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Geographic variation of mutagenic exposures in kidney cancer genomes.

ABSTRACT: International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden¹. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence². Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

SUBMITTER: Senkin S

PROVIDER: S-EPMC11111402 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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Geographic variation of mutagenic exposures in kidney cancer genomes.

Senkin Sergey S Moody Sarah S Díaz-Gay Marcos M Abedi-Ardekani Behnoush B Cattiaux Thomas T Ferreiro-Iglesias Aida A Wang Jingwei J Fitzgerald Stephen S Kazachkova Mariya M Vangara Raviteja R Le Anh Phuong AP Bergstrom Erik N EN Khandekar Azhar A Otlu Burçak B Cheema Saamin S Latimer Calli C Thomas Emily E Atkins Joshua Ronald JR Smith-Byrne Karl K Cortez Cardoso Penha Ricardo R Carreira Christine C Chopard Priscilia P Gaborieau Valérie V Keski-Rahkonen Pekka P Jones David D Teague Jon W JW Ferlicot Sophie S Asgari Mojgan M Sangkhathat Surasak S Attawettayanon Worapat W Świątkowska Beata B Jarmalaite Sonata S Sabaliauskaite Rasa R Shibata Tatsuhiro T Fukagawa Akihiko A Mates Dana D Jinga Viorel V Rascu Stefan S Mijuskovic Mirjana M Savic Slavisa S Milosavljevic Sasa S Bartlett John M S JMS Albert Monique M Phouthavongsy Larry L Ashton-Prolla Patricia P Botton Mariana R MR Silva Neto Brasil B Bezerra Stephania Martins SM Curado Maria Paula MP Zequi Stênio de Cássio SC Reis Rui Manuel RM Faria Eliney Ferreira EF de Menezes Nei Soares NS Ferrari Renata Spagnoli RS Banks Rosamonde E RE Vasudev Naveen S NS Zaridze David D Mukeriya Anush A Shangina Oxana O Matveev Vsevolod V Foretova Lenka L Navratilova Marie M Holcatova Ivana I Hornakova Anna A Janout Vladimir V Purdue Mark P MP Rothman Nathaniel N Chanock Stephen J SJ Ueland Per Magne PM Johansson Mattias M McKay James J Scelo Ghislaine G Chanudet Estelle E Humphreys Laura L de Carvalho Ana Carolina AC Perdomo Sandra S Alexandrov Ludmil B LB Stratton Michael R MR Brennan Paul P

Nature 20240501 8013

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations ...[more]

PMID: 38693263

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Project description:International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not been identified by conventional epidemiology yet potentially make a substantial contribution to cancer burden1. This pertains to clear cell renal cell carcinoma (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence2. Some carcinogens generate somatic mutations and a complementary strategy for detecting past exposures is to sequence the genomes of cancers from populations with different incidence rates and infer underlying causes from differences in patterns of somatic mutations. Here, we sequenced 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in >70% cases and <2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher kidney cancer incidence rates (p-value <6 × 10−18). Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, geographically variable, mutagenic exposures potentially affecting 10s of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics. Linked cross omic data sets:Geographic variation of mutagenic exposures in kidney cancer genomes – patient metadata files (Mutographs) associated with this study are available in the European Genome-Phenome Archive: https://ega-archive.org/datasets/EGAD00001012223.

Project description:IntroductionGeographic variation in the prevalence of chronic kidney disease and incidence of end-stage renal disease has been previously reported. However, the geographic epidemiology of rapid estimated glomerular filtration rate (eGFR) decline has not been examined.MethodsWe built a longitudinal cohort of 2,107,570 US veterans to characterize the spatial epidemiology of and examine the associations between US county characteristics and rapid eGFR decline.ResultsThere were 169,029 (8.02%) with rapid eGFR decline (defined as eGFR slope < -5 ml/min per 1.73 m2/year). The prevalence of rapid eGFR decline adjusted for age, race, gender, diabetes, and hypertension varied by county from 4.10%-6.72% in the lowest prevalence quintile to 8.41%-22.04% in the highest prevalence quintile (P for heterogeneity < 0.001). Examination of adjusted prevalence showed substantial geographic variation in those with and without diabetes and those with and without hypertension (P for heterogeneity < 0.001). Cohort participants had higher odds of rapid eGFR decline when living in counties with unfavorable characteristics in domains including health outcomes (odds ratio [OR] = 1.15; confidence interval [CI] = 1.09-1.22), health behaviors (OR = 1.08; CI = 1.03-1.13), clinical care (OR = 1.11; CI = 1.06-1.16), socioeconomic conditions (OR = 1.15; CI = 1.09-1.22), and physical environment (OR = 1.15; CI = 1.01-1.20); living in counties with high percentage of minorities and immigrants was associated with rapid eGFR decline (OR = 1.25; CI = 1.20-1.31). Spatial analyses suggest the presence of cluster of counties with high prevalence of rapid eGFR decline.DiscussionOur findings show substantial geographic variation in rapid eGFR decline among US veterans; the variation persists in analyses stratified by diabetes and hypertension status; results show associations between US county characteristics in domains capturing health, socioeconomic, environmental, and diversity conditions, and rapid eGFR decline.

Project description:ImportanceThere are stark disparities in cervical cancer burden in the United States, notably by race and ethnicity and geography. Late-stage diagnosis is an indicator of inadequate access to and utilization of screening.ObjectiveTo identify geospatial clusters of late-stage cervical cancer at time of diagnosis in Texas.Design, setting, and participantsThis population-based cross-sectional study used incident cervical cancer data from the Texas Cancer Registry from 2014 to 2018 of female patients aged 18 years or older. Late-stage cervical cancer cases were geocoded at the census tract level (n = 5265) using their residential coordinates (latitude and longitude) at the time of diagnosis. Statistical analysis was performed from April to September 2023.ExposuresCensus tract of residence at diagnosis.Main outcome and measuresLate-stage cervical cancer diagnosis (ie, cases classified by the National Cancer Institute Surveillance, Epidemiology and End Results summary stages 2 to 4 [regional spread] or 7 [distant metastasis]). A Poisson probability-based model of the SaTScan purely spatial scan statistics was applied at the census tract-level to identify geographic clusters of higher (hot spots) or lower (cold spots) proportions than expected of late-stage cervical cancer diagnosis and adjusted for age.ResultsAmong a total of 6484 female patients with incident cervical cancer cases (mean [SD] age, 48.7 [14.7] years), 2300 (35.5%) were Hispanic, 798 (12.3%) were non-Hispanic Black, 3090 (47.6%) were non-Hispanic White, and 296 (4.6%) were other race or ethnicity. Of the 6484 patients, 2892 with late-stage diagnosis (mean [SD] age, 51.8 [14.4] years were analyzed. Among patients with late-stage diagnosis, 1069 (37.0%) were Hispanic, 417 (14.4%) were non-Hispanic Black, 1307 (45.2%) were non-Hispanic White, and 99 (3.4%) were other race or ethnicity. SaTScan spatial analysis identified 7 statistically significant clusters of late-stage cervical cancer diagnosis in Texas, of which 4 were hot spots and 3 were cold spots. Hot spots included 1128 census tracts, predominantly in the South Texas Plains, Gulf Coast, and Prairies and Lakes (North Texas) regions. Of the 2892 patients with late-stage cervical cancer, 880 (30.4%) were observed within hot spots. Census tract-level comparison of characteristics of clusters suggested that hot spots differed significantly from cold spots and the rest of Texas by proportions of racial and ethnic groups, non-US born persons, and socioeconomic status.Conclusions and relevanceIn this cross-sectional study examining geospatial clusters of late-stage cervical cancer diagnosis, place-based disparities were found in late-stage cervical cancer diagnosis in Texas. These findings suggest that these communities may benefit from aggressive cervical cancer interventions.

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Geographic variation of mutagenic exposures in kidney cancer genomes.

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Geographic variation of mutagenic exposures in kidney cancer genomes.

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