The genomic landscape of low-grade serous ovarian/peritoneal carcinoma and its impact on clinical outcomes

Gershenson, David M.; Sun, Charlotte C.; Westin, Shannon N.; Eyada, Mostafa; Cobb, Lauren; Nathan, Lisa C.; Sood, Anil K.; Malpica, Anaís; Hillman, R. Tyler; Wong, Kwong-Kwok

doi:10.1016/j.ygyno.2021.11.019

Cited by 32 publications

(27 citation statements)

References 35 publications

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“…S1. Similar to previous reports [ 7 , 16 ], BRAF (4/6 SBOT, 66.7%) and KRAS (3/22 LGSOC, 13.6%) mutations had the highest frequencies in our cohort. Two novel mutations identified in this analysis, UBR5 (c.935A > C; p.E312A) and EPHA3 (c.2283G > T; p.K761N), have not been previously reported in LGSOC.…”

Section: Resultssupporting

confidence: 91%

“…These results are similar to those previously reported [ 6 , 39 ]. As CDK2NA is frequently deleted in LGSOC [ 16 ], we performed immunostaining for p16 (encoded by CDK2NA ) on an LGSOC tissue microarray (Fig. 3 B).…”

Section: Resultsmentioning

confidence: 99%

“…In the current and previous studies, loss of 9p and homozygous deletions of the CDKN2A/2B locus are common [ 12 , 15 , 16 ]. We further validated the frequent downregulation of p16 protein expression in LGSOC using tissue microarray.…”

Section: Discussionmentioning

confidence: 99%

“…A recent sequencing analysis targeting 127 genes in 71 LGSOCs identified additional recurrent gene mutations, including MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), and ASH1L (4%) [ 15 ]. Another recent targeted sequencing analysis of 215 LGSOCs using various platforms identified additional recurrent mutations such as PIK3CA , ATM , CREBBP , MUTYH, and NOTCH3 [ 16 ]. However, none of these studies included corresponding normal DNA to validate whether these mutations were true somatic mutations.…”

Section: Introductionmentioning

confidence: 99%

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Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors

Wong

Bateman

et al. 2022

J Transl Med

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Background Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as < 40 and > 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors. Methods Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed. Results We identified single-nucleotide variants (SNVs) (range: 5688–14,833 per sample), insertion and deletion variants (indels) (range: 880–1065), and regions with copy number variants (CNVs) (range: 62–335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS, NRAS, EIF1AX, UBR5, and DNM3 mutations. Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3, leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets. Conclusions This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3, which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors

Wong

Bateman

et al. 2022

J Transl Med

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“…[27][28][29] Additionally, activating mutations in the MAPK pathway are frequently identified in LGSC, but not HGSC; in contrast, TP53 mutations are generally associated with HGSC, but not LGSC. [30][31][32][33][34][35] LGSCs is associated with more indolent disease and presents at a younger age than HGSCs; however, they are also often advanced at diagnosis. 28,29,36,37 Approximately 60% of LGSCs (vs 2% of HGSCs) are also associated with serous borderline tumors (low malignant potential).…”

Section: Ov-b 1 Of 3 Principles Of Pathology General •mentioning

confidence: 99%

NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022

Armstrong

Alvarez

Backes

et al. 2022

Journal of the National Comprehensive Cancer Network

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Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

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Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low‐grade ovarian carcinoma

Hendrikse

Ploeg

Kruis

et al. 2023

Cancer

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Background Advanced low‐grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC. Methods Tumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium. Results Patients who had normal ER STP activity had a progression‐free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS. Conclusions Aberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.

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The genomic landscape of low-grade serous ovarian/peritoneal carcinoma and its impact on clinical outcomes

Cited by 32 publications

References 35 publications

Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors

Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors

NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low‐grade ovarian carcinoma

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