Mutational Landscape of Ovarian Adult Granulosa Cell Tumors from Whole Exome and Targeted <i>TERT</i> Promoter Sequencing

Alexiadis, Maria; Rowley, Simone M.; Chu, Simon; Leung, Dilys T.H.; Stewart, Colin J.R.; Amarasinghe, Kaushalya; Campbell, Ian G.; Fuller, Peter J.

doi:10.1158/1541-7786.mcr-18-0359

Cited by 38 publications

(80 citation statements)

References 33 publications

(67 reference statements)

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“…An array CGH analysis of FFPE samples of 40 surgically resected aGCTs confirmed that the most frequent CNV was loss of chromosome 22q; this had occurred in 52% of the primary tumors and 82% of the recurrent tumors. Similar values (ranging from 30 to 53%) have been reported in the literature [10,11,14,15].…”

Section: Chromosome Instability In Recurrent Agctssupporting

confidence: 90%

“…There are also literature reports of trisomy 12, trisomy 14, and loss of chromosome 16, although these CNVs were less frequent in our study. This discrepancy might be due (at least in part) to the number of samples used in the literature studies (10, 15, and 21 samples in references [10,11,14], respectively) or by the high proportion of recurrent tumors in our series [15]. When calculating the GI for each sample, we could not determine a predictive cut-off.…”

Section: Chromosome Instability In Recurrent Agctsmentioning

confidence: 89%

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FOXL2 homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary

et al. 2020

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Copyright: Kraus et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ABSTRACT Introduction: Adult granulosa cell tumors (aGCTs) are extremely rare tumors characterized by the presence of the single missense mutation (c.402 C>G, p. C134W) in the FOXL2 gene. These tumors are frequently associated with a slow, indolent disease progression and a high probability of aggressive tumor recurrence. Hence, the identification of molecular markers that are predictive of recurrence and/or aggressive behavior would be a great asset in the management of aGCT. The present study focused on the influence of the FOXL2 genotype (heterozygous or homozygous) and copy number variations (CNVs) in recurrence by comparing the primary tumor with recurrent lesions in the same patient. We performed array comparative genomic hybridization (CGH) experiments and FOXL2 genotyping by allelic discrimination on 40 tumor samples. Results and Discussion: In array CGH results of recurrent tumors, few samples presented the multiple chromosome losses and gains characteristic of chromosome instability (CIN). We also observed that three recurrent tumors and one primary tumor appeared to be homozygous for the FOXL2 c.402C>G mutation. Interestingly, the homozygous FOXL2 genotype was correlated with a shorter time to relapse. A change in the FOXL2 genotype in cases of recurrence was correlated with the appearance of CIN. Conclusion: Despite the small number of matching primary and recurrent tumors analyzed here, the present study is the first to have shown that the FOXL2 homozygous genotype and CIN are prevalent in recurrent aGCTs. The two mechanisms are probably linked, and both almost certainly have a role in the molecular transformation of aGCTs.

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Section: Chromosome Instability In Recurrent Agctssupporting

confidence: 90%

Section: Chromosome Instability In Recurrent Agctsmentioning

confidence: 89%

FOXL2 homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary

et al. 2020

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“…Our analyses revealed that, consistent with primary PACs, recurrent PACs showed the canonical alterations affecting PRKD genes, including PRKD1 hotspot E710D mutations or a PRKD2 rearrangement. The maintenance of the highly recurrent/pathognomonic genetic alteration that characterises these tumours in the recurrences and after the acquisition of high-grade histological features is consistent with the observations made in other tumour types driven by pathognomonic genetic alterations, [41][42][43][44] and is consistent with the notion that these alterations constitute drivers of the disease. For instance, in the progression of adenoid cystic carcinomas to high-grade tumours, the MYB-NFIB fusion gene is maintained 41 ; likewise, in the progression of granulosa cell tumours, the FOXL2 C134W mutation is conserved.…”

Section: Discussionsupporting

confidence: 88%

“…The maintenance of the highly recurrent/pathognomonic genetic alteration that characterises these tumours in the recurrences and after the acquisition of high‐grade histological features is consistent with the observations made in other tumour types driven by pathognomonic genetic alterations, and is consistent with the notion that these alterations constitute drivers of the disease. For instance, in the progression of adenoid cystic carcinomas to high‐grade tumours, the MYB–NFIB fusion gene is maintained; likewise, in the progression of granulosa cell tumours, the FOXL2 C134W mutation is conserved . Consistent with the notion that, in the progression of tumours driven by pathognomonic mutations, additional genetic alterations are acquired or subclonal genetic alterations present in minor subclones of the primary tumour are selected, we observed that the recurrent tumour RS1‐T2 acquired additional subclonal ERBB2 (V839M) and ZFHX3 (G3527dup) mutations.…”

Section: Discussionsupporting

confidence: 87%

“…For instance, in the progression of adenoid cystic carcinomas to high-grade tumours, the MYB-NFIB fusion gene is maintained 41 ; likewise, in the progression of granulosa cell tumours, the FOXL2 C134W mutation is conserved. [42][43][44] Consistent with the notion that, in the progression of tumours driven by pathognomonic mutations, additional genetic alterations are acquired or subclonal genetic alterations present in minor subclones of the primary tumour are selected, [41][42][43][44] we observed that the recurrent tumour RS1-T2 acquired additional subclonal ERBB2 (V839M) and ZFHX3 (G3527dup) mutations. Moreover, our analyses revealed that a minor subclone of the primary tumour (RS1-T1), which harboured the PIK3CA D350G hotspot mutation, became dominant in the recurrent tumour (RS1-T2; Figure 4), suggesting that recurrence of PACs may be driven by selection of pre-existing subclones.…”

Section: Discussionsupporting

confidence: 86%

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Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

et al. 2019

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Aims Polymorphous adenocarcinoma (PAC) usually follows an indolent course, but some cases may show recurrences and high‐grade features. The genetic events associated with recurrences and high‐grade versions are yet to be defined. Our aim was to determine the genetic underpinning of recurrent PACs of the salivary gland and the repertoire of somatic genetic alterations in cases with high‐grade histology. Methods and results Four PACs from three patients, including one case with matching primary and recurrent tumours, one de‐novo high‐grade PAC, and a PAC that transformed to a high‐grade tumour following multiple recurrences, were subjected to targeted sequencing (Memorial Sloan Kettering Mutation Profiling of Actionable Cancer Targets assay) or whole‐exome sequencing. Both matching primary and recurrent tumours, and the de‐novo high‐grade PAC, harboured clonal PRKD1 E710D hotspot mutations, whereas the PAC that underwent high‐grade transformation upon recurrence, which was wild‐type for PRKD1, harboured a PRKD2 rearrangement. The PACs analysed here also harboured mutations targeting cancer genes such as PIK3CA, SETD2, ARID1A, and NOTCH2. A clonal decomposition analysis of the matching primary and recurrent PACs revealed that a minor subclone from the primary tumour became dominant in the recurrent tumour following a clonal selection evolutionary pattern. Conclusions Our findings demonstrate that recurrent and high‐grade PACs are underpinned by PRKD1 E710D hotspot mutations or PRKD2 rearrangements, and that recurrences of PACs may stem from the selection of pre‐existing subclones in the primary tumour.

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Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Pilsworth

Cochrane²,

Neilson³

et al. 2021

The Journal of Pathology CR

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Adult-type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord-stromal tumors and 2-5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one-third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole-genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon-based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle-related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.

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Mutational Landscape of Ovarian Adult Granulosa Cell Tumors from Whole Exome and Targeted TERT Promoter Sequencing

Cited by 38 publications

References 33 publications

FOXL2 homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary

FOXL2 homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary

Genomic analysis of recurrences and high‐grade forms of polymorphous adenocarcinoma

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

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