bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Prolactin Determinants in Healthy Women: A Large Cross-Sectional Study within the EPIC Cohort
Authors: Tikk Kaja , Sookthai Disorn , Johnson Theron , Dossus Laure , Clavel-Chapelon Françoise , Tjønneland Anne , Olsen Anja , Overvad Kim , Baglietto Laura , Rinaldi Sabina , Romieu Isabelle , Boeing Heiner , Trichopoulou Antonia , Lagiou Pagona , Trichopoulos Dimitrios , Masala Giovanna , Agnoli Claudia , Tumino Rosario , Sacerdote Carlotta , Mattiello Amalia , Buckland Genevieve , Sánchez Soledad , Molina-Montes Esther , Amiano Pilar , Castaño José María Huerta , Barricarte Aurelio , Bueno-de-Mesquita H. Bas , Monninkhof Evelyn M. , Onland-Moret N. Charlotte , Idahl Annika , Lundin Eva , Weiderpass Elisabete , Lund Eiliv , Waaseth Marit , Khaw Kay-Tee , Key Timothy J. , Travis Ruth C. , Gunter Marc J. , Riboli Elio , Kaaks Rudolf
Published: March 2023

Abstract
Background: Experimental and epidemiologic data suggest that higher circulating prolactin is associated with breast cancer risk; however, how various risk factors for breast cancer influence prolactin levels in healthy women is not clear.

Methods: We analyzed cross-sectional associations between several suggested reproductive and lifestyle risk factors for breast cancer and circulating prolactin among pre- and postmenopausal women, taking into account the use of current postmenopausal hormone therapy, among 2,560 controls from a breast cancer nested case–control study within the EPIC cohort.

Results: Adjusted geometric mean prolactin levels were significantly higher among premenopausal women, and among postmenopausal women using hormone therapy compared with nonusers (8.2, 7.0, and 6.3 ng/mL, respectively; Pcat = <0.0001). Furthermore, prolactin levels were significantly higher among users of combined estrogen–progestin hormone therapy compared with users of estrogen-alone hormone therapy (6.66 vs. 5.90 ng/mL; Pcat = 0.001). Prolactin levels were lower among parous women compared with nulliparous women (8.61 vs. 10.95 ng/mL; Pcat = 0.0002, premenopausal women); the magnitude of this difference depended on the number of full-term pregnancies (22.1% lower, ≥3 vs. 1 pregnancy, Ptrend = 0.01). Results for parity were similar but lower in magnitude among postmenopausal women. Prolactin did not vary by other studied factors, with the exception of lower levels among postmenopausal smokers compared with never smokers.

Conclusions: Our study shows that current hormone therapy use, especially the use of combined hormone therapy, is associated with higher circulating prolactin levels in postmenopausal women, and confirms prior findings of lower circulating prolactin in parous women.

Impact: Our study extends the knowledge linking various breast cancer risk factors with circulating prolactin. Cancer Epidemiol Biomarkers Prev; 23(11); 2532–42. ©2014 AACR.
Data from Association between Genetic Variants in the 8q24 Cancer Risk Regions and Circulating Levels of Androgens and Sex Hormone–Binding Globulin
Authors: Chu Lisa W. , Meyer Tamra E. , Li Qizhai , Menashe Idan , Yu Kai , Rosenberg Philip S. , Huang Wen-Yi , Quraishi Sabah M. , Kaaks Rudolf , Weiss Jocelyn M. , Hayes Richard B. , Chanock Stephen J. , Hsing Ann W.
Published: March 2023

Abstract
Background: Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder.

Methods: To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphisms (SNPs) in the 8q24 risk regions spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, 3αdiol G, and bioavailable testosterone), and sex hormone–binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log-transformed biomarker levels.

Results: Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P < 1.1 × 10−3) and bioavailable testosterone (P < 6.3 × 10−4). Suggestive associations were seen for a cluster of nine SNPs in prostate cancer risk region 1 and androstenedione (P < 0.05).

Conclusions: These preliminary findings require confirmation in larger studies but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions might correlate with androgen levels.

Impact: These results might provide some clues for the strong link between 8q24 and prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 19(7); 1848–54. ©2010 AACR.
Data from Glutathione Pathway Genetic Polymorphisms and Lung Cancer Survival After Platinum-Based Chemotherapy
Authors: Moyer Ann M. , Sun Zhifu , Batzler Anthony J. , Li Liang , Schaid Daniel J. , Yang Ping , Weinshilboum Richard M.
Published: March 2023

Abstract
Background: Lung cancer is commonly treated with platinum compounds. The “glutathione pathway” participates in the metabolism of platinum compounds. We set out to test the hypotheses that single nucleotide polymorphisms (SNPs) or copy number polymorphisms for genes within the glutathione pathway might influence survival in lung cancer patients treated with these drugs.

Methods: Germline DNA samples from 973 lung cancer patients were genotyped for 290 glutathione pathway SNPs. GSTT1 copy number was also assayed. We determined the association of these polymorphisms with survival for lung cancer patients, followed by functional genomic validation.

Results: We observed suggestive associations between survival and GSTT1 copy number (P = 0.017), and GSTA5, GSTM4, and ABCC4 SNPs, adjusted for covariates (P = 0.018, 0.002, and 0.002, respectively) or not (P = 0.005, 0.011, and 0.002). One hundred lymphoblastoid cell lines were then treated with cisplatin, and IC50 values were significantly associated with the GSTM4 SNP (P = 0.019). Furthermore, GSTM4, GSTT1, and ABCC4 overexpression significantly decreased cisplatin sensitivity in lung cancer and HEK293T cell lines.

Conclusions: These results suggest that GSTM4 polymorphisms are biomarkers for the prediction of cisplatin response. ABCC4 polymorphisms, as well as GSTT1 copy number, may also help to predict cisplatin response, but further validation is required. These results represent a step toward the individualized chemotherapy of lung cancer. Cancer Epidemiol Biomarkers Prev; 19(3); 811–21
Data from The Heritability of Mammographic Breast Density and Circulating Sex-Hormone Levels: Two Independent Breast Cancer Risk Factors
Authors: Varghese Jajini S. , Smith Paula L. , Folkerd Elizabeth , Brown Judith , Leyland Jean , Audley Tina , Warren Ruth M.L. , Dowsett Mitchell , Easton Douglas F. , Thompson Deborah J.
Published: March 2023

Abstract
Background: Mammographic breast density and endogenous sex-hormone levels are both strong risk factors for breast cancer. This study investigated whether there is evidence for a shared genetic basis between these risk factors.

Methods: Using data on 1,286 women from 617 families, we estimated the heritabilities of serum estradiol, testosterone, and sex-hormone binding globulin (SHBG) levels and of three measures of breast density (dense area, nondense area, and percentage density). We tested for associations between hormone levels and density measures and estimated the genetic and environmental correlations between pairs of traits using variance and covariance components models and pedigree-based maximum likelihood methods.

Results: We found no significant associations between estradiol, testosterone, or SHBG levels and any of the three density measures, after adjusting for body mass index (BMI).

The estimated heritabilities were 63%, 66%, and 65% for square root–transformed adjusted percentage density, dense area, and nondense area, respectively, and 40%, 25%, and 58% for log-transformed–adjusted estradiol, testosterone, and SHBG. We found no evidence of a shared genetic basis between any hormone levels and any measure of density, after adjusting for BMI. The negative genetic correlation between dense and nondense areas remained significant even after adjustment for BMI and other covariates (ρ = −0.34; SE = 0.08; P = 0.0005).

Conclusions: Breast density and sex hormones can be considered as independent sets of traits.

Impact: Breast density and sex hormones can be used as intermediate phenotypes in the search for breast cancer susceptibility loci. Cancer Epidemiol Biomarkers Prev; 21(12); 2167–75. ©2012 AACR.
Data from Lower Risk in Parous Women Suggests That Hormonal Factors Are Important in Bladder Cancer Etiology
Authors: Davis-Dao Carol A. , Henderson Katherine D. , Sullivan-Halley Jane , Ma Huiyan , West Dee , Xiang Yong-Bing , Gago-Dominguez Manuela , Stern Mariana C. , Castelao J. Esteban , Conti David V. , Pike Malcolm C. , Bernstein Leslie , Cortessis Victoria K.
Published: March 2023

Abstract
Background: Urinary bladder cancer is two to four times more common among men than among women, a difference in risk not fully explained by established risk factors. Our objective was to determine whether hormonal and reproductive factors are involved in female bladder cancer.

Methods: We analyzed data from two population-based studies: the Los Angeles–Shanghai Bladder Cancer Study, with 349 female case–control pairs enrolled in Los Angeles and 131 female cases and 138 frequency-matched controls enrolled in Shanghai, and the California Teachers Study (CTS), a cohort of 120,857 women with 196 incident cases of bladder urothelial carcinoma diagnosed between 1995 and 2005. We also conducted a meta-analysis summarizing associations from our primary analyses together with published results.

Results: In primary data analyses, parous women experienced at least 30% reduced risk of developing bladder cancer compared with nulliparous women (Shanghai: OR = 0.38, 95% CI: 0.13–1.10; CTS: RR = 0.69, 95% CI: 0.50–0.95) consistent with results of a meta-analysis of nine studies (summary RR = 0.73, 95% CI: 0.63–0.85). The CTS, which queried formulation of menopausal hormone therapy (HT), revealed a protective effect for use of combined estrogen and progestin compared with no HT (RR = 0.60, 95% CI: 0.37–0.98). Meta-analysis of three studies provided a similar effect estimate (summary RR = 0.65, 95% CI: 0.48–0.88).

Conclusions: A consistent pattern of reduced bladder cancer risk was found among parous women and those who used estrogen and progestin for HT.

Impact: These results suggest that more research is warranted to investigate hormonal and reproductive factors as possible contributors to bladder cancer risk. Cancer Epidemiol Biomarkers Prev; 20(6); 1156–70. ©2011 AACR.
Data from TP53 Arg72Pro Polymorphism and Colorectal Cancer Risk: A Systematic Review and Meta-Analysis
Authors: Dahabreh Issa J. , Linardou Helena , Bouzika Peggy , Varvarigou Vasileia , Murray Samuel
Published: March 2023

Abstract
Background: The TP53 rs1042522 polymorphism (c.215C>G, Arg72Pro) has been extensively investigated as a potential risk factor for colorectal cancer, but the results have thus far been inconclusive.

Methods: We searched multiple electronic databases to identify studies investigating the association between the Arg72Pro polymorphism and colorectal cancer. Individual study odds ratios (OR) and their confidence intervals were estimated using allele-frequency, recessive, and dominant genetic models. Summary ORs where estimated using random effects models.

Results: We identified 23 eligible case-control studies, investigating 6,514 cases and 9,334 controls. There was significant between-study heterogeneity for all genetic models. The control group in one of the studies was not in Hardy-Weinberg equilibrium; only three studies reported that genotyping was blinded to case/control status and five studies used tumor tissue for case genotyping. Overall, we did not identify any association between rs1042522 and colorectal cancer risk under an allele-frequency comparison (OR, 0.99; 95% confidence interval, 0.89–1.09). Likewise, no association was evident under dominant or recessive models. Studies using tumor tissue for case genotyping found a protective effect for the Pro allele, compared with studies using somatic DNA (Pinteraction = 0.03). Results were also inconsistent between different genotyping methods (Pinteraction = 0.03).

Conclusion: We did not identify an association between TP53 rs1042522 and colorectal cancer. Published results seem to be driven by technical artifacts rather than true biological effects.

Impact: Future genetic association studies should use more rigorous genotyping methods and avoid the use of tumor tissue as a source of DNA to prevent genotype misclassification due to loss of heterozygosity. Cancer Epidemiol Biomarkers Prev; 19(7); 1840–7. ©2010 AACR.
Data from The Potential of Genes and Other Markers to Inform about Risk
Authors: Pepe Margaret S. , Gu Jessie W. , Morris Daryl E.
Published: March 2023

Abstract
Background: Advances in biotechnology have raised expectations that biomarkers, including genetic profiles, will yield information to accurately predict outcomes for individuals. However, results to date have been disappointing. In addition, statistical methods to quantify the predictive information in markers have not been standardized.

Methods: We discuss statistical techniques to summarize predictive information, including risk distribution curves and measures derived from them, that relate to decision making. Attributes of these measures are contrasted with alternatives such as receiver operating characteristic curves, R2, percent reclassification, and net reclassification index. Data are generated from simple models of risk conferred by genetic profiles for individuals in a population. Statistical techniques are illustrated, and the risk prediction capacities of different risk models are quantified.

Results: Risk distribution curves are most informative and relevant to clinical practice. They show proportions of subjects classified into clinically relevant risk categories. In a population in which 10% have the outcome event and subjects are categorized as high risk if their risk exceeds 20%, we identified some settings where more than half of those destined to have an event were classified as high risk by the risk model. Either 150 genes each with odds ratio of 1.5 or 250 genes each with odds ratio of 1.25 were required when the minor allele frequencies are 10%. We show that conclusions based on receiver operating characteristic curves may not be the same as conclusions based on risk distribution curves.

Conclusions: Many highly predictive genes will be required to identify substantial numbers of subjects at high risk. Cancer Epidemiol Biomarkers Prev; 19(3); 655–65
Data from Analgesic Use and Sex Steroid Hormone Concentrations in Postmenopausal Women
Authors: Gates Margaret A. , Tworoger Shelley S. , Eliassen A. Heather , Missmer Stacey A. , Hankinson Susan E.
Published: March 2023

Abstract
Prior epidemiologic studies suggest that regular use of analgesics may decrease risk of breast and ovarian cancer. We explored possible hormone-mediated mechanisms for these associations by examining the relationship between use of aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen and sex steroid hormone concentrations among 740 postmenopausal women in the Nurses' Health Study. All women reported their analgesic use in 1988 or 1990 and provided a blood sample in 1989 to 1990. We calculated adjusted geometric mean estrogen and androgen levels for each category of analgesic use and calculated the P value for trend with increasing frequency of use. There was no association between days of use per month of aspirin, nonaspirin NSAIDs, or acetaminophen in 1990 and hormone levels (all Ptrend ≥ 0.09). However, we observed significant inverse trends between the estimated number of aspirin tablets per month in 1988 and concentrations of estrone (Ptrend = 0.04) and estrone sulfate (Ptrend = 0.03). In analyses of total (aspirin and nonaspirin) NSAID use in 1990, women who used NSAIDs at least 15 days per month had significantly lower levels of estradiol compared with women with no NSAID use (Ptrend = 0.03). Frequency of use of all analgesics (aspirin, nonaspirin NSAIDs, and acetaminophen) in 1990 was inversely associated with concentrations of estradiol (Ptrend = 0.001), free estradiol (Ptrend = 0.01), estrone sulfate (Ptrend = 0.03), and the ratio of estradiol to testosterone (Ptrend = 0.04). Among postmenopausal women, regular users of aspirin and other analgesics may have lower estrogen levels than nonusers, which could contribute to a decreased risk of breast or ovarian cancer among analgesic users. Cancer Epidemiol Biomarkers Prev; 19(4); 1033–41. ©2010 AACR.
Data from Serum Pepsinogens and Helicobacter pylori in Relation to the Risk of Esophageal Squamous Cell Carcinoma in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
Authors: Cook Michael B. , Dawsey Sanford M. , Diaw Lena , Blaser Martin J. , Perez-Perez Guillermo I. , Abnet Christian C. , Taylor Philip R. , Albanes Demetrius , Virtamo Jarmo , Kamangar Farin
Published: March 2023

Abstract
Background: Helicobacter pylori can induce gastric atrophy in humans, which in turn increases gastric cancer risk. Whether H. pylori and gastric atrophy also affect the risk of esophageal squamous cell carcinoma (ESCC), however, remains unresolved.

Methods: We performed a nested case-control study within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to assess these relationships. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study is composed of 29,133 Finnish male smokers, ages 50 to 69 years, who were recruited during 1985-1988. Using baseline sera, we assessed H. pylori status (via immunoglobulin G antibodies against whole-cell and CagA antigens) and gastric atrophy status [via the biomarkers pepsinogen I (PGI) and pepsinogen II (PGII)] in 79 ESCC cases and 94 controls. Logistic regression with adjustment for age, date of blood draw, education, cigarette smoking, alcohol, body mass index, and fruit and vegetable intake was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI).

Results: Gastric atrophy (PGI/PGII <4) was associated with ESCC (OR, 4.58; 95% CI, 2.00-10.48). There was no evidence for an association between H. pylori and ESCC (OR, 0.94; 95% CI, 0.40-2.24).

Conclusions: These results could be explained by misclassification of H. pylori status due to serologic amnesia, ESCC risk being dependent on the functional consequences or interactions of H. pylori rather than the infection per se, gastric atrophy having a different histogenesis in ESCC without being primarily dependent on H. pylori acquisition, or a lack of statistical power to detect an effect.

Impact: Validation of these results may warrant mechanistic studies to determine the route of association between gastric atrophy and ESCC. Cancer Epidemiol Biomarkers Prev; 19(8); 1966–75. ©2010 AACR.
Data from Global Patterns of Cancer Incidence and Mortality Rates and Trends
Authors: Jemal Ahmedin , Center Melissa M. , DeSantis Carol , Ward Elizabeth M.
Published: March 2023

Abstract
While incidence and mortality rates for most cancers (including lung, colorectum, female breast, and prostate) are decreasing in the United States and many other western countries, they are increasing in several less developed and economically transitioning countries because of adoption of unhealthy western lifestyles such as smoking and physical inactivity and consumption of calorie-dense food. Indeed, the rates for lung and colon cancers in a few of these countries have already surpassed those in the United States and other western countries. Most developing countries also continue to be disproportionately affected by cancers related to infectious agents, such as cervix, liver, and stomach cancers. The proportion of new cancer cases diagnosed in less developed countries is projected to increase from about 56% of the world total in 2008 to more than 60% in 2030 because of the increasing trends in cancer rates and expected increases in life expectancy and growth of the population. In this review, we describe these changing global incidence and mortality patterns for select common cancers and the opportunities for cancer prevention in developing countries. Cancer Epidemiol Biomarkers Prev; 19(8); 1893–907. ©2010 AACR.
Data from Sex Steroid Hormone Metabolism in Relation to Risk of Aggressive Prostate Cancer
Authors: Black Amanda , Pinsky Paul F. , Grubb Robert L. , Falk Roni T. , Hsing Ann W. , Chu Lisa , Meyer Tamra , Veenstra Timothy D. , Xu Xia , Yu Kai , Ziegler Regina G. , Brinton Louise A. , Hoover Robert N. , Cook Michael B.
Published: March 2023

Abstract
Background: The combined action of androgens and estrogens—specifically their balance—may play a role in prostate carcinogenesis, but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer.

Methods: In a case–control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort, we measured serum estrone, estradiol, and 13 estrogen metabolites, in the 2-, 4-, or 16-hydroxylation pathways, using an LC/MS-MS assay. Cases (n = 195) were non-Hispanic white men ages 55 to 70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7). Controls (n = 195) were non-Hispanic white men without prostate cancer who were frequency matched to cases by age and year at blood draw, and time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate ORs and 95% confidence intervals (95% CI).

Results: Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone ratio (OR4th quartile vs. 1st = 0.27; 95% CI, 0.12–0.59, Ptrend = 0.003) and positively associated with 2:16α-hydroxyestrone ratio (OR4th quartile vs. 1st = 2.44; 95% CI, 1.34–4.45, Ptrend = 0.001). Individual estrogen metabolites were unrelated to risk.

Conclusions: Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer.

Impact: Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions. Cancer Epidemiol Biomarkers Prev; 23(11); 2374–82. ©2014 AACR.
Data from Sun Exposure and Melanoma Survival: A GEM Study
Authors: Berwick Marianne , Reiner Anne S. , Paine Susan , Armstrong Bruce K. , Kricker Anne , Goumas Chris , Cust Anne E. , Thomas Nancy E. , Groben Pamela A. , From Lynn , Busam Klaus , Orlow Irene , Marrett Loraine D. , Gallagher Richard P. , Gruber Stephen B. , Anton-Culver Hoda , Rosso Stefano , Zanetti Roberto , Kanetsky Peter A. , Dwyer Terry , Venn Alison , Lee-Taylor Julia , Begg Colin B.
Published: March 2023

Abstract
Background: We previously reported a significant association between higher UV radiation exposure before diagnosis and greater survival with melanoma in a population-based study in Connecticut. We sought to evaluate the hypothesis that sun exposure before diagnosis was associated with greater survival in a larger, international population-based study with more detailed exposure information.

Methods: We conducted a multicenter, international population-based study in four countries—Australia, Italy, Canada, and the United States—with 3,578 cases of melanoma with an average of 7.4 years of follow-up. Measures of sun exposure included sunburn, intermittent exposure, hours of holiday sun exposure, hours of water-related outdoor activities, ambient ultraviolet B (280–320 nm) dose, histologic solar elastosis, and season of diagnosis.

Results: Results were not strongly supportive of the earlier hypothesis. Having had any sunburn in 1 year within 10 years of diagnosis was inversely associated with survival; solar elastosis—a measure of lifetime cumulative exposure—was not. In addition, none of the intermittent exposure measures—water-related activities and sunny holidays—were associated with melanoma-specific survival. Estimated ambient UVB dose was not associated with survival.

Conclusion: Although there was an apparent protective effect of sunburns within 10 years of diagnosis, there was only weak evidence in this large, international, population-based study of melanoma that sun exposure before diagnosis is associated with greater melanoma-specific survival.

Impact: This study adds to the evidence that sun exposure before melanoma diagnosis has little effect on survival with melanoma. Cancer Epidemiol Biomarkers Prev; 23(10); 2145–52. ©2014 AACR.
Data from ST14 Gene Variant and Decreased Matriptase Protein Expression Predict Poor Breast Cancer Survival
Authors: Kauppinen Jaana M. , Kosma Veli-Matti , Soini Ylermi , Sironen Reijo , Nissinen Minna , Nykopp Timo K. , Kärjä Vesa , Eskelinen Matti , Kataja Vesa , Mannermaa Arto
Published: March 2023

Abstract
Background: Matriptase plays a role in carcinogenesis, but the role of its genetic variation or that of the hepatocyte growth factor activator inhibitor-1 (HAI-1) has not been evaluated. This study aimed to examine the genetic variation of matriptase (ST14 gene) and HAI-1 (SPINT1 gene) in breast cancer risk and prognosis, to assess matriptase and HAI-1 gene and protein expression in breast tumors, and to identify their clinicopathologic correlations and prognostic significance.

Methods: Five single nucleotide polymorphisms in ST14 and three in SPINT1 were genotyped in 470 invasive breast cancer cases and 446 healthy controls. Gene expression analysis was done for 40 breast cancer samples. Protein expression was assessed by immunohistochemical analyses in 377 invasive breast tumors. The statistical significance of the associations among genotypes, clinicopathologic variables, and prognosis was assessed.

Results: The ST14 single nucleotide polymorphism rs704624 independently predicted breast cancer survival, a poor outcome associated with the minor allele (P = 0.001; risk ratio, 2.221; 95% confidence interval, 1.382-3.568). Moreover, ST14 gene expression levels were lower among the minor allele carriers (P = 0.009), and negative/low matriptase protein expression was independently predictive of poorer survival (P = 0.046; risk ratio, 1.554; 95% confidence interval, 1.008-2.396).

Conclusions: The ST14 variant rs704624 and protein expression of matriptase have prognostic significance in breast cancer. This study adds to the evidence for the role of matriptase in breast cancer and has found new evidence for the genotypes having an impact in breast cancer.

Impact: This is the first study showing that genetic variation in matriptase has clinical importance. The results encourage further study on the genetic variation affecting protein levels and function in type II transmembrane serine proteases. Cancer Epidemiol Biomarkers Prev; 19(9); 2133–42. ©2010 AACR.
Data from Enrichment of Low Penetrance Susceptibility Loci in a Dutch Familial Colorectal Cancer Cohort
Authors: Middeldorp Anneke , Jagmohan-Changur Shantie , van Eijk Ronald , Tops Carli , Devilee Peter , Vasen Hans F. A. , Hes Frederik J. , Houlston Richard , Tomlinson Ian , Houwing-Duistermaat Jeanine J. , Wijnen Juul T. , Morreau Hans , van Wezel Tom
Published: March 2023

Abstract
Recent genome-wide association studies have identified several loci that confer an increased risk of colorectal cancer (CRC). We studied the role of the 8q24.21 (rs6983267), 18q21.1 (rs12953717), 15q13.3 (rs4779584), 11q23.1 (rs3802842), 8q23.3 (rs16892766), and 10p14 (rs10795668) risk variants in a series of 995 Dutch CRC cases and 1340 controls. The CRC cases were selected on basis of having a family history of CRC and/or early-onset disease. The detailed clinical and molecular data available on the cases allowed us to examine the relationship between risk variants and clinicopathologic characteristics. We replicated the association with an increased risk of CRC cancer for all loci, except 10p14. The association with the variant on chromosome 15q13.3 was confirmed for the first time. The risks associated with variants in our series were higher (not significant) than those previously reported, consistent with our series reflecting genetic enrichment. Moreover, we show that familial CRC cases possess an increased number of risk alleles compared with solitary CRC cases (early-onset; mean age at diagnosis of 48.5 years). We also identified a significant increase in the number of risk alleles in families with early-onset disease (≤50 years) compared with late-onset families (>50 years). In solitary CRC patients, enrichment for risk alleles was not observed, suggesting that other causes of increased CRC risk play a role in these cases. Overall, our results suggest that clustering of low-risk variants may explain part of the excess risk in CRC families. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3062–7)
Data from A Common Prostate Cancer Risk Variant 5′ of Microseminoprotein-β (MSMB) Is a Strong Predictor of Circulating β-Microseminoprotein (MSP) Levels in Multiple Populations
Authors: Waters Kevin M. , Stram Daniel O. , Le Marchand Loic , Klein Robert J. , Valtonen-André Camilla , Peltola Mari T. , Kolonel Laurence N. , Henderson Brian E. , Lilja Hans , Haiman Christopher A.
Published: March 2023

Abstract
Background: β-Microseminoprotein (MSP) is one of the three most abundantly secreted proteins of the prostate and has been suggested as a biomarker for prostate cancer risk. A common variant, rs10993994, in the 5′ region of the gene that encodes MSP (MSMB) has recently been identified as a risk factor for prostate cancer.

Methods: We examined the association between rs10993994 genotype and MSP levels in a sample of 500 prostate cancer–free men from four racial/ethnic populations in the Multiethnic Cohort (European Americans, African Americans, Latinos, and Japanese Americans). Generalized linear models were used to estimate the association between rs10993994 genotype and MSP levels.

Results: We observed robust associations between rs10994994 genotype and MSP levels in each racial/ethnic population (all P < 10−8), with carriers of the C allele having lower geometric mean MSP levels (ng/mL; CC/CT/TT genotypes: European Americans, 28.8/20.9/10.0; African Americans, 29.0/21.9/10.9; Latinos, 29.2/17.1/8.3; and Japanese Americans, 25.8/16.4/6.7). We estimated the variant accounts for 30% to 50% of the variation in MSP levels in each population. We also observed significant differences in MSP levels between populations (P = 3.5 × 10−6), with MSP levels observed to be highest in African Americans and lowest in Japanese Americans.

Conclusions: Rs10993994 genotype is strongly associated with plasma MSP levels in multiple racial/ethnic populations.

Impact: This supports the hypothesis that rs10993994 may be the biologically functional allele. Cancer Epidemiol Biomarkers Prev; 19(10); 2639–46. ©2010 AACR.
Data from Increased Plasma Soluble uPAR Level Is a Risk Marker of Respiratory Cancer in Initially Cancer-Free Individuals
Authors: Langkilde Anne , Hansen Tine W. , Ladelund Steen , Linneberg Allan , Andersen Ove , Haugaard Steen B. , Jeppesen Jørgen , Eugen-Olsen Jesper
Published: March 2023

Abstract
Background: Soluble urokinase plasminogen activator receptor (suPAR) is a stable plasma biomarker associated with inflammation and disease. This study tested the association between suPAR levels and incident respiratory, gastrointestinal, or other types of cancer in initially cancer-free individuals from a general population-based prospective study.

Methods: Baseline plasma samples, baseline characteristics, and follow-up data were available from 2,656 individuals from the population-based Danish MONICA10 (MONItoring trends and determinants of CArdiovascular disease) study, followed for a median of 12.6 years. Cancer was diagnosed according to international classification of diseases (ICD) 8 and ICD-10 codes and suPAR levels were measured using a commercially available ELISA. The association of suPAR levels with incident cancer during follow-up was analyzed using Cox regression, adjusted for established risk factors and the inflammatory markers C-reactive protein (CRP) and leukocyte numbers.

Results: suPAR levels ranged from 0.6 to 22 ng/mL and median suPAR level was 4.01 ng/mL. An increase of 1 ng/mL in baseline suPAR was associated with adjusted HR of 1.61 (95% CI: 1.23–2.11, P < 0.001), 0.92 (95% CI: 0.69–1.24, P = 0.59), and 1.33 (95% CI: 1.13–1.58, P < 0.001) of being diagnosed with respiratory, gastrointestinal, and other cancer types, respectively.

Conclusion: Elevated suPAR levels were associated with increased risk of incident respiratory cancer and other types of cancer, but not gastrointestinal cancers, independently of established risk factors, CRP, and leukocyte numbers.

Impact: These findings suggest that inflammation is involved in cancer development. Risk algorithms based on established risk factors and risk-associated biomarkers should be developed and evaluated in large, general population-based studies. We suggest suPAR as a candidate for evaluation in cancer risk algorithms. Cancer Epidemiol Biomarkers Prev; 20(4); 609–18. ©2011 AACR.
Data from Risk of Sex-Specific Cancers in Opposite-Sex and Same-Sex Twins in Denmark and Sweden
Authors: Ahrenfeldt Linda J. , Skytthe Axel , Möller Sören , Czene Kamila , Adami Hans-Olov , Mucci Lorelei A. , Kaprio Jaakko , Petersen Inge , Christensen Kaare , Lindahl-Jacobsen Rune
Published: March 2023

Abstract
Background: Increasing evidence shows that some cancers originate in utero. It is hypothesized that elevated exposure to some steroid hormones might increase cancer risk and that hormone transfer between twin fetuses could result in different prenatal exposure to testosterone.

Methods: This large-scale prospective twin study compared opposite-sex (OS) and same-sex (SS) twins to test the impact of intrauterine exposures on cancer risk. On the basis of the Danish and Swedish twin and cancer registries, we calculated incidence rate ratios for OS and SS twins, whereas standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated for OS/SS twins compared with the general population.

Results: A total of 18,001 cancers were identified during 1943–2009. No significant differences were observed between OS and SS twins, neither for the sex-specific cancers nor for cancer at all sites. All-cause cancer was slightly reduced for OS and SS twins compared with the general population, significant for OS males (SIR, 0.95; 95% CI, 0.92–0.98) and for SS males and females (SIR, 0.97; 95% CI, 0.94–0.99).

Conclusions: Our data suggest that having a male co-twin—which may entail higher exposure to prenatal testosterone—does not increase the risk of sex-specific cancers in OS females. Furthermore, the study supports that twinning per se is not a risk factor of cancer.

Impact: Findings are reassuring, as they fail to provide evidence for the hypothesis that endocrine or other difference in the in utero milieu affects the risk of sex-specific cancers. Cancer Epidemiol Biomarkers Prev; 24(10); 1622–8. ©2015 AACR.
Data from Explaining the Obesity Paradox: The Association between Body Composition and Colorectal Cancer Survival (C-SCANS Study)
Authors: Caan Bette J. , Meyerhardt Jeffrey A. , Kroenke Candyce H. , Alexeeff Stacey , Xiao Jingjie , Weltzien Erin , Feliciano Elizabeth Cespedes , Castillo Adrienne L. , Quesenberry Charles P. , Kwan Marilyn L. , Prado Carla M.
Published: March 2023

Abstract
Background: Body composition may partially explain the U-shaped association between body mass index (BMI) and colorectal cancer survival.

Methods: Muscle and adiposity at colorectal cancer diagnosis and survival were examined in a retrospective cohort using Kaplan–Meier curves, multivariable Cox regression, and restricted cubic splines in 3,262 early-stage (I–III) male (50%) and female (50%) patients. Sarcopenia was defined using optimal stratification and sex- and BMI-specific cut points. High adiposity was defined as the highest tertile of sex-specific total adipose tissue (TAT). Primary outcomes were overall mortality and colorectal cancer–specific mortality (CRCsM).

Results: Slightly over 42% patients were sarcopenic. During 5.8 years of follow-up, 788 deaths occurred, including 433 from colorectal cancer. Sarcopenic patients had a 27% [HR, 1.27; 95% confidence interval (CI), 1.09–1.48] higher risk of overall mortality than those who were not sarcopenic. Females with both low muscle and high adiposity had a 64% higher risk of overall mortality (HR, 1.64; 95% CI, 1.05–2.57) than females with adequate muscle and lower adiposity. The lowest risk of overall mortality was seen in patients with a BMI between 25 and <30 kg/m2, a range associated with the greatest number of patients (58.6%) who were not at increased risk of overall mortality due to either low muscle or high adiposity.

Conclusions: Sarcopenia is prevalent among patients with non-metastatic colorectal cancer, and should, along with adiposity be a standard oncological marker.

Impact: Our findings suggest a biologic explanation for the obesity paradox in colorectal cancer and refute the notion that the association between overweight and lower mortality is due solely to methodologic biases. Cancer Epidemiol Biomarkers Prev; 26(7); 1008–15. ©2017 AACR.
Data from Pathway Analyses Identify TGFBR2 as Potential Breast Cancer Susceptibility Gene: Results from a Consortium Study among Asians
Authors: Ma Xiangyu , Beeghly-Fadiel Alicia , Lu Wei , Shi Jiajun , Xiang Yong-Bing , Cai Qiuyin , Shen Hongbing , Shen Chen-Yang , Ren Zefang , Matsuo Keitaro , Khoo Ui Soon , Iwasaki Motoki , Long Jirong , Zhang Ben , Ji Bu-Tian , Zheng Ying , Wang Wenjing , Hu Zhibin , Liu Yao , Wu Pei-Ei , Shieh Ya-Lan , Wang Shenming , Xie Xiaoming , Ito Hidemi , Kasuga Yoshio , Chan Kelvin Y.K. , Iwata Hiroji , Tsugane Shoichiro , Gao Yu-Tang , Shu Xiao Ou , Moses Harold L. , Zheng Wei
Published: March 2023

Abstract
Background: The TGF-β signaling pathway plays a significant role in the carcinogenic process of breast cancer.

Methods: We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multistage, case–control study among Asian women.

Results: In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies ≥ 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was carried out among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (stage III). Pooled analysis of all data indicated that minor allele homozygotes (GG) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared with major allele carriers (AG or AA; OR, 0.76; 95% CI, 0.65–0.89; P = 8.42 × 10−4).

Conclusion: These findings support a role for common genetic variation in TGF-β signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility.

Impact: These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets. Cancer Epidemiol Biomarkers Prev; 21(7); 1176–84. ©2012 AACR.
Data from Determinants of Breast Cancer Treatment Delay Differ for African American and White Women
Authors: McGee Sasha A. , Durham Danielle D. , Tse Chiu-Kit , Millikan Robert C.
Published: March 2023

Abstract
Background: Timeliness of care may contribute to racial disparities in breast cancer mortality. African American women experience greater treatment delay than White women in most, but not all studies. Understanding these disparities is challenging as many studies lack patient-reported data and use administrative data sources that collect limited types of information. We used interview and medical record data from the Carolina Breast Cancer Study (CBCS) to identify determinants of delay and assess whether disparities exist between White and African American women (n = 601).

Methods: The CBCS is a population-based study of North Carolina women. We investigated the association of demographic and socioeconomic characteristics, healthcare access, clinical factors, and measures of emotional and functional well-being with treatment delay. The association of race and selected characteristics with delays of more than 30 days was assessed using logistic regression.

Results: Household size, losing a job due to one's diagnosis, and immediate reconstruction were associated with delay in the overall population and among White women. Immediate reconstruction and treatment type were associated with delay among African American women. Racial disparities in treatment delay were not evident in the overall population. In the adjusted models, African American women experienced greater delay than White women for younger age groups: OR, 3.34; 95% confidence interval (CI), 1.07–10.38 for ages 20 to 39 years, and OR, 3.40; 95% CI, 1.76–6.54 for ages 40 to 49 years.

Conclusions: Determinants of treatment delay vary by race. Racial disparities in treatment delay exist among women younger than 50 years.

Impact: Specific populations need to be targeted when identifying and addressing determinants of treatment delay. Cancer Epidemiol Biomarkers Prev; 22(7); 1227–38. ©2013 AACR.
Data from Circulating Estrogens and Postmenopausal Ovarian Cancer Risk in the Women's Health Initiative Observational Study
Authors: Trabert Britton , Brinton Louise A. , Anderson Garnet L. , Pfeiffer Ruth M. , Falk Roni T. , Strickler Howard D. , Sliesoraitis Sarunas , Kuller Lewis H. , Gass Margery L. , Fuhrman Barbara J. , Xu Xia , Wentzensen Nicolas
Published: March 2023

Abstract
Background: Hormonal and reproductive factors contribute to the development of ovarian cancer, but few studies have examined associations between circulating estrogens and estrogen metabolites and ovarian cancer risk. We evaluated whether serum estrogens and estrogen metabolite levels are associated with ovarian cancer risk among postmenopausal women in a nested case–control study in the Women's Health Initiative (WHI) Observational Study (OS).

Methods: We selected all 169 eligible epithelial ovarian cancer cases and 412 matched controls from women enrolled in WHI-OS who were not using menopausal hormones at baseline. Baseline levels of 15 estrogens and estrogen metabolites were measured via liquid chromatography/tandem mass spectrometry. Associations with ovarian cancer risk overall and stratified by histologic subtype (serous/nonserous) were analyzed using logistic regression. The mean time from serum collection to cancer diagnosis was 6.9 years.

Results: Overall, we observed modest ovarian cancer risk associations among women with higher levels of estrone [OR (95% confidence interval) quintile (Q)5 vs. Q1: 1.54 (0.82–2.90), Ptrend = 0.05], as well as 2- and 4-methoxyestrone metabolites [2.03 (1.06–3.88), Ptrend = 0.02; 1.86 (0.98–3.56), Ptrend = 0.01, respectively]. Associations of estrogens and estrogen metabolites varied substantially by histologic subtype. Associations with serous tumors were universally null, while estrone [2.65 (1.09–6.45), Ptrend = 0.01, Pheterogeneity = 0.04], unconjugated estradiol [2.72 (1.04–7.14), Ptrend = 0.03, Pheterogeneity = 0.02] and many of the 2-, 4-, and 16-pathway metabolites were positively associated with nonserous tumors.

Conclusions: Our study provides novel molecular data showing an association of the parent estrogens and several estrogen metabolites with nonserous ovarian cancers.

Impact: These findings further support the heterogeneous etiology of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 648–56. ©2016 AACR.
Data from Bioavailable Insulin-like Growth Factor-I Inversely Related to Weight Gain in Postmenopausal Women Regardless of Exogenous Estrogen
Authors: Jung Su Yon , Hursting Stephen D. , Guindani Michele , Vitolins Mara Z. , Paskett Electra , Chang Shine
Published: March 2023

Abstract
Background: Weight gain, insulin-like growth factor-I (IGF-I) levels, and excess exogenous steroid hormone use are putative cancer risk factors, yet their interconnected pathways have not been fully characterized. This cross-sectional study investigated the relationship between plasma IGF-I levels and weight gain according to body mass index (BMI), leptin levels, and exogenous estrogen use among postmenopausal women.

Methods: This study included 794 postmenopausal women who enrolled in an ancillary study of the Women's Health Initiative Observational Study between February 1995 and July 1998. The relationship between IGF-I levels and weight gain was analyzed using ordinal logistic regression. We used the molar ratio of IGF-I to IGF binding protein-3 (IGF-I/IGFBP-3) or circulating IGF-I levels adjusting for IGFBP-3 as a proxy of bioavailable IGF-I. The plasma concentrations were expressed as quartiles.

Results: Among the obese group, women in the third quartile (Q3) of IGF-I and highest quartile of IGF-I/IGFBP-3 were less likely to gain weight (>3% from baseline) than were women in the first quartiles (Q1). Among the normal-weight group, women in Q2 and Q3 of IGF-I/IGFBP-3 were 70% less likely than those in Q1 to gain weight. Among current estrogen users, Q3 of IGF-I/IGFBP-3 had 0.5 times the odds of gaining weight than Q1.

Conclusions: Bioavailable IGF-I levels were inversely related to weight gain overall.

Impact: Although weight gain was not consistent with increases in IGF-I levels among postmenopausal women in this report, avoidance of weight gain as a strategy to reduce cancer risk may be recommended. Cancer Epidemiol Biomarkers Prev; 23(3); 534–44. ©2013 AACR.
Data from A BRCA1/2 Mutational Signature and Survival in Ovarian High-Grade Serous Carcinoma
Authors: Dong Fei , Davineni Phani K. , Howitt Brooke E. , Beck Andrew H.
Published: March 2023

Abstract
Background: Mutational signatures have been identified by the broad sequencing of cancer genomes and reflect underlying processes of mutagenesis. The clinical application of mutational signatures is not well defined. Here we aim to assess the prognostic utility of mutational signatures in ovarian high-grade serous carcinoma.

Methods: Open access data of 15,439 somatic mutations of 310 ovarian high-grade serous carcinomas from The Cancer Genome Atlas (TCGA) are used to construct a Bayesian model to classify each cancer as either having or lacking a BRCA1/2 mutational signature. We evaluate the association of the BRCA1/2 signature with overall survival on the TCGA dataset and on an independent cohort of 92 ovarian high-grade serous carcinomas from the Australian Ovarian Cancer Study (AOCS).

Results: Patients from TCGA with tumors harboring the BRCA1/2 mutational signature have improved survival (55.2 months vs. 38.0 months), which is independent of BRCA1/2 gene mutation status, age, stage, and grade (HR = 0.64; P = 0.02). In the AOCS dataset, the BRCA1/2 mutational signature is also associated with improved overall survival (46.3 months vs. 23.6 months) independent of age and stage (HR = 0.52; P = 0.007).

Conclusions: A BRCA1/2 mutational signature is a prognostic marker in ovarian high-grade serous carcinoma. Mutational signature analysis of ovarian cancer genomes may be useful in addition to testing for BRCA1/2 mutations.

Impact: This study identifies the use of mutational signatures as a biomarker for survival outcome in ovarian high-grade serous carcinoma. Cancer Epidemiol Biomarkers Prev; 25(11); 1511–6. ©2016 AACR.