Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

Fisher, Rosalie; Horswell, Stuart; Rowan, Andrew; Salm, Maximilian P; Bruin, Elza C. de; Gulati, Sakshi; McGranahan, Nicholas; Stares, Mark; Gerlinger, Marco; Varela, Ignacio; Crockford, Andrew; Favero, Francesco; Quidville, Virginie; André, Fabrice; Navas, Carolina; Grönroos, Eva; Nicol, David; Hazell, Steve; Hrouda, David; O’Brien, Tim; Matthews, Nik; Phillimore, Ben; Begum, Sharmin; Rabinowitz, Adam; Biggs, Jennifer; Bates, Paul A.; McDonald, Neil Q.; Stamp, Gordon; Spencer‐Dene, Bradley; Hsieh, James J.; Xu, Jianing; Pickering, Lisa; Gore, Martin; Larkin, James; Swanton, Charles

doi:10.1186/s13059-014-0433-z

Cited by 65 publications

(22 citation statements)

References 59 publications

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“…Two prior studies involving hereditary renal cell carcinoma (RCC) concluded that synchronous or metachronous VHL‐associated tumours are as genetically different from each other as tumours from other unrelated individuals with VHL disease . Fisher et al proposed that the divergent genetic profiles found in RCC are probably contingent on early somatic events, but convergence on the phosphoinositide 3‐kinase–AKT–mammalian target of rapamycin signalling pathway was still a common feature across synchronous primary tumours . It is interesting that we have observed stronger evidence for parallel evolution in synchronous PPGL tumours, not only by the detection of common SCNAs, but also by the similarity in the degree of genome instability between the matched PPGL tumours as compared with other cases.…”

Section: Discussionsupporting

confidence: 47%

“…Few studies have performed genomic profiling of multifocal primary tumours. Two prior studies involving hereditary renal cell carcinoma (RCC) concluded that synchronous or metachronous VHL‐associated tumours are as genetically different from each other as tumours from other unrelated individuals with VHL disease . Fisher et al proposed that the divergent genetic profiles found in RCC are probably contingent on early somatic events, but convergence on the phosphoinositide 3‐kinase–AKT–mammalian target of rapamycin signalling pathway was still a common feature across synchronous primary tumours .…”

Section: Discussionmentioning

confidence: 99%

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Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours

Flynn

Dwight

Benn

et al. 2017

The Journal of Pathology

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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.

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Section: Discussionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours

Flynn

Dwight

Benn

et al. 2017

The Journal of Pathology

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“…Evidence for intratumoural heterogeneity (ITH) in PCC/PGL could also be found in other tumours based on low VAF somatic variants and sub‐copy‐number loss detected by SNP‐array analysis in some cases indicating the presence of sub‐clones within tumours (Supplementary Figure 9). Although mutation burden and the general degree of ITH in PCC is lower than in other more aggressive tumour types, ITH in PCC appears to be higher than recently described in familial renal cell carcinomas . Multi‐region type analysis of additional PCC tumours will be required to validate and generalize our findings.…”

Section: Discussionmentioning

confidence: 59%

The genomic landscape of phaeochromocytoma

Flynn

Benn

Clifton‐Bligh

et al. 2015

The Journal of Pathology

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Phaeochromocytomas (PCCs) and paragangliomas (PGLs) are rare neural crest-derived tumours originating from adrenal chromaffin cells or extra-adrenal sympathetic and parasympathetic tissues. More than a third of PCC/PGL cases are associated with heritable syndromes involving 13 or more known genes. These genes have been broadly partitioned into two groups based on pseudo-hypoxic and receptor tyrosine kinase (RTK) signalling pathways. Many of these genes can also become somatically mutated, although up to one third of sporadic cases have no known genetic driver. Furthermore, little is known of the genes that co-operate with known driver genes to initiate and drive tumourigenesis. To explore the genomic landscape of PCC/PGL, we applied exome sequencing, high-density SNP-array analysis, and RNA sequencing to 36 PCCs and four functional PGL tumours. All tumours displayed low mutation frequency, in contrast to frequent large segmental copy-number alterations, aneuploidy, and evidence for chromothripsis in one case. Multi-region sampling of one benign familial PCC tumour provided evidence for the timing of mutations during tumourigenesis and ongoing clonal evolution. Thirty-one of 40 (77.5%) cases could be explained by germline or somatic mutations or structural alterations affecting known PCC/PGL genes. Deleterious somatic mutations were also identified in known tumour-suppressor genes associated with genome maintenance and epigenetic modulation. A multitude of other genes were also found mutated that are likely important for normal neuroendocrine cell function. We revisited the gene-expression subtyping of PCC/PGL by integrating published microarray data with our RNA-seq data, enabling the identification of six robust gene-expression subtypes. The majority of cases in our cohort with no identifiable driver mutation were classified into a gene-expression subtype bearing similarity to MAX mutant PCC/PGL. Our data suggest there are yet unknown PCC/PGL cancer genes that can phenocopy MAX mutant PCC/PGL tumours. This study provides new insight into the molecular diversity and genetic origins of PCC/PGL tumours.

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“…The fact that these findings were not absolute suggests that OCCs may adhere to both linear as well as nonlinear genetic models of progression . In the long term, it will be important to determine whether, the molecular pathways used for tumor growth and survival in these distinct regions move toward concordance, as is observed in other tumors …”

Section: Discussionmentioning

confidence: 99%

Intratumor genetic heterogeneity in squamous cell carcinoma of the oral cavity

et al. 2019

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Background We sought to evaluate intratumor heterogeneity in squamous cell carcinoma of the oral cavity (OCC) and specifically determine the effect of physical separation and histologic differentiation within the same tumor. Methods We performed whole exome sequencing on five biopsy sites—two from well‐differentiated, two from poorly differentiated regions, and one from normal parenchyma—from five primary OCC specimens. Results We found high levels of intratumor heterogeneity and, in four primary tumors, identified only 0 to 2 identical mutations in all subsites. We found that the heterogeneity inversely correlated with physical separation and that pairs of well‐differentiated samples were more similar to each other than analogous poorly differentiated specimens. Only TP53 mutations, but not other purported “driver mutations” in head and neck squamous cell carcinoma, were found in multiple biopsy sites. Conclusion These data highlight the challenges to characterization of the mutational landscape of OCC with single site biopsy and have implications for personalized medicine.

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Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

Cited by 65 publications

References 59 publications

Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours

Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours

The genomic landscape of phaeochromocytoma

Intratumor genetic heterogeneity in squamous cell carcinoma of the oral cavity

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