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Title: Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours.
Authors: Miller, Julie
Other Authors: Flynn, Aidan
Dwight, Trisha
Benn, Diana
Deb, Siddartha
Colebatch, Andrew
Fox, Stephen
Harris, Jessica
Duncan, Emma
Robinson, Bruce
Hogg, Annette
Ellul, Jason
Keywords: Genomics
Hereditary Endocrine Neoplasia
Medullary Thyroid Cancer
Genes, Neoplasm
Tumour Heterogeneity
Autosomal Dominant Mutations
Cancer Genes
Multifocal Disease
Clonal Evolution
Intratumoural Heterogeneity
Adrenal Gland Neoplasms
Germ-Line Mutation
Loss of Heterozygosity
Neoplasms, Multiple Primary
Neoplasms, Second Primary
Neuroendocrine Tumors
Polymorphism, Single Nucleotide
Positron Emission Tomography
Computed Tomography
Proto-Oncogene Proteins c-ret
Succinate Dehydrogenase
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
MAX Protein
SDHB Protein
RET Protein
Department of Surgery, Epworth Healthcare, Melbourne, Victoria, Australia
General Surgery and Gastroenterology Clinical Institute, Epworth HealthCare, Victoria, Australia
Issue Date: Jul-2017
Publisher: Wiley
Citation: J Pathol. 2017 Jul;242(3):273-283
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.
DOI: 10.1002/path.4900
PubMed URL:
ISSN: 1096-9896
Journal Title: The Journal of Pathology
Type: Journal Article
Affiliated Organisations: The Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
Cancer Genetics, Kolling Institute, Royal North Shore Hospital, Sydney, NSW, Australia
University of Sydney, Sydney, NSW, Australia
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
Department of Surgery, Royal Melbourne Hospital, Melbourne, Victoria, Australia
Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
Department of Diabetes and Endocrinology, Western Health, Melbourne, Victoria, Australia
Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia
Type of Clinical Study or Trial: Observational Study
Appears in Collections:Cancer Services

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