title: Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours.
abstract: Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common cooperative changes required for tumourigenesis, while controlling for the genetic background of the individual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET, and MAX. Using whole exome sequencing and high-density single-nucleotide polymorphism arrays, we analysed two to four primary tumours from each patient. We also applied multi-region sampling, to assess intratumoural heterogeneity and clonal evolution, in two cases involving paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary phaeochromocytoma/paraganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Aidan
authors.initials: A
authors.lastname: Flynn
authors.affiliation: Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, NSW, Australia.|University of Sydney, Sydney, NSW, Australia.
authors.forename: Trisha
authors.initials: T
authors.lastname: Dwight
authors.affiliation: Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, NSW, Australia.|University of Sydney, Sydney, NSW, Australia.
authors.forename: Diana
authors.initials: D
authors.lastname: Benn
authors.affiliation: Anatomical Pathology, Anatpath, Melbourne, Victoria, Australia.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Deb
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Colebatch
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fox
authors.affiliation: Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Harris
authors.affiliation: Queensland University of Technology, Brisbane, Queensland, Australia.|Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.|Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.affiliation: Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, NSW, Australia.|University of Sydney, Sydney, NSW, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Robinson
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Annette
authors.initials: A
authors.lastname: Hogg
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.affiliation: Department of Surgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
authors.forename: Henry
authors.initials: H
authors.lastname: To
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Cuong
authors.initials: C
authors.lastname: Duong
authors.affiliation: Department of Surgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia.|Department of Surgery, Epworth Hospital, Melbourne, Victoria, Australia.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Miller
authors.affiliation: Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.|Department of Diabetes and Endocrinology, Western Health, Melbourne, Victoria, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Yates
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: James
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Alison
authors.initials: A
authors.lastname: Trainer
authors.affiliation: University of Sydney, Sydney, NSW, Australia.|Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, NSW, Australia.|University of Sydney, Sydney, NSW, Australia.
authors.forename: Roderick
authors.initials: R
authors.lastname: Clifton-Bligh
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.affiliation: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.|The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Richard W
authors.identifier: 0000-0003-4522-1184
authors.initials: RW
authors.lastname: Tothill
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000473:pathology; D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010235:Paraganglioma / Q000235:genetics; D010673:Pheochromocytoma / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000072078:Positron Emission Tomography Computed Tomography; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics; D055815:Young Adult
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: genomics; hereditary endocrine neoplasia; medullary thyroid cancer; neoplasia; paraganglioma; phaeochromocytoma; tumour heterogeneity