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Cumulative Burden of Colorectal Cancer-Associated Genetic Variants is More Strongly Associated With Early-onset vs Late-onset Cancer

Archambault, Alexi N; Su, Yu-Ru; Jeon, Jihyoun; Thomas, Minta; Lin, Yi; Conti, David V; Win, Aung Ko; Sakoda, Lori C; Lansdorp-Vogelaar, Iris; Peterse, Elisabeth Fp; Zauber, Ann G; Duggan, David; Holowatyj, Andreana N; Huyghe, Jeroen R; Brenner, Hermann; Cotterchio, Michelle; Bézieau, Stéphane; Schmit, Stephanie L; Edlund, Christopher K; Southey, Melissa C; MacInnis, Robert J; Campbell, Peter T; Chang-Claude, Jenny; Slattery, Martha L; Chan, Andrew T; Joshi, Amit D; Song, Mingyang; Cao, Yin; Woods, Michael O; White, Emily; Weinstein, Stephanie J; Ulrich, Cornelia M; Hoffmeister, Michael; Bien, Stephanie A; Harrison, Tabitha A; Hampe, Jochen; Li, Christopher I; Schafmayer, Clemens; Offit, Kenneth; Pharoah, Paul D; Moreno, Victor; Lindblom, Annika; Wolk, Alicja; Wu, Anna H; Li, Li; Gunter, Marc J; Gsur, Andrea; Keku, Temitope O; Pearlman, Rachel; Bishop, D Timothy; Castellví-Bel, Sergi; Moreira, Leticia; Vodicka, Pavel; Kampman, Ellen; Giles, Graham G; Albanes, Demetrius; Baron, John A; Berndt, Sonja I; Brezina, Stefanie; Buch, Stephan; Buchanan, Daniel D; Trichopoulou, Antonia; Severi, Gianluca; Chirlaque, María-Dolores; Sánchez, Maria-José; Palli, Domenico; Kühn, Tilman; Murphy, Neil; Cross, Amanda J; Burnett-Hartman, Andrea N; Chanock, Stephen J; Chapelle, Albert de la; Easton, Douglas F; Elliott, Faye; English, Dallas R; Feskens, Edith Jm; FitzGerald, Liesel M; Goodman, Phyllis J; Hopper, John L; Hudson, Thomas J; Hunter, David J; Jacobs, Eric J; Joshu, Corinne E; Küry, Sébastien; Markowitz, Sanford D; Milne, Roger L; Platz, Elizabeth A; Rennert, Gad; Rennert, Hedy S; Schumacher, Fredrick R; Sandler, Robert S; Seminara, Daniela; Tangen, Catherine M; Thibodeau, Stephen N; Toland, Amanda E; van Duijnhoven, Franzel Jb; Visvanathan, Kala; Vodickova, Ludmila; Potter, John D; Männistö, Satu; Weigl, Korbinian; Figueiredo, Jane; Martín, Vicente; Larsson, Susanna C; Parfrey, Patrick S; Huang, Wen-Yi; Lenz, Heinz-Josef; Castelao, Jose E; Gago-Dominguez, Manuela; Muñoz-Garzón, Victor; Mancao, Christoph; Haiman, Christopher A; Wilkens, Lynne R; Siegel, Erin; Barry, Elizabeth; Younghusband, Ban; Van Guelpen, Bethany; Harlid, Sophia; Zeleniuch-Jacquotte, Anne; Liang, Peter S; Du, Mengmeng; Casey, Graham; Lindor, Noralane M; Le Marchand, Loic; Gallinger, Steven J; Jenkins, Mark A; Newcomb, Polly A; Gruber, Stephen B; Schoen, Robert E; Hampel, Heather; Corley, Douglas A; Hsu, Li; Peters, Ulrike; Hayes, Richard B
BACKGROUND & AIMS/OBJECTIVE:Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS:We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single-nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS:). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI, 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI, 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS:In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer-particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventative measures.
PMID: 31866242
ISSN: 1528-0012
CID: 4243992

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects

Guo, Xingyi; Lin, Weiqiang; Wen, Wanqing; Huyghe, Jeroen; Bien, Stephanie; Cai, Qiuyin; Harrison, Tabitha; Chen, Zhishan; Qu, Conghui; Bao, Jiandong; Long, Jirong; Yuan, Yuan; Wang, Fangqin; Bai, Mengqiu; Abecasis, Goncalo R; Albanes, Demetrius; Berndt, Sonja I; Bézieau, Stéphane; Bishop, D Timothy; Brenner, Hermann; Buch, Stephan; Burnett-Hartman, Andrea; Campbell, Peter T; Castellví-Bel, Sergi; Chan, Andrew T; Chang-Claude, Jenny; Chanock, Stephen J; Cho, Sang Hee; Conti, David V; Chapelle, Albert de la; Feskens, Edith J M; Gallinger, Steven J; Giles, Graham G; Goodman, Phyllis J; Gsur, Andrea; Guinter, Mark; Gunter, Marc J; Hampe, Jochen; Hampel, Heather; Hayes, Richard B; Hoffmeister, Michael; Kampman, Ellen; Kang, Hyun Min; Keku, Temitope O; Kim, Hyeong Rok; Le Marchand, Loic; Lee, Soo Chin; Li, Christopher I; Li, Li; Lindblom, Annika; Lindor, Noralane; Milne, Roger L; Moreno, Victor; Murphy, Neil; Newcomb, Polly A; Nickerson, Deborah A; Offit, Kenneth; Pearlman, Rachel; Pharoah, Paul D P; Platz, Elizabeth A; Potter, John D; Rennert, Gad; Sakoda, Lori C; Schafmayer, Clemens; Schmit, Stephanie L; Schoen, Robert E; Schumacher, Fredrick R; Slattery, Martha L; Su, Yu-Ru; Tangen, Catherine M; Ulrich, Cornelia M; van Duijnhoven, Franzel J B; Van Guelpen, Bethany; Visvanathan, Kala; Vodicka, Pavel; Vodickova, Ludmila; Vymetalkova, Veronika; Wang, Xiaoliang; White, Emily; Wolk, Alicja; Woods, Michael O; Casey, Graham; Hsu, Li; Jenkins, Mark A; Gruber, Stephen B; Peters, Ulrike; Zheng, Wei
BACKGROUND AND AIMS/OBJECTIVE:Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS:Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS:, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS:Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
PMID: 33058866
ISSN: 1528-0012
CID: 4792862

PM2.5 air pollution and cause-specific cardiovascular disease mortality

Hayes, Richard B; Lim, Chris; Zhang, Yilong; Cromar, Kevin; Shao, Yongzhao; Reynolds, Harmony R; Silverman, Debra T; Jones, Rena R; Park, Yikyung; Jerrett, Michael; Ahn, Jiyoung; Thurston, George D
BACKGROUND:Ambient air pollution is a modifiable risk factor for cardiovascular disease, yet uncertainty remains about the size of risks at lower levels of fine particulate matter (PM2.5) exposure which now occur in the USA and elsewhere. METHODS:We investigated the relationship of ambient PM2.5 exposure with cause-specific cardiovascular disease mortality in 565 477 men and women, aged 50 to 71 years, from the National Institutes of Health-AARP Diet and Health Study. During 7.5 x 106 person-years of follow up, 41 286 cardiovascular disease deaths, including 23 328 ischaemic heart disease (IHD) and 5894 stroke deaths, were ascertained using the National Death Index. PM2.5 was estimated using a hybrid land use regression (LUR) geostatistical model. Multivariate Cox regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CI). RESULTS:Each increase of 10  μg/m3 PM2.5 (overall range, 2.9-28.0  μg/m3) was associated, in fully adjusted models, with a 16% increase in mortality from ischaemic heart disease [hazard ratio (HR) 1.16; 95% CI 1.09-1.22] and a 14% increase in mortality from stroke (HR 1.14; CI 1.02-1.27). Compared with PM2.5 exposure <8  μg/m3 (referent), risks for CVD were increased in relation to PM2.5 exposures in the range of 8-12  μg/m3 (CVD: HR 1.04; 95% CI 1.00-1.08), in the range 12-20  μg/m3 (CVD: HR 1.08; 95% CI 1.03-1.13) and in the range 20+ μg/m3 (CVD: HR 1.19; 95% CI 1.10-1.28). Results were robust to alternative approaches to PM2.5 exposure assessment and statistical analysis. CONCLUSIONS:Long-term exposure to fine particulate air pollution is associated with ischaemic heart disease and stroke mortality, with excess risks occurring in the range of and below the present US long-term standard for ambient exposure to PM2.5 (12  µg/m3), indicating the need for continued improvements in air pollution abatement for CVD prevention.
PMID: 31289812
ISSN: 1464-3685
CID: 3976552

Sociobiome - Individual and neighborhood socioeconomic status influence the gut microbiome in a multi-ethnic population in the US

Kwak, Soyoung; Usyk, Mykhaylo; Beggs, Dia; Choi, Heesun; Ahdoot, Dariush; Wu, Feng; Maceda, Lorraine; Li, Huilin; Im, Eun-Ok; Han, Hae-Ra; Lee, Eunjung; Wu, Anna H; Hayes, Richard B; Ahn, Jiyoung
Lower socioeconomic status (SES) is related to increased incidence and mortality due to chronic diseases in adults. Association between SES variables and gut microbiome variation has been observed in adults at the population level, suggesting that biological mechanisms may underlie the SES associations; however, there is a need for larger studies that consider individual- and neighborhood-level measures of SES in racially diverse populations. In 825 participants from a multi-ethnic cohort, we investigated how SES shapes the gut microbiome. We determined the relationship of a range of individual- and neighborhood-level SES indicators with the gut microbiome. Individual education level and occupation were self-reported by questionnaire. Geocoding was applied to link participants' addresses with neighborhood census tract socioeconomic indicators, including average income and social deprivation in the census tract. Gut microbiome was measured using 16SV4 region rRNA gene sequencing of stool samples. We compared α-diversity, β-diversity, and taxonomic and functional pathway abundance by SES. Lower SES was significantly associated with greater α-diversity and compositional differences among groups, as measured by β-diversity. Several taxa related to low SES were identified, especially an increasing abundance of Prevotella copri and Catenibacterium sp000437715, and decreasing abundance of Dysosmobacter welbionis in terms of their high log-fold change differences. In addition, nativity and race/ethnicity have emerged as ecosocial factors that also influence the gut microbiota. Together, these results showed that lower SES was strongly associated with compositional and taxonomic measures of the gut microbiome, and may contribute to shaping the gut microbiota.
PMID: 38467678
ISSN: 2055-5008
CID: 5645682

Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data

van den Puttelaar, Rosita; Meester, Reinier G S; Peterse, Elisabeth F P; Zauber, Ann G; Zheng, Jiayin; Hayes, Richard B; Su, Yu-Ru; Lee, Jeffrey K; Thomas, Minta; Sakoda, Lori C; Li, Yi; Corley, Douglas A; Peters, Ulrike; Hsu, Li; Lansdorp-Vogelaar, Iris
BACKGROUND & AIMS/OBJECTIVE:Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. METHODS:Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. RESULTS:Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. CONCLUSIONS:Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.
PMID: 36906080
ISSN: 1542-7714
CID: 5502372

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Thomas, Minta; Su, Yu-Ru; Rosenthal, Elisabeth A; Sakoda, Lori C; Schmit, Stephanie L; Timofeeva, Maria N; Chen, Zhishan; Fernandez-Rozadilla, Ceres; Law, Philip J; Murphy, Neil; Carreras-Torres, Robert; Diez-Obrero, Virginia; van Duijnhoven, Franzel J B; Jiang, Shangqing; Shin, Aesun; Wolk, Alicja; Phipps, Amanda I; Burnett-Hartman, Andrea; Gsur, Andrea; Chan, Andrew T; Zauber, Ann G; Wu, Anna H; Lindblom, Annika; Um, Caroline Y; Tangen, Catherine M; Gignoux, Chris; Newton, Christina; Haiman, Christopher A; Qu, Conghui; Bishop, D Timothy; Buchanan, Daniel D; Crosslin, David R; Conti, David V; Kim, Dong-Hyun; Hauser, Elizabeth; White, Emily; Siegel, Erin; Schumacher, Fredrick R; Rennert, Gad; Giles, Graham G; Hampel, Heather; Brenner, Hermann; Oze, Isao; Oh, Jae Hwan; Lee, Jeffrey K; Schneider, Jennifer L; Chang-Claude, Jenny; Kim, Jeongseon; Huyghe, Jeroen R; Zheng, Jiayin; Hampe, Jochen; Greenson, Joel; Hopper, John L; Palmer, Julie R; Visvanathan, Kala; Matsuo, Keitaro; Matsuda, Koichi; Jung, Keum Ji; Li, Li; Le Marchand, Loic; Vodickova, Ludmila; Bujanda, Luis; Gunter, Marc J; Matejcic, Marco; Jenkins, Mark A; Slattery, Martha L; D'Amato, Mauro; Wang, Meilin; Hoffmeister, Michael; Woods, Michael O; Kim, Michelle; Song, Mingyang; Iwasaki, Motoki; Du, Mulong; Udaltsova, Natalia; Sawada, Norie; Vodicka, Pavel; Campbell, Peter T; Newcomb, Polly A; Cai, Qiuyin; Pearlman, Rachel; Pai, Rish K; Schoen, Robert E; Steinfelder, Robert S; Haile, Robert W; Vandenputtelaar, Rosita; Prentice, Ross L; Küry, Sébastien; Castellví-Bel, Sergi; Tsugane, Shoichiro; Berndt, Sonja I; Lee, Soo Chin; Brezina, Stefanie; Weinstein, Stephanie J; Chanock, Stephen J; Jee, Sun Ha; Kweon, Sun-Seog; Vadaparampil, Susan; Harrison, Tabitha A; Yamaji, Taiki; Keku, Temitope O; Vymetalkova, Veronika; Arndt, Volker; Jia, Wei-Hua; Shu, Xiao-Ou; Lin, Yi; Ahn, Yoon-Ok; Stadler, Zsofia K; Van Guelpen, Bethany; Ulrich, Cornelia M; Platz, Elizabeth A; Potter, John D; Li, Christopher I; Meester, Reinier; Moreno, Victor; Figueiredo, Jane C; Casey, Graham; Lansdorp Vogelaar, Iris; Dunlop, Malcolm G; Gruber, Stephen B; Hayes, Richard B; Pharoah, Paul D P; Houlston, Richard S; Jarvik, Gail P; Tomlinson, Ian P; Zheng, Wei; Corley, Douglas A; Peters, Ulrike; Hsu, Li
Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
PMID: 37783704
ISSN: 2041-1723
CID: 5609492

A microbial causal mediation analytic tool for health disparity and applications in body mass index

Wang, Chan; Ahn, Jiyoung; Tarpey, Thaddeus; Yi, Stella S; Hayes, Richard B; Li, Huilin
BACKGROUND:Emerging evidence suggests the potential mediating role of microbiome in health disparities. However, no analytic framework can be directly used to analyze microbiome as a mediator between health disparity and clinical outcome, due to the non-manipulable nature of the exposure and the unique structure of microbiome data, including high dimensionality, sparsity, and compositionality. METHODS:Considering the modifiable and quantitative features of the microbiome, we propose a microbial causal mediation model framework, SparseMCMM_HD, to uncover the mediating role of microbiome in health disparities, by depicting a plausible path from a non-manipulable exposure (e.g., ethnicity or region) to the outcome through the microbiome. The proposed SparseMCMM_HD rigorously defines and quantifies the manipulable disparity measure that would be eliminated by equalizing microbiome profiles between comparison and reference groups and innovatively and successfully extends the existing microbial mediation methods, which are originally proposed under potential outcome or counterfactual outcome study design, to address health disparities. RESULTS:Through three body mass index (BMI) studies selected from the curatedMetagenomicData 3.4.2 package and the American gut project: China vs. USA, China vs. UK, and Asian or Pacific Islander (API) vs. Caucasian, we exhibit the utility of the proposed SparseMCMM_HD framework for investigating the microbiome's contributions in health disparities. Specifically, BMI exhibits disparities and microbial community diversities are significantly distinctive between reference and comparison groups in all three applications. By employing SparseMCMM_HD, we illustrate that microbiome plays a crucial role in explaining the disparities in BMI between ethnicities or regions. 20.63%, 33.09%, and 25.71% of the overall disparity in BMI in China-USA, China-UK, and API-Caucasian comparisons, respectively, would be eliminated if the between-group microbiome profiles were equalized; and 15, 18, and 16 species are identified to play the mediating role respectively. CONCLUSIONS:The proposed SparseMCMM_HD is an effective and validated tool to elucidate the mediating role of microbiome in health disparity. Three BMI applications shed light on the utility of microbiome in reducing BMI disparity by manipulating microbial profiles. Video Abstract.
PMID: 37496080
ISSN: 2049-2618
CID: 5592392

Noise Exposure and Cardiovascular Health

Krittanawong, Chayakrit; Qadeer, Yusuf Kamran; Hayes, Richard B; Wang, Zhen; Virani, Salim; Zeller, Marianne; Dadvand, Payam; Lavie, Carl J
Noise is considered an environmental stressor adversely affecting well-being and quality of life, inter-individual communications, and attention and cognitive function and inducing emotional responses, corresponding to noise annoyance. In addition, noise exposure is associated with non-auditory effects including worsening mental health, cognitive impairments, and adverse birth outcomes, sleep disorders, and increased annoyance. An accumulating body of evidence has indicated that traffic noise is also associated with CVD, through multiple pathways. It has been shown that psychological stress and mental health disorders such as depression and anxiety have a negative impact on the development of cardiovascular diseases and outcomes. Likewise, reduced sleep quality and/or duration has been reported to increase sympathetic nervous system activity, which can predispose to conditions like hypertension and diabetes mellitus, known risk factors for CVD. Finally, there seems to be a disruption in the hypothalamic-pituitary-axis secondary to noise pollution that also results in an increased risk of CVD. The World Health Organization has estimated that the number of DALYs (disability-adjusted life-years) lost resulting from environmental noise in Western Europe ranges from 1 to 1.6 million, making noise the second major contributor to the burden of disease in Europe, only after air pollution. Thus, we sought to explore the relationship between noise pollution and risk of CVD.
PMID: 37422031
ISSN: 1535-6280
CID: 5539582

Nonlinear low dose hematotoxicity of benzene; a pooled analyses of two studies among Chinese exposed workers

Vermeulen, Roel; Lan, Qing; Qu, Qingshan; Linet, Martha S; Zhang, Luoping; Li, Guilan; Portengen, Lutzen; Vlaanderen, Jelle; Sungkyoon, Kim; Hayes, Richard B; Yin, Songnian; Smith, Martyn T; Rappaport, Stephen M; Rothman, Nathaniel
BACKGROUND:Impairment of the hematopoietic system is one of the primary adverse health effects from exposure to benzene. We previously have shown that exposure to benzene at low levels (<1 ppm) affects the blood forming system and that these effects were proportionally stronger at lower versus higher levels of benzene exposure. This observation is potentially explained by saturation of enzymatic systems. METHODS:Here we extend these analyses by detailed modeling of the exposure response association of benzene and its major metabolites (i.e. catechol, muconic acid, phenol, and hydroquinone) on peripheral white blood cell (WBC) counts and its major cell-subtypes (i.e. granulocytes, lymphocytes, and monocytes) using two previously published cross-sectional studies among occupationally exposed Chinese workers. RESULTS:Supra-linear exposure response associations were observed between air benzene concentrations (range ∼ 0.1 - 100 ppm) and WBC counts and its cell-subtypes, with a larger than proportional decrease in cell counts at lower than at higher levels of benzene exposure. The hematotoxicity associations were largely similar in shape when the analyses were repeated with benzene urinary metabolites suggesting that enzymatic saturation is not a full explanation of the observed non-linearity with WBC endpoints. DISCUSSION:We hypothesize that the flattening of the exposure response curve especially at higher benzene exposure levels may reflect a response by the bone marrow to maintain hematopoietic homeostasis. Toxicity to the bone marrow and an induced hyper-proliferative response could both contribute to risk of subsequently developing a hematopoietic malignancy. Additional work is needed to explore this hypothesis.
PMID: 37290291
ISSN: 1873-6750
CID: 5533562

Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE consortium

Goyal, Neerav; Hennessy, Max; Lehman, Erik; Lin, Wenxue; Agudo, Antonio; Ahrens, Wolfgang; Boccia, Stefania; Brennan, Paul; Brenner, Hermann; Cadoni, Gabriella; Canova, Cristina; Chen, Chu; Conway, David; Curado, Maria Paula; Dal Maso, Luigino; Daudt, Alexander W; Edefonti, Valeria; Fabianova, Eleonora; Fernandez, Leticia; Franceschi, Silvia; Garavello, Werner; Gillison, Maura; Hayes, Richard B; Healy, Claire; Herrero, Rolando; Holcatova, Ivana; Kanda, Jossy L; Kelsey, Karl; Hansen, Bo T; Koifman, Rosalina; Lagiou, Pagona; La Vecchia, Carlo; Levi, Fabio; Li, Guojun; Lissowska, Jolanta; Mendoza López, Rossana; Luce, Danièle; Macfarlane, Gary; Mates, Dana; Matsuo, Keitaro; McClean, Michael; Menezes, Ana; Menvielle, Gwenn; Morgenstern, Hal; Moysich, Kirsten; Negri, Eva; Olshan, Andrew F; Pandics, Tamas; Polesel, Jerry; Purdue, Mark; Radoi, Loredana; Ramroth, Heribert; Richiardi, Lorenzo; Schantz, Stimson; Schwartz, Stephen M; Serraino, Diego; Shangina, Oxana; Smith, Elaine; Sturgis, Erich M; ÅšwiÄ…tkowska, Beata; Thomson, Peter; Vaughan, Thomas L; Vilensky, Marta; Winn, Deborah M; Wunsch-Filho, Victor; Yu, Guo-Pei; Zevallos, Jose P; Zhang, Zuo-Feng; Zheng, Tongzhang; Znaor, Ariana; Boffetta, Paolo; Hashibe, Mia; Lee, Yuan-Chin A; Muscat, Joshua E
OBJECTIVE:We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. SUBJECTS AND METHODS/METHODS:The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. RESULTS:The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites. CONCLUSION/CONCLUSIONS:These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer.
PMID: 35322907
ISSN: 1601-0825
CID: 5200562