Publications.

Shengjie Ying, Peter Y F Zeng, Kevin Fung, Halema Khan, Matthew J Cecchini, Patrick MacInnis, Jennifer Anderson, Amir H Karimi, MohdWessam Al Jawhri, Harrison Pan, Nhi Le, Krista Joris, Joe S Mymryk, Vanessa Dumeaux, John W Barrett, Anthony C Nichols, R Jun Lin; Canadian Airways Research Group of the Canadian Society of Otolaryngology Collaborative Research Initiative

Serial intralesional steroid injections (ILSIs) were associated with a significantly reduced risk of recurrence in idiopathic subglottic stenosis (HR=0.20 for time-to-first event; HR=0.44 for recurrent events). The median time to recurrence among those who received ILSIs was 2.5 years compared to 1.4 years.

Mohamed Meawad, Dalwinder Singh, Alice Deng, Rohan Sonthalia, Evelyn Cai, Vanessa Dumeaux

Analyzing 9,838 whole-genome metagenomic samples from healthy adults across 29 countries, we identified three distinct functional archetypes defining the boundaries of the gut microbiome's functional space. Archetype 1 is enriched in sugar metabolism; Archetype 2 in fatty acid metabolism; Archetype 3 in amino acid and nitrogen metabolism. Functional archetypes emerged as potential confounders in disease-associated microbial signatures including type-2 diabetes, colorectal cancer, and IBD.

Eliseos J Mucaki, Wenhan Zhang, Aryamaan Saha, Sabina Trebinjac, Sharon Nofech-Mozes, Eileen Rakovitch, Vanessa Dumeaux, Michael T Hallett

FFPE-derived RNA-seq data have a high rate of transcript dropout. We introduce PREFFECT, a probabilistic framework for the analysis of fRNA-seq data. PREFFECT uses generative models to fit distributions to observed expression counts while adjusting for technical and biological variables. The framework exploits multiple expression profiles from matched tissues and leverages sample-sample adjacency networks with graph attention mechanisms.

Noor Rizvi, Eliseos J. Mucaki, Emily L. Salmini, Monica Zhang, Sabina Trebinjac, Ezra Hahn, Lawrence Paszat, Sharon Nofech-Mozes, Michael T. Hallett, Eileen Rakovitch, Vanessa Dumeaux

Through whole-exome sequencing of 147 DCIS cases, we characterized the genomic landscape of pure DCIS and identified genetic alterations associated with the risk of recurrence. DCIS lesions harbored frequent mutations in established cancer drivers (PIK3CA, TP53) that lacked prognostic value. Five genes (SH2B2, PDZD8, MYO7A, MUCL3, DNASE2B) were significantly associated with 10-year risk of local recurrence. We identified distinct molecular programs underlying in-situ versus invasive recurrence.

Shengjie Ying, Peter Y F Zeng, Kevin Fung, Halema Khan, Matthew J Cecchini, Elissa Woo, Jennifer Anderson, Patrick MacInnis, Amir H Karimi, MohdWessam Al Jawhri, Harrison Pan, Nhi Le, Krista Joris, Rui Wen, Joe S Mymryk, Richard Inculet, Vanessa Dumeaux, John W Barrett, Anthony C Nichols, R Jun Lin; Canadian Airways Research Group of the Canadian Society of Otolaryngology Collaborative Research Initiative

Transcriptomic profiling of 56 female iSGS patients showed that lower recurrence rates are associated with retention of respiratory cilia, while adaptive immune responses and increased extracellular matrix deposition are present in those with higher recurrence rates, suggesting pathways for prognostic markers and therapeutic targets.

Anne-Sophie Pepin, Patrycja A Jazwiec, Vanessa Dumeaux, Deborah M SlobodaSarah Kimmins

Paternal obesity corresponded with altered sperm H3K4me3 at promoters of genes involved in metabolism and development. Altered sperm H3K4me3 was also localized at placental enhancers. Paternal obesity was linked to impaired placenta development with altered trophoblast cell lineage specification, implicating paternal obesity effects on placenta as a developmental route to offspring metabolic disease.

Ariane Lismer, Xiaojian Shao^, Marie-Charlotte Dumargne^, Christine Lafleur, Romain Lambrot, Donovan Chan, Gunnar Toft, Jens Peter Bonde, Amanda J. MacFarlane, Riana Bornman, Natalie Aneck-Hahn, Sean Patrick, Janice M. Bailey, Christiaan de Jager, Vanessa Dumeaux†, Jacquetta M. Trasler†, and Sarah Kimmins†

In 50 VhaVenda South African men and 47 Greenlandic Inuit men, serum p,p′-DDE levels associated with dose-responsive differences in sperm DNA methylation and H3K4me3 at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of altered regions was predicted to persist into the pre-implantation embryo and be associated with embryonic gene expression.

Shawn Simpson, Van Bettauer, Arthi Ramachandran, Susanne Kramer, Susan Mahon, Monica Medina, Yvonne Valles, Vanessa Dumeaux, Henri Valles, David Walsh, Michael T Hallett

We studied the microbiome of two Barbadian coral reef sites differing in urbanization. The less urbanized site had a strong concentration of phototrophs; the more urbanized location was enriched for copiotrophs, macroalgal symbionts, and marine-related disease-bearing organisms, concordant with profiles of warm ocean surface waters.

Vanessa Dumeaux†, Samira Massahi, Van Bettauer, Austin Mottola, Anna Dukovny, Sanny Khurdia, Anna Carolina Borges Pereira Costa, Raha Parvizi Omran, Shawn Simpson, Jinglin Lucy Xie, Malcolm Whiteway, Judith Berman, Michael T Hallett†

Using nanoliter droplet-based transcriptomics, we profiled thousands of individual C. albicans cells. At two days post-fluconazole exposure, surviving cells bifurcate into two subpopulations: one enriched for ribosomal proteins and mitochondrial respiration (Ribo-dominant, Rd), and one enriched for stress responses (Stress-dominant, Sd). The Ribosome Assembly Stress Response (RASTR) is activated in these subpopulations and may facilitate cell survival.

Van Bettauer, Anna Carolina Borges Pereira Costa, Raha P Omran, Samira Massahi, Eftyhios Kirbizakis, Shawn Simpson, Vanessa Dumeaux, Chris Law, Malcolm Whiteway, Michael T Hallett

Candescence automatically detects C. albicans cells from DIC microscopy and labels each with one of nine morphologies using a fully convolutional one-stage object detector with a novel cumulative curriculum-based learning strategy. Generative adversarial networks capture morphological plasticity with genetically modified strains. Candescence achieves ~85% recall and 81% precision.

Anne-Sophie Pepin, Christine Lafleur, Romain Lambrot, Vanessa Dumeaux, Sarah Kimmins

Obesity-induced alterations in H3K4me3 occurred in genes implicated in metabolic, inflammatory, and developmental processes associated with offspring metabolic dysfunction. Transgenerational susceptibility to metabolic disease was only observed when obese F0 had a pre-existing modified sperm epigenome, coinciding with increased H3K4me3 alterations in sperm and more severe phenotypes in offspring.

Van Bettauer, Anna Carolina Borges Pereira Costa, Raha P Omran, Samira Massahi, Eftyhios Kirbizakis, Shawn Simpson, Vanessa Dumeaux, Chris Law, Malcolm Whiteway, Michael T Hallett

Candescence detects C. albicans cells from DIC microscopy and labels each with one of nine morphologies using a fully convolutional one-stage object detector trained with a novel cumulative curriculum-based strategy. Generative adversarial networks capture the essence of each morphology and identify subcomponents of the latent space that control technical variables, developmental trajectories, and morphological switches.

Ariane Lismer, Romain Lambrot, Christine Lafleur, Vanessa Dumeaux, Sarah Kimmins

A detailed protocol for tracking sperm chromatin intergenerationally by ChIP-seq, and for probing pre-implantation embryo chromatin and gene expression. Emphasizes how to obtain high-quality, quantifiable datasets from low-input sperm and embryos, and highlights the limitations of working at such scale.

Anne-Sophie Pepin, Christine Lafleur, Romain Lambrot, Vanessa Dumeaux, Sarah Kimmins

Using a genetic model of epigenetic inheritance, obesity-induced alterations in sperm H3K4me3 associated with offspring phenotypes and corresponded to embryonic and placental chromatin profiles and gene expression. Transgenerational susceptibility was only observed when grandsires had a pre-existing genetic predisposition to metabolic dysfunction.

Ariane Lismer, Vanessa Dumeaux, Christine Lafleur, Romain Lambrot, Julie Brind'Amour, Matthew C. Lorincz, Sarah Kimmins

A folate-deficient diet alters H3K4me3 in sperm at developmental genes and putative enhancers. A subset of H3K4me3 alterations in sperm are retained in the pre-implantation embryo and associated with deregulated embryonic gene expression. Paternal H3K4me3 is transmitted to the embryo and influences gene expression and development.

Romain Lambrot, Donovan Chan, Xiaojian Shao, Mahmoud Aarabbi, Toni Kwan, Guillaume Bourque, Sergey Moskovtsev, Clifford Librach, Jacquetta Trasler, Vanessa Dumeaux", Sarah Kimmins". ("co-corresponding authors)

Deep sequencing of H3K4me3 and DNA methylation in 37 men shows H3K4me3 is localized throughout the genome at fertility and development genes, regions escaping epigenetic reprogramming, embryonic enhancers, and SINEs. Significant overlap in H3K4me3 and DNA methylation suggests an interplay between marks previously reported to be mutually exclusive in sperm.

Renee J. Tamming, Vanessa Dumeaux, Yan Jiang,, Sarfraz Shafiq, Luana Langlois, Jacob Ellegood, Lily R. Qiu, Jason P. Lerch, Nathalie G. Bérubé

Deletion of neuronal Atrx leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and male-specific impairments in long-term contextual memory linked to altered miR-137 levels. ATRX directly binds the miR-137 locus; the suppressive histone mark H3K27me3 is significantly reduced upon ATRX loss.

Van Bettauer, Samira Massahi, Sanny Khurdia, CAnna Carolina Borges Pereira Costa, Raha Parvizi Omran, Nassim Khosravi, Shawn Simpson, Mathieu Harb, Vanessa Dumeaux, Malcolm Whiteway, Michael T Hallett

Using a modified nanolitre droplet-based single-cell RNA-seq protocol, thousands of C. albicans cells were profiled after exposure to fluconazole, caspofungin or nystatin. Tolerant cells partition into distinct subpopulations with unique regulatory survival strategies; those that reach resistance show coordinated multivariate epigenetic responses engaging efflux pumps, chaperones, transport, and cell wall maintenance. Live-cell fluorescent imaging validated which molecular responses most often led to survival.

Gargi Jaju Bhattad, Mariyan J. Jeyarajah, Megan G. McGill, Vanessa Dumeaux, Hiroaki Okae, Takahiro Arima, Patrick Lajoie, Nathalie G. Bérubé, Stephen Renaud

Human syncytiotrophoblast development is associated with deacetylation of multiple core histone residues; ChIP-seq reveals dynamic H3 acetylation changes at TEAD4, TP63, OVOL1, CGB, and at novel trophoblast regulators LHX4 and SYDE1. Both pharmacological and genetic inhibition of HDACs blocks trophoblast fusion, with HDAC1 and HDAC2 identified as the critical mediators of cytotrophoblast differentiation.

Ariane Lismer', Keith Siklenka', Christine Lafleur, Vanessa Dumeaux", Sarah Kimmins". ('co-first authors ; "co-corresponding authors)

In KDM1A transgenic males with altered sperm epigenomes, specific changes in H3K4me3 enrichment were identified that predominantly occurred independently from bivalent regions. Many regions with altered H3K4me3 in sperm were identified on the paternal allele of the pre-implantation embryo, suggesting sperm H3K4me3 functions in transgenerational phenotype transmission.

Renee J. Tamming, Vanessa Dumeaux, Luana Langlois, Jacob Ellegood, Lily R. Qiu, Yan Jiang, Jason P. Lerch, Nathalie G. Bérubé

Ablation of the ATRX chromatin remodeler in forebrain excitatory neurons causes male-specific deficits in long-term spatial memory, associated with miR-137 overexpression, transcriptional changes, and structural alterations at CA1 synapses. Preprint version of the Cell Reports 2020 paper.

Bjørn Fjukstad, Vanessa Dumeaux, Michael Hallett, Lars Ailo Bongo

We built walrus, a system to support reproducible analyses for iteratively developed analysis pipelines. walrus leverages software containers for reproducible execution environments and integrates with modern version control systems to capture provenance of data and pipeline parameters.

Anna Carolina Borges Pereira Costa, Raha Parvizi Omran, Tuana Oliveira Correia-Mesquita, Vanessa Dumeaux, Malcolm Whiteway

Twenty-nine conditional mutants were identified from GRACE library screening for biofilm defects. The ILS1 conditional strain was unable to grow as yeast-phase cells but capable of producing tridimensional biofilm structure despite reduced metabolic activity, relying on classical biofilm genes while differentially inducing adhesion and protein synthesis genes.

Eileen Rakovitch, Rinku Sutradhar, Michael Hallett, Alastair M Thompson, Sumei Gu, Vanessa Dumeaux, Timothy J Whelan, Lawrence Paszat

LR risk peaked at 2 years, declined until year 7, then remained steady. RT was associated with reduction in early LR risk (HR=0.52) but did not reduce late LR risk (HR=0.89), demonstrating the time-varying nature of radiotherapy benefit in DCIS.

Amjad Islam, Faiza Tebbji, Jaideep Mallick, Hannah Regan, Vanessa Dumeaux, Raha Parvizi Omran, Malcolm Whiteway

Screening the GRACE conditional library identified 69 C. albicans mutants that trigger invasive filamentation when repressed; strikingly, the SUMO E3 ligase Mms21 and other members of the sumoylation pathway all fall into this group. Mms21-null mutants show invasive filamentation even without Efg1, upregulate hyphal-specific genes (ECE1, HWP1, ALS1/3, HGC1, …), and become sensitive to genotoxic, cell-wall, thermal and antifungal stressors — placing SUMOylation at the center of C. albicans differentiation and stress response.

Bjørn Fjukstad, Vanessa Dumeaux, Michael Hallett, Lars Ailo Bongo

walrus supports reproducible analyses for iteratively developed bioinformatics pipelines by combining software containers (for reproducible execution environments) with modern version control (to capture the provenance of data and pipeline parameters). Designed for the single servers and small clusters typical in clinical precision-medicine settings, and validated on a patient's primary tumor, adjacent normal tissue, and metastatic lesions.

Tatiana Traboulsi, Mohamed El Ezzy, Vanessa Dumeaux, Eric Audemard, Sylvie Mader

Pure antiestrogens like fulvestrant induce transient ERα binding followed by rapid release from DNA (30–40 min), accompanied by SUMO2/3 marks at ERα target regions and chromatin closure. Depleting SUMOylation via SENP1 overexpression, or the V534E mutation found in a hormone-resistant breast metastasis, prevents ERα sumoylation and de-represses estrogen target genes — identifying SUMOylation as a mechanistic distinction between pure antiestrogens and SERMs.

Bjørn Fjukstad, Vanessa Dumeaux, Karina Standahl Olsen, Eiliv Lund, Michael Hallett, Lars Ailo Bongo

A microservice-based architecture, with components packaged in software containers, enables composable interactive data exploration tools in systems biology. Demonstrated through MIxT blood-tumor, a web application for exploring and comparing transcriptional profiles from blood and matched tumor samples in breast cancer patients.

E R Paquet, R Lesurf, A Tofigh, V Dumeaux, M T Hallett

AIPS can identify the activation status of 1733 biological processes from an individual breast cancer microarray or RNA-seq profile without recourse to a broad cohort. AIPS is stable — the inferred pathway state is not affected by dataset composition. 74.5% of models distinguish luminal A from luminal B cancer.

Vanessa Dumeaux, Bjørn Fjukstad, Hans E Fjosne, Jan-Ole Frantzen, Marit Muri Holmen, Enno Rodegerdts, Ellen Schlichting, Anne-Lise Børresen-Dale, Lars Ailo Bongo, Eiliv Lund, Michael Hallett

We profiled RNA in blood and matched tumor from 173 breast cancer patients and designed MIxT (Matched Interactions Across Tissues) to systematically explore and link molecular processes expressed in each tissue. MIxT confirmed that processes active in the patient systemic response are especially relevant to BC immunogenicity, with subtype-specific patterns of interaction across tissues.

Vanessa Dumeaux, Josie Ursini-Siegel, Arnar Flatberg, Hans E Fjosne, Jan-Ole Frantzen, Marit Muri Holmen, Enno Rodegerdts, Ellen Schlichting, Eiliv Lund

Many genes in peripheral blood cells show differential expression when untreated breast cancer is present. We constructed a 50-gene signature distinguishing BC patients from population-based controls, characterized by underexpression of immune-specific pathways and universal cell programs driven by MYC.

Oxana Gavrilyuk, Tonje Braaten, Guri Skeie, Elisabete Weiderpass, Vanessa Dumeaux, Eiliv Lund

Among 97,926 postmenopausal NOWAC women (462 incident endometrial cancers, 10.9-year follow-up), drinking ≥8 cups/day of coffee was associated with a 48% reduction in endometrial cancer risk (HR=0.52, 95% CI 0.34–0.79), independent of filtered vs boiled brewing method. The risk reduction was strongest in overweight women (BMI ≥25) and in current smokers.

Ali Tofigh, Matthew Suderman, Eric R Paquet, Julie Livingstone, Nicholas Bertos, Sadiq M Saleh, Hong Zhao, Margarita Souleimanova, Sean Cory, Robert Lesurf, Solmaz Shahalizadeh, Norberto Garcia Lopez, Yasser Riazalhosseini, Atilla Omeroglu, Josie Ursini-Siegel, Morag Park, Vanessa Dumeaux, Michael Hallett

The ubiquity of prognostic signatures in breast cancer is an apparition caused by poor understanding of the interrelatedness between subtype and molecular determinants of prognosis. Our approach identifies inherently difficult patients (~7% of BC) predicted to have good outcome but who experience distant metastasis within 5 years.

Hege Landmark-HøyvikVanessa Dumeaux, Daniel Nebdal, Eiliv Lund, Jörg Tost, Yoichiro Kamatani, Victor Renault, Anne-Lise Børresen-Dale, Vessela Kristensen, Hege Edvardsen

Expression-QTL analysis in blood from 288 breast cancer survivors identified SNPs in 100 genes associated with expression of human leukocyte antigen (HLA) genes. These associations were largely absent in 81 healthy women, and the survivor-specific associations were enriched for immune-system processes — suggesting the immune constitution of BC survivors differs systematically from that of healthy controls.

Rebecca Ritte, Kaja Tikk, Annekatrin Lukanova, Anne Tjønneland, Anja Olsen, Kim Overvad, Laure Dossus, Agnès Fournier, Françoise Clavel-Chapelon, Verena Grote, Heiner Boeing, Krasimira Aleksandrova, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, Domenico Palli, Franco Berrino, Amalia Mattiello, Rosario Tumino, Carlotta Sacerdote, José Ramón Quirós, Genevieve Buckland, Esther Molina-Montes, María-Dolores Chirlaque, Eva Ardanaz, Pilar Amiano, H Bas Bueno-de-Mesquita, Carla H van Gils, Petra Hm Peeters, Nick Wareham, Kay-Tee Khaw, Timothy J Key, Ruth C Travis, Elisabete Weiderpass, Vanessa Dumeaux, Eliv Lund, Malin Sund, Anne Andersson, Isabelle Romieu, Sabina Rinaldi, Paulo Vineis, Melissa A Merritt, Elio Riboli, Rudolf Kaaks

Among EPIC women (998 ER−PR− and 3,567 ER+PR+ breast cancers), later age at first full-term childbirth increased ER+PR+ risk (HR=1.47 for ≥35 vs ≤19) but not ER−PR− risk (p=0.03 for heterogeneity). Menarcheal age and time between menarche and first full-term birth showed similar-direction but weaker associations with ER−PR− tumors, supporting partially shared etiology across hormone-receptor subtypes.

C A González, F Megraud, A Buissonniere, L Lujan Barroso, A Agudo, E J Duell, M C Boutron-Ruault, F Clavel-Chapelon, D Palli, V Krogh, A Mattiello, R Tumino, C Sacerdote, J R Quirós, E Sanchez-CantalejoC Navarro, A Barricarte, M Dorronsoro, K-T Khaw, N Wareham, N E Allen, K K Tsilidis, H Bas Bueno-de-Mesquita, S M Jeurnink, M E Numans, P H M Peeters, P Lagiou, E ValanouA Trichopoulou, R Kaaks, A Lukanova-McGregor, M M Bergman, H Boeing, J Manjer, B Lindkvist, R Stenling, G Hallmans, L M Mortensen, K Overvad, A Olsen, A Tjonneland, K Bakken, V Dumeaux, E LundM Jenab, I Romieu, D Michaud, T Mouw, F Carneiro, C Fenge, E Riboli

In a nested case-control from the Eurogast-EPIC cohort (88 noncardia gastric cancers, 338 controls), western-blot immunoblot detected 93.2% of cases as H. pylori positive versus 88.6% by ELISA; the resulting odds ratio for noncardia gastric cancer tripled (21.4 vs 6.8). Supports H. pylori infection as a near-necessary condition for noncardia gastric cancer once detection accounts for antibody clearance during atrophy.

Hege Landmark-Høyvik, Vanessa Dumeaux, Kristin V Reinertsen, Hege Edvardsen, Sophie D Fosså, Anne-Lise Børresen-Dale

To extend knowledge on the mechanisms and pathways involved in maintenance of radiation-induced fibrosis (RIF) by performing gene expression profiling of whole blood from breast cancer (BC) survivors with and without…

Anke M Leufkens, Fränzel J B Van Duijnhoven, Peter D Siersema, Hendriek C Boshuizen, Alina Vrieling, Antonio Agudo, Inger T Gram, Elisabete Weiderpass, Christina Dahm, Kim Overvad, Anne Tjønneland, Anja Olsen, Marie-Christine Boutron-Ruault, Françoise Clavel-Chapelon, Sophie Morois, Domenico Palli, Sara Grioni, Rosario Tumino, Charlotta Sacerdote, Amalia Mattiello, Silke Herman, Rudolf Kaaks, Annika Steffen, Heiner Boeing, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, Petra H Peeters, Carla H van Gils, Henk van Kranen, Eliv Lund, Vanessa Dumeaux, Dagrun Engeset, Laudina Rodríguez, Maria-José Sánchez, Maria-Dolores Chirlaque, Aurelio Barricarte, Jonas Manjer, Martin Almquist, Bethany van Guelpen, Göran Hallmans, Kay-Tee Khaw, Nick Wareham, Konstantinos K Tsilidis, Kurt Straif, Maria Leon-Roux, Paul Vineis, Teresa Norat, Elio Riboli, H Bas Bueno-de-Mesquita

Among 465,879 EPIC participants (2,741 colorectal cancers, mean 8.7-year follow-up), ever smoking conferred a 1.18-fold hazard of colon carcinoma, with the excess risk concentrated in the proximal colon rather than distal colon or rectum (p=0.02 for heterogeneity). Twenty or more years of cessation returned risk to that of never smokers.

Kjersti Bakken, Agnès Fournier, Eiliv Lund, Marit Waaseth, Vanessa Dumeaux, Françoise Clavel-Chapelon, Alban Fabre, Bertrand Hémon, Sabina Rinaldi, Véronique Chajes, Nadia Slimani, Naomi E Allen, Gillian K Reeves, Sheila Bingham, Kay-Tee Khaw, Anja Olsen, Anne Tjønneland, Laudina Rodriguez, Maria-José Sánchez, Pilar Amiano Etxezarreta, Eva Ardanaz, Maria-José Tormo, Petra H Peeters, Carla H van Gils, Annika Steffen, Mandy Schulz, Jenny Chang-Claude, Rudolf Kaaks, Rosario Tumino, Valentina Gallo, Teresa Norat, Elio Riboli, Salvatore Panico, Giovanna Masala, Carlos A González, Franco Berrino

Among 133,744 EPIC postmenopausal women (4,312 incident breast cancers), current estrogen-only MHT conferred RR=1.42 and current combined MHT RR=1.77. Continuous combined regimens carried 43% higher risk than sequential regimens; risk did not differ by route of administration or by estrogen compound, highlighting the progestin regimen as the dominant driver.

Marit Waaseth, Karina S Olsen, Charlotta Rylander, Eiliv Lund, Vanessa Dumeaux

In 285 postmenopausal NOWAC women, gene set analysis revealed a novel estradiol signature: 22 gene sets differed between high and low plasma estradiol (HT users excluded), including seven estrogen-related sets and seven immune-response sets. Eleven of 15 progesterone-associated sets overlapped with estradiol sets; no significant patterns were detected for testosterone, FSH or SHBG.

Charlotta Rylander, Vanessa Dumeaux, Karina Standahl Olsen, Marit Waaseth, Torkjel M Sandanger, Eiliv Lund

In 270 postmenopausal NOWAC women, whole-blood expression of two gene sets related to the citric acid cycle differed significantly between high (>30 ng/mL) and low PFOS serum groups — one of the first demonstrations in a general-population sample that persistent perfluoroalkyl exposures leave detectable signatures in circulating blood gene expression.

Vanessa Dumeaux, Karina S Olsen, Gregory Nuel, Ruth H Paulssen, Anne-Lise Børresen-Dale, Eiliv Lund

In 286 postmenopausal NOWAC women, whole-blood gene expression shifts caused by inter-individual and exposure factors are subtle and technical variability cannot be ignored. Despite small effect sizes, new candidate genes were identified as differentially expressed by fasting, BMI and smoking — establishing baseline normal variability and the feasibility of large population-based blood gene expression profiling.

Fangyi Gu, Fredrick R Schumacher, Federico Canzian, Naomi E Allen, Demetrius Albanes, Christine D Berg, Sonja I Berndt, Heiner Boeing, H Bas Bueno-de-Mesquita, Julie E Buring, Nathalie Chabbert-Buffet, Stephen J Chanock, Françoise Clavel-Chapelon, Vanessa Dumeaux, J Michael Gaziano, Edward L Giovannucci, Christopher A Haiman, Susan E Hankinson, Richard B Hayes, Brian E Henderson, David J Hunter, Robert N Hoover, Mattias Johansson, Timothy J Key, Kay-Tee Khaw, Laurence N Kolonel, Pagona Lagiou, I-Min Lee, Loic LeMarchand, Eiliv Lund, Jing Ma, N Charlotte Onland-Moret, Kim Overvad, Laudina Rodriguez, Carlotta Sacerdote, Maria-José Sánchez, Meir J Stampfer, Pär Stattin, Daniel O Stram, Gilles Thomas, Michael J Thun, Anne Tjønneland, Dimitrios Trichopoulos, Rosario Tumino, Jarmo Virtamo, Stephanie J Weinstein, Walter C Willett, Meredith Yeager, Shumin M Zhang, Rudolf Kaaks, Elio Riboli, Regina G Ziegler, Peter Kraft

In >5,500 Caucasian men and >5,500 women from the Breast and Prostate Cancer Cohort Consortium, 302 tag SNPs in 18 IGF-pathway genes were tested against circulating IGF-I and IGFBP-3. SNPs in IGF1 and SSTR5 influenced IGF-I levels; SNPs in IGFBP3 and IGFALS influenced IGFBP-3. But multi-SNP predictors explained only 0.6–3.9% of variance and did not associate with prostate or breast cancer risk.

Jørgen Aarøe, Torbjørn Lindahl, Vanessa Dumeaux, Solve Saebø, Derek Tobin, Nina Hagen, Per Skaane, Anders Lönneborg, Praveen Sharma, Anne-Lise Børresen-Dale

In 121 women referred for diagnostic mammography (67 with breast cancer, 54 without) plus 9 healthy controls, a 738-probe blood gene-expression signature discriminated cancer from non-cancer with 79.5% accuracy (sensitivity 80.6%, specificity 78.3%). Deregulated genes related to defense response, translation, and lipid/steroid metabolism — supporting peripheral blood as an informative tissue for early BC detection.

Birgit Hoeft, Jakob Linseisen, Lars Beckmann, Karin Müller-Decker, Federico Canzian, Anika Hüsing, Rudolf Kaaks, Ulla Vogel, Marianne U Jakobsen, Kim Overvad, Rikke D Hansen, Sven Knüppel, Heiner Boeing, Antonia Trichopoulou, Yvoni Koumantaki, Dimitrios Trichopoulos, Franco Berrino, Domenico Palli, Salvatore Panico, Rosario Tumino, H B Bueno-de-Mesquita, Fränzel J B van Duijnhoven, Carla H van Gils, Petra H Peeters, Vanessa Dumeaux, Eiliv Lund, José M Huerta Castaño, Xavier Muñoz, Laudina Rodriguez, Aurelio Barricarte, Jonas Manjer, Karin Jirström, Bethany Van Guelpen, Göran Hallmans, Elizabeth A Spencer, Francesca L Crowe, Kay-Tee Khaw, Nick Wareham, Sophie Morois, Marie-Christine Boutron-Ruault, Françoise Clavel-Chapelon, Veronique Chajes, Mazda Jenab, Paolo Boffetta, Paolo Vineis, Traci Mouw, Teresa Norat, Elio Riboli, Alexandra Nieters

Among 1,225 colorectal cancer cases and 2,032 EPIC controls, 392 tag SNPs in 43 fatty-acid metabolism genes were genotyped. Variants in HPGD, PLA2G6 and TRPV3 were associated with higher CRC risk while PTGER2 variants were associated with lower risk; haplotype analyses reinforced prostanoid signaling as a key pathway in colon carcinogenesis.

Laure Dossus, Naomi Allen, Rudolf Kaaks, Kjersti Bakken, Eiliv Lund, Anne Tjonneland, Anja Olsen, Kim Overvad, Francoise Clavel-Chapelon, Agnes Fournier, Nathalie Chabbert-Buffet, Heiner Boeing, Madlen Schütze, Antonia Trichopoulou, Dimitrios Trichopoulos, Pagona Lagiou, Domenico Palli, Vittorio Krogh, Rosario Tumino, Paolo Vineis, Amalia Mattiello, H Bas Bueno-de-Mesquita, N Charlotte Onland-Moret, Petra H M Peeters, Vanessa Dumeaux, Maria-Luisa Redondo, Eric Duell, Emilio Sanchez-Cantalejo, Larraitz Arriola, Maria-Dolores Chirlaque, Eva Ardanaz, Jonas Manjer, Signe Borgquist, Annie Lukanova, Eva Lundin, Kay-Tee Khaw, Nicholas Wareham, Tim Key, Veronique Chajes, Sabina Rinaldi, Nadia Slimani, Traci Mouw, Valentina Gallo, Elio Riboli

Among 302,618 EPIC women (1,017 incident endometrial cancers), late menarche, early menopause, past OC use, high parity, and short time since last full-term pregnancy were each independently associated with reduced endometrial cancer risk. After mutual adjustment, menstrual-life factors gave 7–8% risk reduction per year while cumulative full-term-pregnancy duration gave 22% per year — consistent with a dominant role for hormonal mechanisms in endometrial carcinogenesis.

Sabina Rinaldi, Rebecca Cleveland, Teresa Norat, Carine Biessy, Sabine Rohrmann, Jakob Linseisen, Heiner Boeing, Tobias Pischon, Salvatore Panico, Claudia Agnoli, Domenico Palli, Rosario Tumino, Paolo Vineis, Petra H M Peeters, Carla H van Gils, Bas H Bueno-de-Mesquita, Alina Vrieling, Naomi E Allen, Andrew Roddam, Sheila Bingham, Kay-Tee Khaw, Jonas Manjer, Signe Borgquist, Vanessa Dumeaux, Inger Torhild Gram, Eiliv Lund, Antonia Trichopoulou, Georgios Makrygiannis, Vassiliki Benetou, Esther Molina, Ignacio Donate Suárez, Aurelio Barricarte Gurrea, Carlos A Gonzalez, Maria-Jose Tormo, Jone M Altzibar, Anja Olsen, Anne Tjonneland, Henning Grønbaek, Kim Overvad, Françoise Clavel-Chapelon, Marie-Christine Boutron-Ruault, Sophie Morois, Nadia Slimani, Paolo Boffetta, Mazda Jenab, Elio Riboli, Rudolf Kaaks

In the EPIC nested case-control (1,121 colorectal cancer cases, 1,121 matched controls), serum IGF-I and IGFBP-3 showed no overall association with CRC risk; modest positive associations appeared only in younger participants and in those with low milk intake. Pooled with 9 prior prospective studies, IGF-I conferred a modest 7% per-SD increase in overall CRC risk.

Hege Landmark-HøyvikKristin V Reinertsen, Jon H Loge, Vessela N Kristensen, Vanessa Dumeaux, Sophie D Fosså, Anne-Lise Børresen-Dale, Hege Edvardsen

Systematic review of 40 studies on the genetics and epigenetics of chronic fatigue and chronic fatigue syndrome. The literature implicates the HPA axis, the serotonergic system, and infectious agents, but most studies were underpowered and limited by phenotype heterogeneity — motivating larger integrative designs that combine SNPs, gene expression, and environmental context with functional validation.

Eiliv Lund, Vanessa Dumeaux

Position paper arguing that integrating causality across biology, epidemiology and multistage mathematical models requires a dynamic, functional description of carcinogenesis. Proposes using transcriptome and epigenome analyses from prospective cohorts — with somatic tumor data linked to blood-based surrogate profiles — to ground biological plausibility in observational human data and move toward true systems epidemiology.

H Landmark-Høyvik, K V Reinertsen, J H Loge, S D Fosså, A L Børresen-Dale, V Dumeaux

Whole-blood microarrays in breast cancer survivors 2–6 years post-diagnosis show that chronically fatigued survivors differ from non-fatigued peers in plasma- and B-cell-pathway gene sets, and carry higher circulating leukocyte, lymphocyte and neutrophil counts — implicating B-cell-mediated inflammation and immune activation in the biology of post-cancer chronic fatigue.

Zafer Barutcuoglu, Edoardo M Airoldi, Vanessa Dumeaux, Robert E Schapire, Olga G Troyanskaya

The heterogeneity of cancer cannot always be recognized by tumor morphology, but may be reflected by the underlying genetic aberrations.

Curtis Huttenhower, Erin M Haley, Matthew A Hibbs, Vanessa Dumeaux, Daniel R Barrett, Hilary A Coller, Olga G Troyanskaya

Regularized Bayesian integration of ~30,000 genome-scale experiments across ~25,000 human genes yields functional maps summarizing interactions in over 200 areas of human cellular biology, made interactively explorable through the HEFalMp web tool. Experimental follow-up confirmed novel roles for AP3B1, ATP6AP1, BLOC1S1, LAMP2 and RAB11A in the initiation of macroautophagy in amino-acid-starved fibroblasts.

Anders Lönneborg, Jørgen Aarøe, Vanessa Dumeaux, Anne-Lise Børresen-Dale

Review of emerging blood biomarkers — multicomponent protein panels, circulating tumor cells, and peripheral-blood RNA expression signatures — that may complement mammography for early breast cancer detection, with particular promise for younger women and those with dense breasts where imaging is least sensitive.

Vanessa Dumeaux, Eiliv Lund, Anne-Lise Børresen-Dale

Comparison of three globin RNA processing approaches (no reduction, PNA-based, and Ambion GlobinClear beads) on whole-blood samples using the Applied Biosystems microarray platform. PNA-based reduction yielded slight sensitivity gains at the cost of reproducibility, while the bead kit also lowered remaining cRNA — illustrating that globin reduction must be optimized per microarray system and was not beneficial on this platform.

Vanessa Dumeaux, Anne-Lise Børresen-Dale, Jan-Ole Frantzen, Merethe Kumle, Vessela N Kristensen, Eiliv Lund

Design paper for the NOWAC postgenome cohort: ~50,000 women born 1943–1957 provided PAXgene blood samples (2003–2006) within the broader NOWAC cohort (172,471 women), with matched tumor biopsies collected from incident breast cancer cases and matched controls. The design enables blood gene expression as a diagnostic test for breast cancer, surrogate-tissue biomonitoring of hormone exposures, and gene-environment analyses by molecular subtype.

Marit Waaseth, Kjersti Bakken, Vanessa Dumeaux, Karina S Olsen, Charlotta Rylander, Yngve Figenschau, Eiliv Lund

Cross-sectional validation of NOWAC postgenome cohort questionnaires in 425 women aged 48–62: users of systemic estradiol-containing HRT had plasma estradiol and FSH levels comparable to premenopausal women; oral E2 preparations raised SHBG, while vaginal E2 did not influence systemic levels. Questionnaire performance was strong (88–92% sensitivity and 87–100% specificity for current HRT use and menopausal status).

Eiliv Lund, Vanessa Dumeaux

Position paper proposing the 'globolomic' study design: extend prospective cohorts by collecting matched tumor and blood tissue at diagnosis so multiple -omics can be integrated into a new discipline of systems epidemiology. Using in vivo gene expression to verify mechanistic biology shifts the causality criterion of 'biological plausibility' from in vitro argument to human observational data.

Eiliv Lund, Kjersti Bakken, Vanessa Dumeaux, Vegard Andersen, Merethe Kumle

Among 30,118 postmenopausal NOWAC women (540 incident breast cancers), current HRT conferred higher breast cancer risk in former OC users (RR=2.45) than in never OC users (RR=1.67, p=0.002 for difference). The elevation held for both estrogen-only and estrogen-plus-progestin HRT, with substantial public-health implications as the proportion of postmenopausal women with prior OC use continues to grow.

Vanessa Dumeaux, Jostein Johansen, Anne-Lise Børresen-Dale, Eiliv Lund

In 100 postmenopausal NOWAC women (50 HRT users, 50 non-users), whole-blood microarrays did not yield a signature that accurately predicted HRT exposure (LOO error rate 0.40), even in the continuous-combined subgroup (0.26). Effect sizes in whole blood after HRT use are small, motivating more quantitative platforms and larger samples, though modest enrichment of receptor/transporter, immune and metabolic processes was detected.

Vanessa Dumeaux, Agnès Fournier, Eiliv Lund, Françoise Clavel-Chapelon

In a French cohort of 68,670 postmenopausal women (1,405 incident breast cancers), ever-use of oral contraceptives was associated with a non-significant ~10% decrease in postmenopausal breast cancer risk, with no significant interaction with HRT. Risk decreased significantly with increasing time since first OC use (p-trend=0.01), suggesting the induction window for OC-related risk closes by postmenopause.

Pedro Kringen, Yun Wang, Vanessa Dumeaux, Jahn M Nesland, Gunnar Kristensen, Anne-Lise Borresen-Dale, Anne Dorum

Somatic TP53 mutations were profiled in ovarian carcinomas from 30 BRCA1 founder-mutation carriers (20 × 1675delA, 10 × 1135insA) and 100 sporadic cases. Familial cases were diagnosed a decade earlier than sporadic (49 vs 59 years); among women diagnosed at ≥50 years, sporadic cases trended toward better survival than familial — suggesting shared genetic factors beyond BRCA1 mutation type may shape ovarian cancer outcomes.

Vanessa Dumeaux, Eiliv Lund, Anette Hjartåker

In NOWAC (86,948 women, 1,130 invasive breast cancers), alcohol intake ≥10 g/day conferred a relative risk of 1.69 with a linear dose-response. A significant negative interaction between OC duration and alcohol was observed (p=0.01): excess risk from OC use appeared only among women with low alcohol consumption (<5 g/day), suggesting alcohol and OCs act antagonistically on breast cancer risk through a shared pathway.

Vanessa Dumeaux, Elin Alsaker, Eiliv Lund

In the prospective Norwegian Women and Cancer study (NOWAC; 96,362 women, 851 incident breast cancers), ever-use of oral contraceptives conferred a 25% higher adjusted breast cancer risk, with risk rising with duration of use and with cumulative levonorgestrel dose. The multivariate analysis implicates the estrogen component as the primary driver (significant trend with milligram-months of estrogen exposure, p=0.002).