Open Access

COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration

  • Melissa C Southey1Email author,
  • Daniel J Park1,
  • Tu Nguyen-Dumont1,
  • Ian Campbell2, 39,
  • Ella Thompson2, 39,
  • Alison H Trainer3, 40,
  • Georgia Chenevix-Trench4,
  • Jacques Simard5,
  • Martine Dumont5,
  • Penny Soucy5,
  • Mads Thomassen6,
  • Lars Jønson7,
  • Inge S Pedersen8,
  • Thomas VO Hansen7,
  • Heli Nevanlinna9,
  • Sofia Khan9,
  • Olga Sinilnikova10, 11,
  • Sylvie Mazoyer10,
  • Fabienne Lesueur12,
  • Francesca Damiola10,
  • Rita Schmutzler13, 14,
  • Alfons Meindl15,
  • Eric Hahnen13, 14,
  • Michael R Dufault15,
  • TL Chris Chan16, 17,
  • Ava Kwong16, 18, 41, 42,
  • Rosa Barkardóttir19, 43,
  • Paolo Radice20,
  • Paolo Peterlongo21,
  • Peter Devilee22,
  • Florentine Hilbers22, 44,
  • Javier Benitez23, 45,
  • Anders Kvist24,
  • Therese Törngren24,
  • Douglas Easton25,
  • David Hunter26,
  • Sara Lindstrom26,
  • Peter Kraft26,
  • Wei Zheng27,
  • Yu-Tang Gao28,
  • Jirong Long27,
  • Susan Ramus29,
  • Bing-Jian Feng30,
  • Jeffrey N Weitzel31, 46,
  • Katherine Nathanson32,
  • Kenneth Offit33,
  • Vijai Joseph33,
  • Mark Robson33,
  • Kasmintan Schrader33,
  • San Ming Wang34,
  • Yeong C Kim34,
  • Henry Lynch35,
  • Carrie Snyder35,
  • Sean Tavtigian36,
  • Susan Neuhausen37,
  • Fergus J Couch38 and
  • David E Goldgar36
Breast Cancer Research201315:402

DOI: 10.1186/bcr3434

Published: 21 June 2013

Linkage analysis, positional cloning, candidate gene mutation scanning and genome-wide association study approaches have all contributed significantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identified genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered.

The application of massively parallel sequencing has further demonstrated the complexity of human genetic variation and has raised many challenges for computational and statistical methods for searching for additional breast cancer predisposition genes. Early findings are consistent with previous indications that no single gene is likely to account for a large proportion of the remaining unexplained genetic susceptibility [1, 2].

Coordinated international collaboration offers great potential to advance the discovery of additional breast cancer susceptibility genes by increasing the likelihood of identifying functionally relevant genetic variants in the same genes in multiple families. A new consortium, COMPLEXO (a name chosen to reflect the complexity of the exome), has been formed to facilitate collaborations between researchers actively applying massively parallel sequencing to understand the genetics of breast and ovarian cancer. The consortium has defined activities aimed at bringing together data and resources suitable for exome/genome sequencing initiatives and for large case-control-family study resources suitable for validation of candidate susceptibility genes in which rare mutations are associated with high to moderate risk of breast cancer. The aim of COMPLEXO is to bring to massively parallel sequencing the same power of large sample sets that have proven so successful in examining the role of common variants in cancer populations via the consortium model, such as the Breast Cancer Association Consortium (BCAC), the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), the Ovarian Cancer Association Consortium (OCAC) and the Collaborative Oncology Gene-environment Study (COGS) [35]. However, sequencing studies provide additional challenges in terms of defining specific modes of collaboration given differences in sequencing and targeted capture platforms, bioinformatics platforms, the need to integrate ongoing studies in many centers and socio-ethical-legal issues that are not as relevant to initiatives that are genotyping common genetic variation.

COMPLEXO invites collaboration from any researcher who would like to contribute to this consortium either by contributing data to the combined COMPLEXO data set, contributing resources for large-scale validation of candidate breast cancer predisposition genes or refining analytical and bioinformatic pipelines for massively parallel sequencing data filtering and prioritization. COMPLEXO also has interests in the critical assessment of current platforms and protocols and in developing and improving data filtering and gene prioritization strategies to enhance gene discovery initiatives. These approaches are relevant to all complex human diseases.

Interested researchers can engage with COMPLEXO via any local member or by contacting the corresponding author.



MCS is a National Health and Medical Research Council (Australia), Senior Research Fellow and Victorian Breast Cancer Research Consortium Group Leader. TN-D is a Susan G Komen for the Cure Postdoctoral Fellow. FJC is supported by the Breast Cancer Research Foundation. JB is the Head of Human Cancer Genetics Programme and coordinator of the Familial Cancer Exome Project in the Network of Research in Rare Diseases (CIBERER). SLN is the Morris and Horowitz Families Professor in Cancer Etiology and Outcomes Research. IGC is an NHMRC Principal Research Fellow. KO acknowledges grant support from Breast Cancer Reseach Foundation, Geoffrey Beene Cancer Research Foundation and STARR Cancer Consortium. JS is Chairholder of the Canada Research Chair in Oncogenetics. ERT is the recipient of a National Breast Cancer Foundation (Australia) Postdoctoral Training Fellowship. Support was received from R01CA155767 and the Victorian Breast Cancer Research Consortium.

Authors’ Affiliations

Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre
Familial Cancer Center, The Peter MacCallum Cancer Centre
The Queensland Institute of Medical Research, Royal Brisbane Hospital
Cancer Genomics Laboratory, Centre Hospitalier de Québec Research Center and Laval University
Department of Clinical Genetics, Odense University Hospital
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen
Department of Clinical Biochemistry, Section of Molecular Diagnostics, Aalborg University Hospital
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital
CNRS UMR5286 INSERM U1052, Cancer Research Center of Lyon, Center Leon Berard, Université Lyon 1
Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon, Centre Leon Berard
INSERM, Unité U900, Mines ParisTech, Equipe Epidémiologie Génétique des Cancers, Institut Curie
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne
Center for Molecular Medicine Cologne (CMMC), University of Cologne
Department of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University
Hong Kong Hereditary Breast Cancer Family Registry
Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong SAR and Departments of Pathology and Surgery, The University of Hong Kong
Department of Surgery, The University of Hong Kong
Department of Pathology, Landspitali-University Hospital, Hringbraut
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT)
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Department of Human Genetics, Leiden University Medical Center
Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO)
Department of Oncology, Clinical Sciences, Lund, University and Skåne University Hospital
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care and Department of Oncology, University of Cambridge, Strangeways Research Laboratory
Harvard School of Public Health
Division of Epidemiology, Vanderbilt University School of Medicine
Department of Epidemiology, Shanghai Cancer Institute
Department of Preventive Medicine, University of Southern California
Department of Dermatology, University of Utah School of Medicine
Division of Clinical Cancer Genetics, City of Hope
Translational Medicine and Human, Genetics and Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center
Department of Preventive Medicine, Creighton University School of Medicine
Department of Genetics, Cell Biology & Anatomy, College of Medicine University of Nebraska Medical Center
Huntsman Cancer Institute, The University of Utah School of Medicine
Department of Population Sciences, Beckman Research Institute of City of Hope
Division of Experimental Pathology, Department of Laboratory Medicine. and Pathology, Mayo Clinic
Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne
Familial Cancer Centre, The Royal Melbourne Hospital
Department of Surgery, Hong Kong Sanatorium and Hospital
Department of Oncology, Stanford University School of Medicine
BMC, Faculty of Medicine, University of Iceland
Department of Pathology, Leiden University Medical Center
Spanish Network on Rare Diseases (CIBERER)
Clinical Cancer Genetics Community Research Network


  1. Thompson ER, Doyle MA, Ryland GL, Rowley SM, Choong DY, Tothill RW, Thorne H, kConFab, Barnes DR, Li J, Ellul J, Philip GK, Antill YC, James PA, Trainer AH, Mitchell G, Campbell IG: Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet. 2012, 8: e1002894-10.1371/journal.pgen.1002894.PubMedPubMed CentralView ArticleGoogle Scholar
  2. Park DJ, Lesueur F, Nguyen-Dumont T, Pertesi M, Odefrey F, Hammet F, Neuhausen SL, John EM, Andrulis IL, Terry MB, Daly M, Buys S, Le Calvez-Kelm F, Lonie A, Pope BJ, Tsimiklis H, Voegele C, Hilbers FM, Hoogerbrugge N, Barroso A, Osorio A, Breast Cancer Family Registry, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Giles GG, Devilee P, Benitez J, Hopper JL, Tavtigian SV, Goldgar DE, Southey MC: Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet. 2012, 90: 734-739. 10.1016/j.ajhg.2012.02.027.PubMedPubMed CentralView ArticleGoogle Scholar
  3. []
  4. CIMBA (The Consortium of Investigators of Modifiers of BRCA1/2). []
  5. Collaborative Oncological Gene-environment Study. []


© BioMed Central Ltd 2013