Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes

Hunter, Sally M.; Anglesio, Michael S.; Ryland, Georgina L; Sharma, Raghwa; Chiew, Yoke-Eng; Rowley, Simone M.; Doyle, Maria A.; Li, Jason; Gilks, C. Blake; Moss, Phillip; Allan, Prue E.; Stephens, Andrew N.; Huntsman, David G.; deFazio, Anna; Bowtell, David D.L.; Gorringe, Kylie L.; Campbell, Ian

doi:10.18632/oncotarget.5438

Cited by 148 publications

(154 citation statements)

References 46 publications

(64 reference statements)

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…Whereas BRAF and KRAS mutations were found in both SBT/APSTs and invasive tumors, NRAS mutations were not found in any pure, non-ambiguous SBT/APST tumors tested. Another study demonstrated that NRAS mutations were detected in 26.3% of LGSCs, but none were detected in the SBT/APST cohort [18]. Consistent with previous findings, we did not observe NRAS mutations in either SBT/APSTs or niLGSCs.…”

Section: Discussionsupporting

confidence: 91%

“…Similar to previous findings, our study, based on a large retrospective cohort, did not identify NRAS mutations in either SBT/APSTs or non-invasive LGSCs [17, 18]. We observed a relatively low mutation frequency (3.6%) of NRAS in invasive LGSCs.…”

Section: Discussionsupporting

confidence: 89%

“…Consistent with this finding, another study identified several potential markers of progression and candidate driver genes of LGSC including NRAS , USP9X , and EIF1AX [18]. In this recent report, NRAS mutations were present in 26.3% (5/19) of LGSCs but were absent in SBT, and NRAS was thought to be a potent driver of LGSC tumorigenesis [18]. To further explore the role of NRAS in the development of LGSC, we investigated the mutational status of NRAS among our existing patient cohorts obtained from the Johns Hopkins Hospital and the Denmark National Patient Registry.…”

Section: Introductionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 56%

See 3 more Smart Citations

Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma

et al. 2017

View full text Add to dashboard Cite

Activating mutations involving the members of the RAS signaling pathway, including KRAS, NRAS, and BRAF, have been reported in ovarian low-grade serous carcinoma and its precursor lesion, serous borderline tumor (SBT). Whether additional genetic alterations in the RAS oncogene family accumulate during the progression of serous borderline tumor (SBT) to invasive low grade serous carcinoma (LGSC) remains largely unknown. While mutations of KRAS and BRAF occur at a very early stage of progression, even preceding the development of SBT, additional driving events, such as NRAS mutations, have been postulated to facilitate progression. In this study, we analyzed NRAS exon 3 mutational status in 98 cases that were diagnosed with SBT/atypical proliferative serous tumor (SBT/APST), non-invasive LGSC (niLGSC), or invasive LGSC (iLGSC). Of the latter, NRAS Q61R (CAA to CGA) mutations were detected in only 2 of 56 (3.6%) cases. The same mutation was not detected in any of the SBT/APSTs or niLGSCs. Mutational analysis for hotspots in KRAS and BRAF demonstrated a wildtype pattern of KRAS and BRAF in one of the NRAS-mutated cases. Interestingly, another LGSC case with NRAS mutation harbored a concurrent BRAF V600L mutation. These findings indicate that, although recurrent NRAS mutations are present, their low prevalence indicates that NRAS plays a limited role in the development of LGSC. Further studies to identify other oncogenic drivers of LGSC progression is warranted.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Section: Introductionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 56%

See 2 more Smart Citations

Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In contrast to the block staining in endometriosis‐associated carcinomas, complete absence was associated with unfavorable outcome in LGSC in keeping with the tumor suppressor function. Although investigating the underlying mechanism of absence of p16 expression is beyond the scope of the current study, the 12% of LGSC showing complete absence of p16 by IHC is strikingly similar to the 15% frequency of the homozygous deletion of the CDKN2A locus reported by Hunter et al 7. We have previously shown that progesterone receptor (PGR) expression is a favorable prognostic factor in LGSC 18.…”

Section: Discussionsupporting

confidence: 86%

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Rambau

Vierkant

Intermaggio

et al. 2018

The Journal of Pathology CR

Self Cite

View full text Add to dashboard Cite

We aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

show abstract

Genomic analysis of low‐grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities

Cheasley

Nigam

Zethoven

et al. 2020

The Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Low-grade serous ovarian carcinoma (LGSOC) is associated with a poor response to existing chemotherapy, highlighting the need to perform comprehensive genomic analysis and identify new therapeutic vulnerabilities. The data presented here represent the largest genetic study of LGSOCs to date (n = 71), analysing 127 candidate genes derived from whole exome sequencing cohorts to generate mutation and copy-number variation data. Additionally, immunohistochemistry was performed on our LGSOC cohort assessing oestrogen receptor, progesterone receptor, TP53, and CDKN2A status. Targeted sequencing identified 47% of cases with mutations in key RAS/RAF pathway genes (KRAS, BRAF, and NRAS), as well as mutations in putative novel driver genes including USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), and ASH1L (4%). Immunohistochemistry evaluation revealed frequent oestrogen/progesterone receptor positivity (85%), along with CDKN2A protein loss (10%) and CDKN2A protein overexpression (6%), which were linked to shorter disease outcomes. Indeed, 90% of LGSOC samples harboured at least one potentially actionable alteration, which in 19/71 (27%) cases were predictive of clinical benefit from a standard treatment, either in another cancer's indication or in LGSOC specifically. In addition, we validated ubiquitin-specific protease 9X (USP9X), which is a chromosome X-linked substrate-specific deubiquitinase and tumour suppressor, as a relevant therapeutic target for LGSOC. Our comprehensive genomic study highlighted that there is an addiction to a limited number of unique 'driver' aberrations that could be translated into improved therapeutic paths.

show abstract

Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes

Cited by 148 publications

References 46 publications

Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma

Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Genomic analysis of low‐grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities

Contact Info

Product

Resources

About