out a meta-analysis on prospective studies. The study-specific RR estimates were first transformed to a common comparable scale and then were pooled by a random-effects model. The dataset was composed of 13,894 cases and 71,672 controls from 28 studies in 25 articles. In the comparison of the longest versus shortest third of TL, we observed a marginally positive association between longer TL and higher risk of total cancers [OR = 1.086; 95% confidence interval (CI), 0.952–1.238]. Subgroup analyses showed that the association was stronger in lung cancer (n = 3; OR = 1.690; 95% CI, 1.253–2.280), in men (n = 6; OR = 1.302; 95% CI, 1.120–1.514) and in studies with more precise methods for DNA extraction (phenol–chloroform, salting-out or magnetic bead, n = 6, OR = 1.618; 95% CI, 1.320–1.985) and TL measurement (multiplex Q-PCR, n = 8; OR = 1.439; 95% CI, 1.118–1.852). Our meta-analysis suggested longer TL in peripheral blood cells is a likely risk factor for lung cancer or cancers in men. Accurate DNA extraction and TL measurement methods make it more liable to find significant associations between TL and cancer risk and thus should be taken into consideration in future epidemiologic studies. Cancer Epidemiol Biomarkers Prev; 26(9); 1381–90. ©2017 AACR.
Data from Gene Expression Profiles in Peripheral Blood Mononuclear Cells of Chinese Nickel Refinery Workers with High Exposures to Nickel and Control Subjects
Authors: Arita Adriana , Muñoz Alexandra , Chervona Yana , Niu Jingping , Qu Qingshan , Zhao Najuan , Ruan Ye , Kiok Kathrin , Kluz Thomas , Sun Hong , Clancy Hailey A. , Shamy Magdy , Costa Max
Published: March 2023

Abstract
Background: Occupational exposure to nickel (Ni) is associated with an increased risk of lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, alter the cell's epigenetic homeostasis, and activate signaling pathways. However, changes in gene expression associated with Ni exposure have only been investigated in vitro. This study was conducted in a Chinese population to determine whether occupational exposure to Ni was associated with differential gene expression profiles in the peripheral blood mononuclear cells (PBMC) of Ni-refinery workers when compared with referents.

Methods: Eight Ni-refinery workers and ten referents were selected. PBMC RNA was extracted and gene expression profiling was conducted using Affymetrix exon arrays. Differentially expressed genes (DEG) between both groups were identified in a global analysis.

Results: There were a total of 2,756 DEGs in the Ni-refinery workers relative to the referents [false discovery rate (FDR) adjusted P < 0.05] with 770 upregulated genes and 1,986 downregulated genes. DNA repair and epigenetic genes were significantly overrepresented (P < 0.0002) among the DEGs. Of 31 DNA repair genes, 29 were repressed in the Ni-refinery workers and 2 were overexpressed. Of the 16 epigenetic genes, 12 were repressed in the Ni-refinery workers and 4 were overexpressed.

Conclusions: The results of this study indicate that occupational exposure to Ni is associated with alterations in gene expression profiles in PBMCs of subjects.

Impact: Gene expression may be useful in identifying patterns of deregulation that precede clinical identification of Ni-induced cancers. Cancer Epidemiol Biomarkers Prev; 22(2); 261–9. ©2012 AACR.
Data from Genome-Wide Association Study of Prostate Cancer–Specific Survival
Authors: Szulkin Robert , Karlsson Robert , Whitington Thomas , Aly Markus , Gronberg Henrik , Eeles Rosalind A. , Easton Douglas F. , Kote-Jarai Zsofia , Al Olama Ali Amin , Benlloch Sara , Muir Kenneth , Giles Graham G. , Southey Melissa C. , FitzGerald Liesel M. , Henderson Brian E. , Schumacher Fredrick R. , Haiman Christopher A. , Sipeky Csilla , Tammela Teuvo L.J. , Nordestgaard Børge G. , Key Timothy J. , Travis Ruth C. , Neal David E. , Donovan Jenny L. , Hamdy Freddie C. , Pharoah Paul D.P. , Pashayan Nora , Khaw Kay-Tee , Stanford Janet L. , Thibodeau Stephen N. , McDonnell Shannon K. , Schaid Daniel J. , Maier Christiane , Vogel Walther , Luedeke Manuel , Herkommer Kathleen , Kibel Adam S. , Cybulski Cezary , Lubiński Jan , Kluźniak Wojciech , Cannon-Albright Lisa , Brenner Hermann , Herrmann Volker , Holleczek Bernd , Park Jong Y. , Sellers Thomas A. , Lim Hui-Yi , Slavov Chavdar , Kaneva Radka P. , Mitev Vanio I. , Spurdle Amanda , Teixeira Manuel R. , Paulo Paula , Maia Sofia , Pandha Hardev , Michael Agnieszka , Kierzek Andrzej , Batra Jyotsna , Clements Judith A. , Albanes Demetrius , Andriole Gerald L. , Berndt Sonja I. , Chanock Stephen , Gapstur Susan M. , Giovannucci Edward L. , Hunter David J. , Kraft Peter , Le Marchand Loic , Ma Jing , Mondul Alison M. , Penney Kathryn L. , Stampfer Meir J. , Stevens Victoria L. , Weinstein Stephanie J. , Trichopoulou Antonia , Bueno-de-Mesquita Bas H. , Tjønneland Anne , Cox David G. , Maehle Lovise , Schleutker Johanna , Lindström Sara , Wiklund Fredrik
Published: March 2023

Abstract
Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.

Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).

Results: We observed no significant association between genetic variants and prostate cancer survival.

Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study.

Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.
Dietary Fats and All-cause and Breast Cancer–specific Mortality among Women with Breast Cancer: The Western New York Exposures and Breast Cancer Study
Authors: Meyer Danielle S. , Millen Amy E. , Nie Jing , Trevisan Maurizio , Freudenheim Jo L.
Published: March 2023

Background:

Study results of prediagnostic dietary fat intake and breast cancer mortality have been inconclusive. While dietary fat subtypes [saturated (SFA), polyunsaturated (PUFA), and monounsaturated (MUFA) fatty acids] may have different biological effects, there is little evidence regarding the association of dietary fat and fat subtype intake with mortality after breast cancer diagnosis.

Methods:

Women with incident, pathologically confirmed invasive breast cancer and complete dietary data (n = 793) were followed in a population-based study, the Western New York Exposures and Breast Cancer study. Usual intake before diagnosis of total fat and subtypes were estimated from a food frequency questionnaire completed at baseline. HRs and 95% confidence intervals (CI) for all-cause and breast cancer–specific mortality were estimated with Cox proportional hazards models. Interactions by menopausal status, estrogen receptor (ER) status, and tumor stage were examined.

Results:

Median follow-up time was 18.75 years; 327 (41.2%) participants had died. Compared with lower intake, greater intake of total fat (HR, 1.05; 95% CI, 0.65–1.70), SFA (1.31; 0.82–2.10), MUFA (0.99; 0.61–1.60), and PUFA (0.99; 0.56–1.75) was not associated with breast cancer–specific mortality. There was also no association with all-cause mortality. Results did not vary by menopausal status, ER status, or tumor stage.

Conclusions:

Prediagnostic intake of dietary fat and fat subtypes was not associated with either all-cause or breast cancer mortality in a population-based cohort of breast cancer survivors.

Impact:

Understanding factors affecting survival among women diagnosed with breast cancer is critically important. Dietary fat intake prior to diagnosis may not impact that survival.
Osimertinib and Selpercatinib Efficacy, Safety, and Resistance in a Multicenter, Prospectively Treated Cohort of EGFR-Mutant and RET Fusion-Positive Lung Cancers
Authors: Rotow Julia , Patel Jyoti D. , Hanley Matthew P. , Yu Helena , Awad Mark , Goldman Jonathan W. , Nechushtan Hovav , Scheffler Matthias , Kuo Chih-Hsi S. , Rajappa Senthil , Harada Guilherme , Clifford Sarah , Santucci Alison , Silva Laura , Tupper Rebecca , Oxnard Geoffrey R. , Kherani Jennifer , Drilon Alexander
Published: March 2023

Purpose:

Acquired RET fusions have been reported at resistance to treatment with EGFR inhibitors in EGFR-mutant non–small cell lung cancer (NSCLC); however, a multicenter cohort of patients with EGFR-mutant lung cancers treated with osimertinib and selpercatinib for RET fusion–mediated osimertinib resistance has not previously been published.

Patients and Methods:

Patients who received selpercatinib in combination with osimertinib on a prospective expanded access clinical trial (NCT03906331) and single-patient compassionate use programs across five countries were centrally analyzed. All patients had advanced EGFR-mutant NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected.

Results:

Fourteen patients with EGFR-mutant and RET fusion–positive lung cancers who experienced prior progression on osimertinib received osimertinib and selpercatinib. EGFR exon 19 deletions (±T790M, 86%) and non-KIF5B fusions (CCDC6-RET 50%, NCOA4-RET 36%) predominated. Osimertinib 80 mg daily and selpercatinib 80 mg twice daily were the most commonly administered dosages. The response rate, disease control rate, and median treatment duration were 50% [95% confidence interval (CI), 25%–75%, n = 12], 83% (95% CI, 55%–95%), and 7.9 months (range, 0.8–25+), respectively. Resistance was complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target (EML4–ALK/STRN–ALK, KRAS G12S, BRAF V600E) mechanisms; RET fusion loss; or polyclonal mechanisms.

Conclusions:

For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible and safe and offered clinical benefit, supporting the prospective evaluation of this combination.

See related commentary by Krebs and Popat, p. 2951