Rationale:

Identifying the genes involved in cancer development leads to a greater understanding of the biological pathways involved in the carcinogenic process and, through the observation of gene–environment interactions, can elucidate how environmental factors exert their effects. It also has increasing utility in risk management, detection, diagnosis, and the clinical management of many types of cancer. Within its research goals, the Genetic Cancer Susceptibility Group (GCS) aims to describe the genes involved in cancer susceptibility and development and, subsequently, how they exert their effects. GCS uses a multidisciplinary genomic approach, integrating data from genetics, pathology, epidemiology, and multi-genomic techniques to assist the Group's research.

GCS works on common cancers, such as lung cancer, but tends to focus on rare cancers, such as those of the head and neck (including oesophageal and nasopharyngeal cancers), kidney and thoracic tumours, and lymphomas. In addition, GCS is exploring the potential for genomic techniques to be used as measures of circulating genomic biomarkers, testing their utility as mechanisms of minimally invasive early detection and surveillance of cancer.

The final role of GCS is to support the Agency's capacity in genomics. GCS aims to adapt laboratory, pathology, and bioinformatics-related genomic techniques to suit IARC's particular needs and mission, and to support genomics-related activities across the Agency through the Genetics Platform (GSP).

Objectives:

The main objective of GCS's research interests is to investigate the influence of genetic variation on cancer etiology: to identify the genes involved, the mechanisms by which genetic variants exert their effect, and how they interact with environmental factors. To achieve this, GCS scientists with backgrounds in genetics, genomics, bioinformatics, and pathology work together to develop innovative genomics-based study designs. The objective of GCS is therefore to develop multidisciplinary genomic applications, including:

  • Laboratory: Optimization of laboratory workflows and quality control procedures for the particular setting of samples collected across a variety of settings.
  • Pathology: Ensuring appropriate morphological review, adapting sampling methods to ensure that the relevant tissue types are available for study, and making the link between morphological and molecular features.
  • Computational science: Developing and implementing the bioinformatics resources required for the analysis of the genomics data. GCS develops methods that enable the integration of these multi-layered genomics data and, ideally, augment the more traditional analysis approaches.

  • GCS then applies these methods in epidemiological studies, particularly within large international consortia. An example is GCS's recent work in the lung cancer OncoArray project as part of the Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative. First, GCS used its genetics and bioinformatics skills to harmonize, combine, and analyse very large genetic datasets across multiple studies. Second, GCS used its laboratory skills to confirm the veracity of the findings arising from this first analysis by confirming the fidelity of genotyping results. Finally, GCS explored the functional effects by using genomic measures to determine the functional effects of these genetic variants.

    GCS continues to undertake this type of study but also focuses on the genomic analysis of exceptional samples identified within these large studies; examples are patients who have inherited susceptibility alleles, nasopharyngeal cancers that arise in patients who have consumed large amounts of salted fish in South-East Asia, and multi-omics studies of very rare lung neuroendocrine neoplasms and mesothelioma collected across multicentre studies.

    The other major objective of GCS is the Group's responsibilities regarding genomics at the Agency. Here, the focus is on the adaptation of genomic techniques to suit IARC's particular needs and mission, while ensuring their optimal application and cost-effectiveness. These techniques are applied in GCS's research and, through the Genetics Platform (GSP), also in scientific activities across IARC. The GSP makes these genomic techniques accessible to IARC scientific groups and provides support throughout the complete project life-cycle, including planning, execution, quality control, and subsequent analysis. Working closely with various IARC committees (Laboratory Steering Committee [LSC] and Computational Biology, Bioinformatics, and Biostatistics [C3B] Steering Committee) and scientific groups, GCS also coordinates the development of the Agency's genomic and bioinformatics capacity and provides training at IARC and elsewhere, in these areas.


    Current Research Topics:


    • 1. Identify the genes involved in lung cancer susceptibility: GCS is using exome sequencing-based approaches and very large imputation-based genome-wide association studies (GWAS) to investigate genetic susceptibility to lung cancer. GCS also studies the lung tumours that arise in patients who have inherited lung cancer susceptibility alleles, to explore the impact that genetic susceptibility has on the subsequent tumour phenotype (supported by the United States National Cancer Institute [NCI], the French Institut National du Cancer [INCa], and France Génomique). GCS has similar interests in other types of cancer, particularly lymphomas.
    • 2. Explore the mechanisms by which genetic variants influence the carcinogenic process: Nasopharyngeal cancer is common in southern and eastern Asia, whereas it is relatively rare in Europe and North America. It has been linked with genetic susceptibility, consumption of salted fish (and nitrosamines), and exposure to Epstein–Barr virus (EBV). This project aims to investigate how these three factors interact to influence the carcinogenic process (supported by the World Cancer Research Fund).
    • 3. Test the utility of circulating tumour DNA (ctDNA) as a biomarker for detecting cancer at early stages: Using and further expanding the genomic tools that GCS has developed for detecting low-abundance ctDNA mutations, GCS assesses the potential of tumour-derived alterations as an early biomarker in lung, oesophageal, and urinary bladder cancer, as well as exploring the prevalence of ctDNA in apparently healthy individuals (supported by the French INCa and La Ligue Nationale contre le Cancer, and the National Institute for Medical Research Development, Islamic Republic of Iran).
    • 4. Multi-omics molecular characterization of malignant pleural mesothelioma (MESOMICS): This project aims to compile a comprehensive molecular characterization of malignant mesothelioma. It is hoped that this may lead to a more comprehensive understanding of the disease, which will help improve its diagnosis, identify potential markers for early detection, and ultimately provide patients with more promising therapeutic options (supported by the French INCa and La Ligue Nationale contre le Cancer, and the French national mesothelioma biobank).
    • 5. Unveil the molecular pathways underlying the development of pulmonary carcinoids (LungNENomics): GCS is working within a multicentre study across 16 centres and 7 countries to put together material for a genomics study of these rare and understudied lung tumours. The main goal of this project is to generate comprehensive, multidisciplinary, and multi-omics datasets that will shed light on the pathogenesis of pulmonary carcinoids and that will thereby improve the diagnosis and clinical management of these diseases (supported by the United States NIH, the French INCa and La Ligue Nationale contre le Cancer, and the Dutch Cancer Society).
    • 6. Apply pathology in genetics and genomics studies: GCS also works towards optimizing morphological review, integrating and adapting sampling methods to ensure that the relevant tissue types are selected for genomic studies running across the Agency. As an example, GCS coordinates and manages the whole pathology workflow for the Mutographs project. This includes contributing to the development of operating protocols for multicentre sample collection, defining precise morphological criteria to be evaluated by the expert panel of pathologists via online review, and facilitating the linkage between morphological features and genomic findings. GCS also leads training initiatives in pathology within the Agency, as well as training in standardized sampling methods in several low- and middle-income countries.
    • 7. Develop computational biology tools: GCS aims to develop and implement the bioinformatics resources to analyse the genomics data and to then integrate these multi-layered genomics data into GCS studies. Sharing of bioinformatics pipelines takes place across IARC groups, and GCS is involved in coordinating the activities of the bioinformaticians nested within IARC's scientific groups. This focuses on ease of use, reproducibility, and portability, enabling analyses to be performed easily on personal computers, on high-performance computing clusters, or in the cloud. These developments are shared with the wider community as open-source projects (cf. https://github.com/IARCbioinfo/). This aspect is especially important to ensure that scientists from low- and middle-income countries can also benefit from IARC developments in bioinformatics, and GCS is working towards identifying how IARC can provide additional training in this context.

    • Recent Publications:

      1. George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Muller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmuller J, Becker C, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland A, Solberg S, Ansen S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sanger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Buttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L, Thomas RK. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nature communications. 2018;9(1):1048. 29535388. PMC5849599.

      2. McKay JD, Hung RJ, Han Y, Zong X, Carreras-Torres R, Christiani DC, Caporaso NE, Johansson M, Xiao X, Li Y, Byun J, Dunning A, Pooley KA, Qian DC, Ji X, Liu G, Timofeeva MN, Bojesen SE, Wu X, Le Marchand L, Albanes D, Bickeboller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Shen H, Hong YC, Yuan JM, Bertazzi PA, Pesatori AC, Ye Y, Diao N, Su L, Zhang R, Brhane Y, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman CA, Wilkens LR, Fernandez-Somoano A, Fernandez-Tardon G, van der Heijden HFM, Kim JH, Dai J, Hu Z, Davies MPA, Marcus MW, Brunnstrom H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Doherty JA, Barnett MP, Chen C, Goodman GE, Cox A, Taylor F, Woll P, Bruske I, Wichmann HE, Manz J, Muley TR, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd FA, Tsao MS, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Koh WP, Gao YT, Houlston RS, McLaughlin J, Stevens VL, Joubert P, Lamontagne M, Nickle DC, Obeidat M, Timens W, Zhu B, Song L, Kachuri L, Artigas MS, Tobin MD, Wain LV, Rafnar T, Thorgeirsson TE, Reginsson GW, Stefansson K, Hancock DB, Bierut LJ, Spitz MR, Gaddis NC, Lutz SM, Gu F, Johnson EO, Kamal A, Pikielny C, Zhu D, Lindstroem S, Jiang X, Tyndale RF, Chenevix-Trench G, Beesley J, Bosse Y, Chanock S, Brennan P, Landi MT, Amos CI. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nature genetics. 2017;49(7):1126-32. 28604730. PMC5510465.

      3. Anantharaman D, Abedi-Ardekani B, Beachler DC, Gheit T, Olshan AF, Wisniewski K, Wunsch-Filho V, Toporcov TN, Tajara EH, Levi JE, Moyses RA, Boccia S, Cadoni G, Rindi G, Ahrens W, Merletti F, Conway DI, Wright S, Carreira C, Renard H, Chopard P, McKay-Chopin S, Scelo G, Tommasino M, Brennan P, D’Souza G. Geographic heterogeneity in the prevalence of human papillomavirus in head and neck cancer. International journal of cancer. 2017;140(9):1968-75. 28108990.

      4. Wang Y, McKay JD, Rafnar T, Wang Z, Timofeeva MN, Broderick P, Zong X, Laplana M, Wei Y, Han Y, Lloyd A, Delahaye-Sourdeix M, Chubb D, Gaborieau V, Wheeler W, Chatterjee N, Thorleifsson G, Sulem P, Liu G, Kaaks R, Henrion M, Kinnersley B, Vallee M, Le Calvez-Kelm F, Stevens VL, Gapstur SM, Chen WV, Zaridze D, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Krokan HE, Gabrielsen ME, Skorpen F, Vatten L, Njolstad I, Chen C, Goodman G, Benhamou S, Vooder T, Valk K, Nelis M, Metspalu A, Lener M, Lubinski J, Johansson M, Vineis P, Agudo A, Clavel-Chapelon F, Bueno-de-Mesquita HB, Trichopoulos D, Khaw KT, Johansson M, Weiderpass E, Tjonneland A, Riboli E, Lathrop M, Scelo G, Albanes D, Caporaso NE, Ye Y, Gu J, Wu X, Spitz MR, Dienemann H, Rosenberger A, Su L, Matakidou A, Eisen T, Stefansson K, Risch A, Chanock SJ, Christiani DC, Hung RJ, Brennan P, Landi MT, Houlston RS, Amos CI. Corrigendum: Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nature genetics. 2017;49(4):651. 28358128.

      5. Le Calvez-Kelm F, Foll M, Wozniak MB, Delhomme TM, Durand G, Chopard P, Pertesi M, Fabianova E, Adamcakova Z, Holcatova I, Foretova L, Janout V, Vallee MP, Rinaldi S, Brennan P, McKay JD, Byrnes GB, Scelo G. KRAS mutations in blood circulating cell-free DNA: a pancreatic cancer case-control. Oncotarget. 2016;7(48):78827-40. 27705932. PMC5346680.

      6. Fernandez-Cuesta L, Perdomo S, Avogbe PH, Leblay N, Delhomme TM, Gaborieau V, Abedi-Ardekani B, Chanudet E, Olivier M, Zaridze D, Mukeria A, Vilensky M, Holcatova I, Polesel J, Simonato L, Canova C, Lagiou P, Brambilla C, Brambilla E, Byrnes G, Scelo G, Le Calvez-Kelm F, Foll M, McKay JD, Brennan P. Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer. EBioMedicine. 2016;10:117-23. 27377626.

      7. Cozen W, Timofeeva MN, Li D, Diepstra A, Hazelett D, Delahaye-Sourdeix M, Edlund CK, Franke L, Rostgaard K, Van Den Berg DJ, Cortessis VK, Smedby KE, Glaser SL, Westra HJ, Robison LL, Mack TM, Ghesquieres H, Hwang AE, Nieters A, de SS, Lightfoot T, Becker N, Maynadie M, Foretova L, Roman E, Benavente Y, Rand KA, Nathwani BN, Glimelius B, Staines A, Boffetta P, Link BK, Kiemeney L, Ansell SM, Bhatia S, Strong LC, Galan P, Vatten L, Habermann TM, Duell EJ, Lake A, Veenstra RN, Visser L, Liu Y, Urayama KY, Montgomery D, Gaborieau V, Weiss LM, Byrnes G, Lathrop M, Cocco P, Best T, Skol AD, Adami HO, Melbye M, Cerhan JR, Gallagher A, Taylor GM, Slager SL, Brennan P, Coetzee GA, Conti DV, Onel K, Jarrett RF, Hjalgrim H, van den Berg A, McKay JD. A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nature communications. 2014;5:3856. 24920014. PMC4055950.

      Last update 13/02/2019