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| Status |
Public on Feb 02, 2017 |
| Title |
Intra and inter-tumoral heterogeneity in syndromic neuroendocrine tumors |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by SNP array
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| Summary |
Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma (PPGL) and medullary thyroid cancer (MTC), are caused by autosomal dominant mutations in a multitude of 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 a unique opportunity to discover common co-operative changes required for tumorigenesis while controlling for the genetic background of the individual. We performed an in-depth genomic analysis of synchronous and metachronous tumours from five patients harbouring germline mutations in the genes SDHB, RET and MAX. Using whole exome sequencing and high-density SNP-arrays we analyzed between two and four primary tumours from each patient. Furthermore, we applied multi-regional sampling to assess intra-tumoral heterogeneity and clonal evolution in two cases involving PPGL and MTC, 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 PPGL. Convergent events also occurred during clonal evolution of metastatic MTC. 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.
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| Overall design |
The Affymetrix CytoscanHD platform was used to perform copy number profiling on four synchronous paragangliomas from a patient (C1) with a germline SDHB mutation. The Affymetrix CytoscanHD platform was also used to analyse a primary tumour and metastasis from a medullary thyroid carcinoma from a patient (C5) with a germline RET mutation. In addition, the Affymetrix OncoScan platform was used to analyse high interest regions from within the first primary, as well as two additional primary tumours from patient C5.
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| Contributor(s) |
Flynn AJ, Tothill RW |
| Citation(s) |
28369925 |
| Submission date |
Feb 01, 2017 |
| Last update date |
Jul 13, 2018 |
| Contact name |
Aidan John Flynn |
| E-mail(s) |
aidan.ja.flynn@gmail.com
|
| Organization name |
Peter MacCallum Cancer Center
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| Department |
Research
|
| Lab |
Molecular Imaging and Targeted Therapeutics
|
| Street address |
305 Grattan St
|
| City |
Melbourne |
| State/province |
Victoria |
| ZIP/Postal code |
3000 |
| Country |
Australia |
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| Platforms (2) |
| GPL16131 |
[CytoScanHD_Array] Affymetrix CytoScan HD Array |
| GPL18602 |
[OncoScan] Affymetrix OncoScan FFPE Assay |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA369548 |
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