The Mutographs biorepository: A unique genomic resource to study cancer around the world.

Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites. Genomic, exposure, and clinical data will be publicly available through the International Cancer Genome Consortium Accelerating Research in Genomic Oncology platform. The Mutographs sample and metadata biorepository constitutes a legacy resource for new projects and collaborations aiming to increase our current research efforts in cancer genomic epidemiology globally.

Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) soil contamination in Lausanne, Switzerland: Combining pollution mapping and human exposure assessment for targeted risk management.

In December 2020, high soil concentrations of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) were discovered across large parts of Lausanne, Switzerland. Concentrations reached up to 640 ng TEQWHO-2005/kg dry weight. The most likely source was a former municipal waste incinerator. A three-step, multidisciplinary approach to human health risk assessment was conducted to determine the potential population exposure to PCDD/Fs and identify appropriate preventive measures. First, exposure scenarios were developed based on contaminated land uses. Second, the toxicological risks of different scenarios were evaluated using a toxicokinetic model estimating increases in blood serum PCDD/F concentrations over background concentrations from the general population's food consumption. Third, a detailed geostatistical mapping of PCDD/F soil contamination was performed. Stochastic simulations with an external drift and an anisotropic model of the variogram were generated to incorporate the effects of distance from emission source, topography, and main wind directions on the spatial distribution of PCDD/Fs in topsoil. Three main scenarios were assessed: i) direct ingestion of soil by children in playgrounds; ii) consumption of vegetables from private gardens by children and adults; and iii) consumption of food from livestock and poultry raised on contaminated soil. The worst exposure scenario involved the consumption of eggs from private hen houses, resulting in PCDD/F concentrations in serum an order of magnitude higher than might normally be expected. No relevant increases in serum concentrations were calculated for direct soil ingestion and vegetable consumption, except for cucurbitaceous vegetables. Combining mapping and exposure scenario assessment resulted in targeted protective measures for land users, especially concerning food consumption. The results also raised concerns about the potential unsafe consumption of products derived from animals raised on land with PCDD/F concentrations only moderately over environmental background levels.

Geographic heterogeneity in the prevalence of human papillomavirus in head and neck cancer.

Human papillomavirus (HPV) causes oropharyngeal squamous cell carcinoma (OPSCC), although strongly divergent results have been reported regarding the prevalence of HPV16 in different countries, whether this represents important differences in etiology remains unclear. Applying rigorous protocols for sample processing, we centrally evaluated 1,420 head and neck tumors (533 oropharynx, 395 oral cavity and 482 larynx) from studies conducted in the US, Europe and Brazil for mucosal HPV DNA and p16INK4a expression to evaluate regional heterogeneity in the proportion of HPV16-associated OPSCC and other head and neck cancer, and to assess covariates associated with the risk of HPV16-positive OPSCC. While majority of OPSCC in the US (60%) were HPV16-positive, this proportion was 31% in Europe and only 4% in Brazil (p < 0.01). Similar differences were observed for other head and neck tumors, ranging from 7% in the US and 5% in Europe, to 0% in South America. The odds of HPV16-positive OPSCC declined with increasing pack years of smoking (OR: 0.75; 95% CI: 0.64-0.87) and drink years of alcohol use (OR: 0.64; 95% CI: 0.54-0.76). These results suggest that while the contribution of HPV16 is substantial for the oropharynx, it remains limited for oral cavity and laryngeal cancers.

Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand.

BACKGROUND: The incidence of nasopharyngeal carcinoma (NPC) varies substantially worldwide, with an endemic pocket in Southeast Asia. METHOD: We assessed lifestyle and genetic factors in relation to NPC risk among 681 NPC cases and 1,078 controls from Thailand. Evaluated lifestyle factors included traditionally preserved foods, tobacco smoking, betel quid chewing, and alcohol consumption. Genetic factors included six variants implicated in a previous a genome-wide association study (GWAS) of NPC and three variants residing near the CHRNA3 and TERT genes that were linked to lung cancer risk in Asian populations. Odds ratios (OR) and 95 % confidence intervals (95 % CI) were estimated using unconditional logistic regression. RESULTS: Frequent consumption of fermented vegetables was associated with increased NPC risk (OR of consumption ≥weekly vs. ≤rare 1.78, 95 % CI 1.24-2.55, p (trend) = 0.005), as was tobacco smoking (p (trend) < 0.001), former and current smokers displaying OR of 1.57 (95 % CI 1.10-2.30) and 2.00 (95 % CI 1.48-2.71) compared to never smokers, respectively. Four out of six genetic variants implicated in the recent NPC GWAS were associated with NPC risk (p (trend) ≤ 0.03), as well as two variants (rs402710 and rs2736098) on the TERT locus at 5p15.33 (p = 0.004 and p = 0.04, respectively). CONCLUSIONS: These results strengthen our previous observation that tobacco smoking is an important risk factor of NPC in this population. Four out of six genetic variants identified in a recent NPC GWAS were confirmed, and the association noted with variants on 5p15.33 suggests that this locus is involved in NPC susceptibility, representing a novel finding in NPC epidemiology.

Smoking related cancers and loci at chromosomes 15q25, 5p15, 6p22.1 and 6p21.33 in the Polish population.

Genetic factors associated with the risk of smoking related cancers have until recently remained elusive. Since the publication of a genome-wide association study (GWAS) on lung cancer new genetic loci have been identified that appear to be associated with disease risk. In this replication study we genotyped 14 single nucleotide polymorphisms (SNPs) located at the 5p12.3-p15.33, 6p21.3-p22.1, 6q23-q27 and 15q25.1 loci in 874 lung, 450 bladder, 418 laryngeal cancer cases and cancer-free controls, matched by year of birth and sex to the cases. Our results revealed that loci in the chromosome region 15q25.1 (rs16969968[A], rs8034191[G]) and 5p15 (rs402710[T]) are associated with lung cancer risk in the Polish population (smoking status adjusted OR = 1.45, 1.35, 0.77; p ≤ 0.0001, 0.0005, 0.002; 95%CI 1.23-1.72, 1.14-1.59, 0.66-0.91 respectively). None of the other regions analyzed herein were implicated in the risk of lung, bladder or laryngeal cancer. This study supports previous findings on lung cancer but fails to show association of SNPs located in 15q25.1 and 5p15 region with other smoking related cancers like bladder and laryngeal cancer.

Personal use of hair dyes--increased risk of non-Hodgkin's lymphoma in Thailand.

The use of hair dyes has been inconsistently associated with an increased risk of lymphomas. To further evaluate this possibility, we examined hair dye use and lymphoma risk in a case-control study in the Thai population. A total of 390 histologically confirmed incident non-Hodgkin's lymphoma (NHL) cases and 422 controls were included. Information on hair dye use was obtained through a personal interview together with information on other known risk factors of lymphoma. Analysis was performed using logistic regression; odds ratios (ORs) estimates and 95% confidence intervals (CI) were calculated. Ever use of hair dyes was not associated with an increase risk of NHL both overall (OR=1.1, 95%CI 0.8-1.5) and in women (OR=1.4, 95%CI 0.9-2.3). However, NHL was significantly higher among persons who began using hair dyes before 1980 (OR=2.1, 95%CI 1.0-4.1). An increased risk was also observed among women who reported use of permanent hair dye product (OR=1.8, 95% CI 1.0-3.1). Analyses by NHL subtype showed an increased risk for diffuse large B-cell lymphoma among users of permanent hair dyes (OR=1.6, 95%CI 1.0-2.5) while follicular lymphoma was associated with the use of dark-colored dyes (OR=3.7, 95%CI 1.1-12.8). No association was observed with duration of use, nor total lifetime applications. These results indicate that personal hair dye use may play role in risks of NHL among person who used hair dyes before 1980.

Factorial Kriging Analysis as a tool for explaining the complex spatial distribution of metals in sediments.

Rivers flowing through urbanized and industrial areas are usually greatly damaged by anthropogenic activities discharging contaminants. Characterizing the spatial distribution of pollutants in sediments is of high importance for selecting a suitable remediation operation, but is a complex task because this spatial variability is the result of various physical and chemical mechanisms occurring at different scales. Factorial Kriging Analysis (FKA) was applied on data collected in a canalized river (Scarpe, France) for that purpose, because this geostatistical technique allows to decompose a given variable into components of different spatial correlations and map them separately. This decomposition is meaningful provided that it can be related to physical phenomena occurring at the identified spatial scales. FKA applied to Cd and Zn concentrations in sediments of the Scarpe river proved to be effective, allowing their mapping to be decomposed in a first map related to a short-range spatial correlation corresponding to hot spots interpreted as the impact of industrial and urban inputs located along the canal, and a second map related to a long-range spatial variability associated with long pollutant plumes interpreted as the effect of one major upstream pollutant input.

Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history.

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in non-small cell lung cancer (NSCLC) of never smokers, whereas HER2 mutations are rare. We have analyzed EGFR and HER2 mutations and the expression of the two products of the CDKN2A gene (p14(arf) and p16(INK4a)) in 116 NSCLC that have been previously analyzed for TP53 and KRAS mutations in relation to smoking history of patients. EGFR mutations were detected in 20 of 116 (17%) tumors, whereas five (4.3%) tumors contained HER2 mutations. No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from never smokers, and 32% were from former smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among never smokers, 11 of 16 tumors with EGFR mutation also had TP53 mutation, in contrast with two of 17 tumors without EGFR mutation (P = 0.0008). Expression of p14(arf), but not p16(ink4a), was more frequently down-regulated in never smokers (62.5%) than ever smokers (35%; P = 0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14(arf) expression. These observations suggest that functional inactivation of the p14(arf)/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals.

A genome wide linkage search for breast cancer susceptibility genes.

Mutations in known breast cancer susceptibility genes account for a minority of the familial aggregation of the disease. To search for further breast cancer susceptibility genes, we performed a combined analysis of four genome-wide linkage screens, which included a total of 149 multiple case breast cancer families. All families included at least three cases of breast cancer diagnosed below age 60 years, at least one of whom had been tested and found not to carry a BRCA1 or BRCA2 mutation. Evidence for linkage was assessed using parametric linkage analysis, assuming both a dominant and a recessive mode of inheritance, and using nonparametric methods. The highest LOD score obtained in any analysis of the combined data was 1.80 under the dominant model, in a region on chromosome 4 close to marker D4S392. Three further LOD scores over 1 were identified in the parametric analyses and two in the nonparametric analyses. A maximum LOD score of 2.40 was found on chromosome arm 2p in families with four or more cases of breast cancer diagnosed below age 50 years. The number of linkage peaks did not differ from the number expected by chance. These results suggest regions that may harbor novel breast cancer susceptibility genes. They also indicate that no single gene is likely to account for a large fraction of the familial aggregation of breast cancer that is not due to mutations in BRCA1 or BRCA2.

Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance.

Classification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that approximately 80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants.

Linkage analysis of complex diseases using microsatellites and single-nucleotide polymorphisms: application to alcoholism.

The efficacy of linkage studies using microsatellites and single-nucleotide polymorphisms (SNPs) was evaluated. Analyzed data were supplied by the Collaborative Study on the Genetics of Alcoholism (COGA). Alcoholism was analyzed together with a simulated trait caused by a gene of known position, through a nonparametric linkage test (NPL). For the alcoholism trait, four densities of SNPs (1 SNP per 0.2 cM, 0.5 cM, 1 cM and 2 cM) showed higher peaks of NPL z scores and smaller significant p-values than the usual 10-cM density of microsatellites. However, the two highest densities of SNPs had unstable z score signals, and therefore were difficult to interpret. Analyzing a simulated trait with the same markers in the same pedigrees, we confirmed the higher power of all four densities of SNPs compared to the 10-cM microsatellites panel, although the existence of other confounding peaks was confirmed for maps that are denser than 1 SNP/cM. We further showed that estimating the gene position using SNPs is far less biased than using the usual panel of microsatellites (biases of 0-2 cM for SNPs vs. 8.9 cM for microsatellites). We conclude that using dense maps of SNPs in linkage analysis is more powerful and less biased than using the 10-cM maps of microsatellites. However, linkage signals can be unstable and difficult to interpret when several SNPs are genotyped per centimorgan. The power and accuracy of 1 SNP/cM or 1 SNP/2 cM may be sufficient in a genome-wide linkage scan while denser maps may be most useful in fine-gene mapping studies exploiting linkage disequilibrium.

Geostatistical approach for assessing soil volumes requiring remediation: validation using lead-polluted soils underlying a former smelting works.

Assessing the volume of soil requiring remediation and the accuracy of this assessment constitutes an essential step in polluted site management. If this remediation volume is not properly assessed, misclassification may lead both to environmental risks (polluted soils may not be remediated) and financial risks (unexpected discovery of polluted soils may generate additional remediation costs). To minimize such risks, this paper proposes a geostatistical methodology based on stochastic simulations that allows the remediation volume and the uncertainty to be assessed using investigation data. The methodology thoroughly reproduces the conditions in which the soils are classified and extracted at the remediation stage. The validity of the approach is tested by applying it on the data collected during the investigation phase of a former lead smelting works and by comparing the results with the volume that has actually been remediated. This real remediated volume was composed of all the remediation units that were classified as polluted after systematic sampling and analysis during clean-up stage. The volume estimated from the 75 samples collected during site investigation slightly overestimates (5.3% relative error) the remediated volume deduced from 212 remediation units. Furthermore, the real volume falls within the range of uncertainty predicted using the proposed methodology.

Forecasting the number of soil samples required to reduce remediation cost uncertainty.

Sampling scheme design is an important step in the management of polluted sites. It largely controls the accuracy of remediation cost estimates. In practice, however, sampling is seldom designed to comply with a given level of remediation cost uncertainty. In this paper, we present a new technique that allows one to estimate of the number of samples that should be taken at a given stage of investigation to reach a forecasted level of accuracy. The uncertainty is expressed both in terms of volume of polluted soil and overall cost of remediation. This technique provides a flexible tool for decision makers to define the amount of investigation worth conducting from an environmental and financial perspective. The technique is based on nonlinear geostatistics (conditional simulations) to estimate the volume of soil that requires remediation and excavation and on a function allowing estimation of the total cost of remediation (including investigations). The geostatistical estimation accounts for support effect, information effect, and sampling errors. The cost calculation includes mainly investigation, excavation, remediation, and transportation. The application of the technique on a former smelting work site (lead pollution) demonstrates how the tool can be used. In this example, the forecasted volumetric uncertainty decreases rapidly for a relatively small number of samples (20-50) and then reaches a plateau (after 100 samples). The uncertainty related to the total remediation cost decreases while the expected total cost increases. Based on these forecasts, we show how a risk-prone decision maker would probably decide to take 50 additional samples while a risk-averse decision maker would take 100 samples.

Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium.

The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate "BRCA3" locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (alpha) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603-9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (alpha = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at alpha = 0.65 was -11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.