Somatic genetic alterations in synchronous and metachronous low‐grade serous tumours and high‐grade carcinomas of the adnexa

Murali, Rajmohan; Selenica, Pier; Brown, David; Cheetham, R. Keira; Chandramohan, Raghu; Claros, Nidia L; Bouvier, Nancy; Cheng, Donavan T.; Soslow, Robert A.; Weigelt, Britta; McCluggage, W. Glenn

doi:10.1111/his.13796

Cited by 18 publications

(7 citation statements)

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“…Clonal composition analysis revealed that primary aGCTs and their matched recurrences, despite their generally simple genomes with few mutations and copy number alterations, display intra-lesion heterogeneity harboring clonal and subclonal mutations. In the progression from primary to metastatic disease, the acquisition of additional mutations, loss of heterozygosity of the wild-type allele of a given mutated gene as well as clonal shifts of genes affected by somatic mutations have been described [49][50][51]. Through the analysis of paired primary and matched recurrent aGCTs, we found that the acquisition of mutations, including those affecting TP53, TET2, MED12 and SH2D1A, was most commonly associated with disease progression.…”

Section: Discussionmentioning

confidence: 86%

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary

et al. 2020

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Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n=7), primary aGCTs that subsequently recurred (n=9) and their matched recurrences (n=9), and aGCT recurrences without matched primary tumors (n=10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, 3 primary non-recurrent aGCTs and 9 aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p =0.017). In addition, mutations affecting TP53 , MED12 and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT , MED12 and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

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Section: Discussionmentioning

confidence: 86%

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary

et al. 2020

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“…Yet, all four samples with sequencing data from this patient showed LOH on the whole chromosome 17 and a clonal TP53 mutation in addition to NRAS . Cases with such genomic and morphological features from both high and low-grade serous carcinomas have previously been reported as rare variants of serous ovarian neoplasms [20, 37]. A further study on the potential origin and genomic and histological evolution of this and the two BRAF -mutated HGSC cases discovered through exploration in GenomeSpy is ongoing.…”

Section: Resultsmentioning

confidence: 99%

Deciphering Cancer Genomes with GenomeSpy: A Grammar-Based Visualization Toolkit

Lavikka,

Oikkonen,

et al. 2023

Preprint

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BackgroundVisualization is an indispensable facet of genomic data analysis. Despite the abundance of specialized visualization tools, there remains a distinct need for tailored solutions. However, their implementation typically requires extensive programming expertise from bioinformaticians and software developers, especially when building interactive applications. Toolkits based on visualization grammars offer a more accessible, declarative way to author new visualizations. Nevertheless, current grammar-based solutions fall short in adequately supporting the interactive analysis of large data sets with extensive sample collections, a pivotal task often encountered in cancer research.ResultsWe present GenomeSpy, a grammar-based toolkit for authoring tailored, interactive visualizations for genomic data analysis. Users can implement new visualization designs with little effort by using combinatorial building blocks that are put together with a declarative language. These fully customizable visualizations can be embedded in web pages or end-user-oriented applications. The toolkit also includes a fully customizable but user-friendly application for analyzing sample collections, which may comprise genomic and clinical data. Findings can be bookmarked and shared as links that incorporate provenance information. A distinctive element of GenomeSpy’s architecture is its effective use of the graphics processing unit (GPU) in all rendering. GPU usage enables a high frame rate and smoothly animated interactions, such as navigation within a genome. We demonstrate the utility of GenomeSpy by characterizing the genomic landscape of 753 ovarian cancer samples from patients in the DECIDER clinical trial. Our results expand the understanding of the genomic architecture in ovarian cancer, particularly the diversity of chromosomal instability. We also show how GenomeSpy enabled the discovery of clinically actionable genomic aberrations.ConclusionsGenomeSpy is a visualization toolkit applicable to a wide range of tasks pertinent to genome analysis. It offers high flexibility and exceptional performance in interactive analysis. The toolkit is open source with an MIT license, implemented in JavaScript, and available athttps://genomespy.app/.

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“…Although the vast majority of extrauterine classic high-grade serous carcinomas originate from STIC, a small subset of ovarian high-grade carcinomas (which are probably variably diagnosed as highgrade serous carcinoma in routine practice) represent high-grade transformation of ovarian serous borderline tumours/low-grade serous carcinomas. [108][109][110][111][112][113] While morphology alone is by no means perfect in diagnosing STIC, the added use of immunohistochemistry for p53 and Ki-67 to supplement the histological features will help to establish a more reliable diagnosis. Molecular classification of tubal lesions, including reactive tubal epithelium, p53 signature and STIC, represents an unmet need to refine STIC diagnosis beyond histology.…”

Section: Discussionmentioning

confidence: 99%

“…Much has been learned during the last several years regarding the identification of STIC and its important roles in the development of invasive high‐grade serous carcinomas of the ovary, fallopian tube and peritoneum. Although the vast majority of extrauterine classic high‐grade serous carcinomas originate from STIC, a small subset of ovarian high‐grade carcinomas (which are probably variably diagnosed as high‐grade serous carcinoma in routine practice) represent high‐grade transformation of ovarian serous borderline tumours/low‐grade serous carcinomas 108–113 . While morphology alone is by no means perfect in diagnosing STIC, the added use of immunohistochemistry for p53 and Ki‐67 to supplement the histological features will help to establish a more reliable diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Serous tubal intra‐epithelial carcinoma: what do we really know at this point?

Vang

Shih

2022

Histopathology

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Serous tubal intra‐epithelial carcinoma (STIC) is the earliest morphologically recognisable step in the development of invasive high‐grade serous carcinoma of the fallopian tube. Lesions occurring prior to STIC within the carcinogenic sequence for the pathogenesis of invasive high‐grade serous carcinoma include the p53 signature and secretory cell outgrowth (SCOUT). Variable histological criteria have been used for diagnosing STIC, but a combination of morphology and immunohistochemistry for p53/Ki‐67 improves interobserver agreement. Half of all carcinomas identified in risk‐reducing salpingo‐oophorectomy specimens are in the form of STIC; however, STIC also may be incidentally found on occasion in specimens from women at low or average risk of ovarian/tubal/peritoneal carcinoma. TP53 mutation is the earliest known DNA sequence alteration in STIC and almost all invasive high‐grade serous carcinomas of the ovary and peritoneum. Data on the clinical behaviour of STIC are limited. While the short‐term follow‐up in the prior literature suggests a low risk of malignant progression, a more recent meta‐analysis indicates a 10‐year risk of 28%. STIC probably should be best regarded as a lesion with uncertain malignant potential at present, and future molecular analysis will help to classify those with higher risk of dissemination. This review provides an update on the current knowledge of STIC and related issues.

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Somatic genetic alterations in synchronous and metachronous low‐grade serous tumours and high‐grade carcinomas of the adnexa

Cited by 18 publications

References 64 publications

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary

Deciphering Cancer Genomes with GenomeSpy: A Grammar-Based Visualization Toolkit

Serous tubal intra‐epithelial carcinoma: what do we really know at this point?

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