Rationale:

Genetic susceptibility plays a role in many types of cancer. Identifying the genes involved in susceptibility to cancer may have potential utility in risk management, lead to greater understanding of the biological pathways involved in cancer development, and elucidate how environmental factors exert their effects in combination with genetic variants.

The Genetic Cancer Susceptibility Group (GCS) aims to evaluate the inherited genetic factors involved in susceptibility to human cancers. A proportion of the familial cancer susceptibility can be explained by rare mutations in high-penetrance genes, exemplified by mutations in BRCA1 and BRCA2 genes implicated in breast cancer susceptibility. Some of the familial risk can also be explained by genetic variants that are common in the general population but individually confer modest to small risk. The genome-wide association study (GWAS) approach has been successful in identifying this latter type of genetic variants. Nevertheless, the genetic risk explained by the variants identified so far accounts for only a minor proportion of familial clustering, implying that much of the genetic risk remains to be discovered. Within its research goals, GCS aims to use genomic sequencing techniques to further describe genetic susceptibility to cancer and explore how the genetic susceptibility might be mediated, particularly how the germline events may relate to the somatic events. Although GCS does work on common cancers, such as lung cancer, the Group's research tends to focus on rare cancers such as those of the head and neck (including nasopharynx) and kidney.

GCS is responsible for an important proportion of the Agency's capacity in genomics. GCS aims to adapt genomic techniques to suit IARC's particular needs and mission, and support genomics-related activities across the Agency through the Genetic Services Platform (GSP). In addition to its work on genetic susceptibility, GCS is exploring the potential for genomic techniques to be used as measures of circulating genomic biomarkers, such as circulating tumour DNA, and testing their utility as mechanisms of minimally invasive early detection and surveillance of cancer.


Objectives:

The main objective of the Genetic Cancer Susceptibility Group's (GCS's) research interests is to investigate the influence of germline genetic factors on cancer etiology: to identify the genes involved, the mechanisms by which susceptibility alleles exert their effect, and how they interact with environmental factors. GCS uses a variety of study designs, including both familial and case-control studies, and has a major focus on the incorporation of data derived from advanced genomic and bioinformatics techniques into the genetic analysis.

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 Genetic Services Platform (GSP), also in scientific activities across IARC. The GSP makes these genomic techniques accessible to IARC scientific groups and provides support through the complete project life-cycle, including planning, execution, quality control, and subsequent bioinformatics analysis. In the context of the laboratory, GCS strives to develop semi-automated workflows for tailored, flexible, and cost-effective genomic analysis of IARC's large and heterogeneous sample collections. In addition, GCS provides bioinformatics capacity, ensuring that the necessary computing resources and analytical protocols are available for genomic analysis. GCS incorporates quality control measures throughout these processes to ensure the data quality expected of IARC. Working closely with various IARC committees (Laboratory Steering Committee [LSC] and Bioinformatics Steering Committee [BISC]) and scientific groups, GCS also coordinates the development of the Agency's genomic and bioinformatics capacity.

A detailed list of the Genetic Services Platform (GSP) capabilities and publications can be found at the GSP website

Relevant GCS-specific outputs include the development of (i) the Electronic Laboratory Notebook, now used routinely across the Agency (Voegele et al., Bioinformatics 2012), and (ii) sample management systems across the Agency (Voegele et al., Bioinformatics 2010).


Current Research Topics:


The areas of GCS′s studies on lung cancer, head and neck (including nasopharyngeal) cancer, and lymphomas include:

  • Investigating the contribution of germline genetic variation to cancer susceptibility, particularly uncommon genetic variants assessed by next-generation sequencing and genome-wide association study (GWAS) approaches. Findings are validated and explored using larger-scale targeted sequencing in cases and controls selected within bio-repositories in the Section of Genetics (GEN) (focused on selected genes in many individuals), or through imputation techniques within the large GWAS resources available to GEN. Examples of GCS activities include:

    • Identifying the BRCA2 genetic variant rs11571833 (K3326X) to be associated with lung cancer (Wang et al., Nat Genetics 2014)
    • Identifying that genetic variation in the TCF3 gene is linked with Hodgkin lymphoma, and potentially through alterations in gene expression levels (expression quantitative trait loci [eQTLs]) (Cozen et al., Nat Commun 2014)
    • Identifying RINK1 as a potential breast cancer susceptibility gene (Park et al., Cancer Discovery 2014).

  • Exploring how genetic susceptibility may be mediated by considering how susceptibility alleles relate to gene expression levels and number or types of somatic mutations (mutation signatures and their dosage). In addition, GCS explores novel analytical methods to assess whether the identification of somatic events could further enhance susceptibility gene discovery, particularly in rare cancers, by considering unexpected correlations between somatic and germline events. Recent examples of GCS activities include:

    • Identifying that genetic variants that are eQTLs are enriched for association with Hodgkin lymphoma (Cozen et al., Nat Commun 2014)
    • Developing Bayesian methods that allow data integration into genetic studies (Johansson et al., PLoS One 2012).

  • Investigating genetic susceptibility to nasopharyngeal cancer within the South-East Asian population, including interactions with environmental exposures, Epstein-Barr virus, and tumour biology across populations and ethnicities.

    • Identifying genetic variants in TERT to be linked with nasopharyngeal cancer (Fachiroh et al., Cancer Causes Control 2012).

  • Although the Group′s primary focus is on genetic susceptibility, most recently GCS is exploring and developing laboratory and bioinformatics analysis protocols, for the evaluation of novel non-invasive biomarkers for early diagnosis of cancer, such as circulating tumour DNA or exosomal RNAs from plasma samples.


Recent Publications:

1. 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, LeCalvez-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 (2014) Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat 46(7):736-41

2. 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 Sanjose S, 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 (2014) A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nat Commun. 5:3856

3. Park DJ, Tao K, Le Calvez-Kelm F, Nguyen-Dumont T, Robinot N, Hammet F, Odefrey F, Tsimiklis H, Teo ZL, Thingholm LB, Young EL, Voegele C, Lonie A, Pope BJ, Roane TC, Bell R, Hu H, Shankaracharya, Huff CD, Ellis J, Li J, Makunin IV, John EM, Andrulis IL, Terry MB, Daly M, Buys SS, Snyder C, Lynch HT, Devilee P, Giles GG, Hopper JL, Feng BJ, Lesueur F, Tavtigian SV, Southey MC, Goldgar DE (2014) Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers. Cancer discovery 4(7):804-15

4. Anantharaman D, Chabrier A, Gaborieau V, Franceschi S, Herrero R, Rajkumar T, Samant T, Mahimkar MB, Brennan P, McKay JD (2014) Genetic variants in nicotine addiction and alcohol metabolism genes, oral cancer risk and the propensity to smoke and drink alcohol: a replication study in India. PLoS One 9(2):e88240

5. Voegele C, Bouchereau B, Robinot N, McKay J, Damiecki P, Alteyrac L (2013) A universal open-source Electronic Laboratory Notebook. Bioinformatics 29(13):1710-12

6. Urayama KY, Jarrett RF, Hjalgrim H, Diepstra A, Kamatani Y, Chabrier A, Gaborieau V, Boland A, Nieters A, Becker N, Foretova L, Benavente Y, Maynadie M, Staines A, Shield L, Lake A, Montgomery D, Taylor M, Smedby KE, Amini RM, Adami HO, Glimelius B, Feenstra B, Nolte IM, Visser L, van Imhoff GW, Lightfoot T, Cocco P, Kiemeney L, Vermeulen SH, Holcatova I, Vatten L, Macfarlane GJ, Thomson P, Conway DI, Benhamou S, Agudo A, Healy CM, Overvad K, Tjonneland A, Melin B, Canzian F, Khaw KT, Travis RC, Peeters PH, Gonzalez CA, Quiros JR, Sanchez MJ, Huerta JM, Ardanaz E, Dorronsoro M, Clavel-Chapelon F, Bueno-de-Mesquita HB, Riboli E, Roman E, Boffetta P, de Sanjose S, Zelenika D, Melbye M, van den Berg A, Lathrop M, Brennan P, McKay JD (2012) Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. J Natl Cancer Inst 104(3):240-53

7. Fachiroh J, Sangrajrang S, Johansson M, Renard H, Gaborieau V, Chabrier A, Chindavijak S, Brennan P, McKay JD (2012) Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand. Cancer Causes Control 23(12):1995-2002

8. Wozniak MB, Le Calvez-Kelm F, Abedi-Ardekani B, Byrnes G, Durand G, Carreira C, Michelon J, Janout V, Holcatova I, Foretova L, Brisuda A, Lesueur F, McKay J, Brennan P, Scelo G (2013) Integrative genome-wide gene expression profiling of clear cell renal cell carcinoma in Czech Republic and in the United States. PLoS One 8(3):e57886

9. Johansson M, Roberts A, Chen D, Li Y, Delahaye-Sourdeix M, Aswani N, Greenwood MA, Benhamou S, Lagiou P, Holcatova I, Richiardi L, Kjaerheim K, Agudo A, Castellsague X, Macfarlane TV, Barzan L, Canova C, Thakker NS, Conway DI, Znaor A, Healy CM, Ahrens W, Zaridze D, Szeszenia-Dabrowska N, Lissowska J, Fabianova E, Mates IN, Bencko V, Foretova L, Janout V, Curado MP, Koifman S, Menezes A, Wunsch-Filho V, Eluf-Neto J, Boffetta P, Franceschi S, Herrero R, Fernandez Garrote L, Talamini R, Boccia S, Galan P, Vatten L, Thomson P, Zelenika D, Lathrop M, Byrnes G, Cunningham H, Brennan P, Wakefield J, McKay JD (2012) Using prior information from the medical literature in GWAS of oral cancer identifies novel susceptibility variant on chromosome 4--the AdAPT method. PLoS One 7(5):e36888

10. McKay JD, Truong T, Gaborieau V, Chabrier A, Shu-chun Chuang, Byrnes G, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Blanche H, Gut IG, Galan P, Heath S, Hashibe M, Hayes RB, Boffetta P, Lathrop M, Brennan P (2011) A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet 7(3):e1001333

11. Le Calvez-Kelm F, Lesueur F, Damiola F, Vallée M, Voegele C, Babikyan D, Durand G, Forey N, McKay-Chopin S, Robinot N, Nguyen-Dumont T, Thomas A, Byrnes GB; Breast Cancer Family Registry, Hopper JL, Southey MC, Andrulis IL, John EM, Tavtigian SV (2011) Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res, 18 13(1):R6

12. Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) A genome-wide association study identifies a susceptibility locus for lung cancer encompassing nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452:633-7

13. McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P (2008) Lung cancer susceptibility locus at 5p15.33. Nature Genet 40(12):1404-6