Aromatic amines and heterocyclic aromatic amines (HAAs) are structurally related classes of carcinogens that are formed during the combustion of tobacco or during the high-temperature cooking of ...meats. Both classes of procarcinogens undergo metabolic activation by N-hydroxylation of the exocyclic amine group to produce a common proposed intermediate, the arylnitrenium ion, which is the critical metabolite implicated in toxicity and DNA damage. However, the biochemistry and chemical properties of these compounds are distinct, and different biomarkers of aromatic amines and HAAs have been developed for human biomonitoring studies. Hemoglobin adducts have been extensively used as biomarkers to monitor occupational and environmental exposures to a number of aromatic amines; however, HAAs do not form hemoglobin adducts at appreciable levels, and other biomarkers have been sought. A number of epidemiologic studies that have investigated dietary consumption of well-done meat in relation to various tumor sites reported a positive association between cancer risk and well-done meat consumption, although some studies have shown no associations between well-done meat and cancer risk. A major limiting factor in most epidemiological studies is the uncertainty in quantitative estimates of chronic exposure to HAAs, and thus, the association of HAAs formed in cooked meat and cancer risk has been difficult to establish. There is a critical need to establish long-term biomarkers of HAAs that can be implemented in molecular epidemioIogy studies. In this review, we highlight and contrast the biochemistry of several prototypical carcinogenic aromatic amines and HAAs to which humans are chronically exposed. The biochemical properties and the impact of polymorphisms of the major xenobiotic-metabolizing enzymes on the biological effects of these chemicals are examined. Lastly, the analytical approaches that have been successfully employed to biomonitor aromatic amines and HAAs, and emerging biomarkers of HAAs that may be implemented in molecular epidemiology studies are discussed.
Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and
) account for some familial aggregation of colorectal cancer, their population prevalence and the ...causes of the remaining familial aggregation are not known.
We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and
We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.
We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (
= 1 in 1,946,
= 1 in 2,841,
= 1 in 758,
= 1 in 714), 1 in 45 carry mutations in
, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).
Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.
Our findings could aid gene discovery and development of better colorectal cancer risk prediction models.
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Inflammation is a facilitating process for multiple cancer types. It is believed to affect cancer development and progression through several etiologic pathways, including increased levels of DNA ...adduct formation, increased angiogenesis, and altered antiapoptotic signaling. This review highlights the application of inflammatory biomarkers in epidemiologic studies and discusses the various cellular mediators of inflammation characterizing the innate immune system response to infection and chronic insult from environmental factors. Included is a review of six classes of inflammation-related biomarkers: cytokines/chemokines, immune-related effectors, acute-phase proteins, reactive oxygen and nitrogen species, prostaglandins and cyclooxygenase-related factors, and mediators such as transcription factors and growth factors. For each of these biomarkers, we provide a brief overview of the etiologic role in the inflammation response and how they have been related to cancer etiology and progression within the literature. We provide a discussion of the common techniques available for quantification of each marker, including strengths, weaknesses, and potential pitfalls. Subsequently, we highlight a few under-studied measures to characterize the inflammatory response and their potential utility in epidemiologic studies of cancer. Finally, we suggest integrative methods for future studies to apply multifaceted approaches to examine the relationship between inflammatory markers and their roles in cancer development.
The Coronavirus Disease of 2019 (COVID-19) has impacted the health and day-to-day life of individuals, especially the elderly and people with certain pre-existing medical conditions, including ...cancer. The purpose of this study was to investigate how COVID-19 impacted access to cancer screenings and treatment, by studying the participants in the Multiethnic Cohort (MEC) study.
The MEC has been following over 215,000 residents of Hawai'i and Los Angeles for the development of cancer and other chronic diseases since 1993-1996. It includes men and women of five racial and ethnic groups: African American, Japanese American, Latino, Native Hawaiian, and White. In 2020, surviving participants were sent an invitation to complete an online survey on the impact of COVID-19 on their daily life activities, including adherence to cancer screening and treatment. Approximately 7,000 MEC participants responded. A cross-sectional analysis was performed to investigate the relationships between the postponement of regular health care visits and cancer screening procedures or treatment with race and ethnicity, age, education, and comorbidity.
Women with more education, women with lung disease, COPD, or asthma, and women and men diagnosed with cancer in the past 5 years were more likely to postpone any cancer screening test/procedure due to the COVID-19 pandemic. Groups less likely to postpone cancer screening included older women compared to younger women and Japanese American men and women compared to White men and women.
This study revealed specific associations of race/ethnicity, age, education level, and comorbidities with the cancer-related screening and healthcare of MEC participants during the COVID-19 pandemic. Increased monitoring of patients in high-risk groups for cancer and other diseases is of the utmost importance as the chance of undiagnosed cases or poor prognosis is increased as a result of delayed screening and treatment.
This research was partially supported by the Omidyar 'Ohana Foundation and grant U01 CA164973 from the National Cancer Institute.
Coffee intake has been associated with risk of various cancers, but the findings, mostly from studies in white populations, are inconsistent. We examined the association of coffee consumption with ...overall cancer incidence and specific cancer sites in a large prospective study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites.
167,720 participants of the Multiethnic Cohort Study in Hawaii and Los Angeles were included. Baseline coffee intake was assessed by a validated food-frequency questionnaire. HRs and 95% confidence intervals (CIs) for sixteen cancers associated with coffee intake were calculated using Cox regressions.
During a mean follow-up of 15.3 years, 34,031 incident cancer cases were identified among study participants. Coffee intake was associated inversely with liver (≥4 cups/day vs. none: HR = 0.57; 95% CI, 0.38-0.87;
< 0.001), ovarian (HR = 0.33; 95% CI, 0.17-0.65;
= 0.007), and thyroid (HR = 0.44; 95% CI, 0.23-0.87;
= 0.007) cancers and melanoma (HR = 0.72; 95% CI, 0.52-0.99;
= 0.002). Coffee intake was also inversely associated with endometrial cancer among women with a body mass index >30 kg/m
(HR = 0.31; 95% CI, 0.14-0.72;
= 0.04). The associations were similar across five ethnic groups (
> 0.06) and were mainly observed among those who drank caffeinated coffee.
On the basis of our prospective data in diverse populations, we found a decreased risk of liver, ovarian, thyroid, and endometrial cancers and melanoma associated with higher coffee intake.
These results suggest that coffee drinking may protect against liver, ovarian, thyroid, and endometrial cancers, and melanoma.
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The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations ...described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The incidence of colorectal cancer in the United States declined substantially over the past 20 years, but evidence suggests that among younger adults (under 50 years at diagnosis), incidence is ...increasing. However, data on age- and stage-specific incidence trends across racial/ethnic groups are limited.
All incident cases of colorectal cancer diagnosed from 1990 through 2014 in adults aged 20 years and older were obtained from the California Cancer Registry. Incidence rates (per 100,000), incidence rate ratios, and triannual percent changes in incidence were estimated for each age group at diagnosis (20-49, 50-74, 75+ years), sex, stage, and race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and 7 Asian American groups).
Of 349,176 incident colorectal cancer cases diagnosed from 1990 through 2014, 9% were in adults younger than 50 years. Increases in incidence of early-onset colorectal cancer, especially in regional/distant stage disease, were observed in most racial/ethnic groups (statistically significant for non-Hispanic whites and Hispanics, ranging from 0.9% to 2.9% every 3 years). Incidence also increased in Vietnamese and other Southeast Asian groups of screening age (50-74 years). The incidence of colorectal cancer in non-Hispanic blacks aged 50+ declined over the 25-year period, but remained significantly higher than in non-Hispanic whites.
Further research is needed to understand the causes of the increasing incidence of early-onset colorectal cancer. The rising incidence of colorectal cancer among Southeast Asians of screening age and the persistently high incidence in non-Hispanic blacks also warrant attention.
Our findings may have implications for revisiting screening guidelines in the United States.
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Obesity has been more consistently associated with breast cancer than type II diabetes. This analysis examined the combination of the two factors in the Multiethnic Cohort (MEC).
Women ages 45-75 ...years entered the MEC in 1993-1996 by completing a questionnaire. Type II diabetes status was self-reported at baseline, two follow-up questionnaires, and confirmed by administrative data. Cancers were identified from tumor registries and deaths through vital records until 2010. Cox regression was applied to estimate HRs and 95% confidence intervals (CI) for BMI and type II diabetes status alone and in combination.
Among 103,721 (25,146 white, 20,255 African American, 7,681 Native Hawaiian, 28,012 Japanese American, 22,627 Latina) women with 14,558 type II diabetes cases, 6,692 women developed breast cancer during 14.8 ± 4.1 years of follow-up. Type II diabetes was significantly associated with breast cancer risk (HR, 1.15; 95% CI, 1.07-1.23), but including body mass index (BMI) lowered the HR to 1.08 (95% CI, 1.00-1.16). Ethnic-specific BMI-adjusted models showed elevated risks for type II diabetes in Latinas only (HR, 1.30; 95% CI, 1.11-1.52). In contrast, obesity predicted statistically significant 21%-46% higher risks, after type II diabetes adjustment, in all ethnic groups except Latinas (HR, 1.17; 95% CI, 0.99-1.38).
As reported previously, inclusion of BMI weakened the association of type II diabetes with breast cancer. Type II diabetes status, but not BMI, was primarily associated with higher breast cancer risk in Latinas.
The role of obesity and type II diabetes in breast cancer etiology may differ by ethnicity suggesting metabolic differences related to obesity.
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Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival.
To investigate whether changes in circulating metabolites characterize the early stages of ...colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y.
The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk.
These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development.
This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully ...genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3 × 10(-5)) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5 × 10(-7) only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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