Showing papers by "Florence Demenais published in 2019"
Johns Hopkins University1, University of North Carolina at Chapel Hill2, University of Cambridge3, Cancer Council Victoria4, University of Melbourne5, Monash University6, Laval University7, Karolinska Institutet8, The Cyprus Institute of Neurology and Genetics9, Netherlands Cancer Institute10, University of Hamburg11, German Cancer Research Center12, QIMR Berghofer Medical Research Institute13, American Cancer Society14, Fred Hutchinson Cancer Research Center15, University of Southern California16, University of Virginia17, Wellcome Trust Centre for Human Genetics18, University of Birmingham19, Brigham and Women's Hospital20, Harvard University21, University of Leeds22, French Institute of Health and Medical Research23, University of Western Australia24, Baylor College of Medicine25, Institute of Cancer Research26, University of California, Berkeley27, Umeå University28, Case Western Reserve University29, International Agency for Research on Cancer30, University of Utah31, Mayo Clinic32, Duke University33, Cedars-Sinai Medical Center34, University of Michigan35, Roswell Park Cancer Institute36, National Institutes of Health37, Yale University38, University of Texas MD Anderson Cancer Center39, Copenhagen University Hospital40, Technical University of Denmark41, University of Pennsylvania42
TL;DR: It is shown that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.
Abstract: We analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum thousands of independent susceptibility variants. For some malignancies, particularly chronic lymphoid leukemia (CLL) and testicular cancer, susceptibility variants have a larger proportion of variants with larger effect sizes than those for other cancers. In contrast, most variants for lung and breast cancers have very small associated effect sizes. We estimate a wide range of GWAS sample sizes for different cancer sites required to explain 80% of GWAS heritability, varying from 60,000 cases for CLL to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk-scores, compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.
39 citations
Texas A&M University1, University of Pennsylvania2, Paris Descartes University3, University of Leeds4, French Institute of Health and Medical Research5, University of Genoa6, University of Barcelona7, University of Sydney8, Hospital of the University of Pennsylvania9, Pontifícia Universidade Católica do Rio Grande do Sul10, Leiden University11, Karolinska Institutet12, QIMR Berghofer Medical Research Institute13, Lund University14, Federal University of São Paulo15, University of the Republic16, Latvian Biomedical Research and Study centre17, Carlos III Health Institute18, Leiden University Medical Center19
TL;DR: GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in counselling these patients towards genetic testing or cancer risk counselling.
Abstract: Background Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved. Methods In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics. Results MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P Conclusion The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
15 citations
University of L'Aquila1, European Institute of Oncology2, University of Milano-Bicocca3, University of Florence4, University of Brescia5, Paris Descartes University6, French Institute of Health and Medical Research7, University of Paris8, Karolinska Institutet9, University of Sydney10, University of California, Irvine11, University of Southern California12, University of British Columbia13, Cancer Care Ontario14, The George Institute for Global Health15, University of North Carolina at Chapel Hill16, Memorial Sloan Kettering Cancer Center17, University of New Mexico18, University of Barcelona19, University of Genoa20, University of Milan21, Military Medical Academy22, University of Bari23, National and Kapodistrian University of Athens24, University of Turin25, University of Parma26, University of Trieste27, University of Murcia28, Indiana University – Purdue University Indianapolis29, National Institutes of Health30, University of Ottawa31, University of Leeds32, University of London33
TL;DR: The pooled analysis of MC1R genetic data of young patients with melanoma showed thatMC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger.
11 citations
TL;DR: People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes.
Abstract: Background: People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes. Objective: We examined whether associations of these phenotypes with melanoma risk differed by ambient sun exposure or participant characteristics in two population-based, case–control studies with comparable ancestry but different ambient sun exposure. Methods: Data were analysed from 616 cases and 496 controls from the Australian Melanoma Family Study and 2012 cases and 504 controls from the Leeds (UK) case–control study. Questionnaire, interview and dermatological skin examination data were collected using the same measurement protocols. Relative risks were estimated as odds ratios using unconditional logistic regression, adjusted for potential confounders. Results: Hair and skin colour were the strongest pigmentary phenotype risk factors. All associations of pigmentary phenotype with melanoma risk were similar across countries. The median number of clinically assessed naevi was approximately three times higher in Australia than Leeds, but the relative risks for melanoma associated with each additional common or dysplastic naevus were higher for Leeds than Australia, especially for naevi on the upper and lower limbs. Higher naevus counts on the head and neck were associated with a stronger relative risk for melanoma for women than men. The two countries had similar relative risks for melanoma based on self-reported naevus density categories, but personal perceptions of naevus number differed by country. There was no consistent evidence of interactions between phenotypes on risk. Conclusions: Classifying people at high risk of melanoma based on their number of naevi should ideally take into account their country of residence, type of counts (clinical or self-reported), body site on which the naevus counts are measured and sex. The presence of naevi may be a stronger indicator of a genetic predisposition in the UK than in Australia based on less opportunity for sun exposure to influence naevus development.
10 citations
TL;DR: Using an efficient scalable approach to streamline GWAS follow-up functional studies, multiple candidate melanoma susceptibility genes and variants are identified and a pleiotropic function of MX2 is uncovered in melanomas susceptibility.
Abstract: Genome-wide association studies (GWAS) have identified ∼20 melanoma susceptibility loci. To identify susceptibility genes and variants simultaneously from multiple GWAS loci, we integrated massively-parallel reporter assays (MPRA) with cell type-specific epigenomic data as well as melanocyte-specific expression quantitative trait loci (eQTL) profiling. Starting from 16 melanoma loci, we selected 832 variants overlapping active regions of chromatin in cells of melanocytic lineage and identified 39 candidate functional variants displaying allelic transcriptional activity by MPRA. For four of these loci, we further identified four colocalizing melanocyte cis-eQTL genes (CTSS, CASP8, MX2, and MAFF) matching the allelic activity of MPRA functional variants. Among these, we further characterized the locus encompassing the HIV-1 restriction gene, MX2, on chromosome band Chr21q22.3 and validated a functional variant, rs398206, among multiple high LD variants. rs398206 mediates allelic transcriptional activity via binding of the transcription factor, YY1. This allelic transcriptional regulation is consistent with a significant cis-eQTL of MX2 in primary human melanocytes, where the melanoma risk-associated A allele of rs398206 is correlated with higher MX2 levels. Melanocyte-specific transgenic expression of human MX2 in a zebrafish model demonstrated accelerated melanoma formation in a BRAFV600E background. Thus, using an efficient scalable approach to streamline GWAS follow-up functional studies, we identified multiple candidate melanoma susceptibility genes and variants, and uncovered a pleiotropic function of MX2 in melanoma susceptibility.
8 citations
TL;DR: Early‐life tobacco smoke (ELTS) exposure is a major asthma risk factor and only a few genetic loci have been reported to interact with ELTS exposure in asthma.
Abstract: BACKGROUND Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. OBJECTIVE Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood. METHODS We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totalling 8273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analysed. RESULTS The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P = 4.3 × 10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P < 5 × 10-6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P = 4.9 × 10-7 ), 14q22 (rs7493885 near NIN; P = 2.9 × 10-6 ) and 2p22 (rs232542 near CYP1B1; P = 4.1 × 10-6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings. CONCLUSIONS AND CLINICAL RELEVANCE We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms.
7 citations
TL;DR: The SNPs showing interaction with ETS belong to the ATP8A1 and ABCA1 genes, which play a role in the maintenance of asymmetry and homeostasis of lung membrane lipids.
Abstract: Background A positional cloning study of bronchial hyper-responsiveness (BHR) at the 17p11 locus in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families showed significant interaction between early-life environmental tobacco smoke (ETS) exposure and genetic variants located in DNAH9 . This gene encodes the heavy chain subunit of axonemal dynein, which is involved with ATP in the motile cilia function. Our goal was to identify genetic variants at other genes interacting with ETS in BHR by investigating all genes belonging to the ‘ ATP-binding ’ and ‘ ATPase activity ’ pathways which include DNAH9, are targets of cigarette smoke and play a crucial role in the airway inflammation. Methods Family-based interaction tests between ETS-exposed and unexposed BHR siblings were conducted in 388 EGEA families. Twenty single-nucleotide polymorphisms (SNP) showing interaction signals (p ≤ 5.10 −3 ) were tested in the 253 Saguenay-Lac-Saint-Jean (SLSJ) families. Results One of these SNPs was significantly replicated for interaction with ETS in SLSJ families (p=0.003). Another SNP reached the significance threshold after correction for multiple testing in the combined analysis of the two samples (p=10 −5 ). Results were confirmed using both a robust log-linear test and a gene-based interaction test. Conclusion The SNPs showing interaction with ETS belong to the ATP8A1 and ABCA1 genes, which play a role in the maintenance of asymmetry and homeostasis of lung membrane lipids.
4 citations