Comprehensive Genomic Profiling of Epithelial Ovarian Cancer by Next Generation Sequencing-Based Diagnostic Assay Reveals New Routes to Targeted Therapies

Ross, Jeffrey S.; Ali, Siraj M.; Wang, K.; Palmer, Gary A.; Yelensky, Roman; Lipson, Doron; Miller, VA; Zajchowski, Deborah A.; Shawver, Laura K.; Stephens, P.J.

doi:10.1097/01.ogx.0000436776.14414.33

Cited by 8 publications

(12 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22 MYC amplification has been reported in up to 25% of epithelial ovarian cancers, although no Brenner tumors were studied. 23 In our study, MYC amplification appeared to co-occur with amplification of either CDK4 (three cases) or CCND1 (two cases). MYC amplification was mutually exclusive with RAS mutations, suggesting an alternate mechanism of pathway activation.…”

Section: Discussionsupporting

confidence: 44%

Molecular Genetic Analysis of Ovarian Brenner Tumors and Associated Mucinous Epithelial Neoplasms

Tafe

Muller

Ananda

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Benign ovarian Brenner tumors often are associated with mucinous cystic neoplasms, which are hypothesized to share a histogenic origin and progression, however, supporting molecular characterization is limited. Our goal was to identify molecular mechanisms linking these tumors. DNA from six Brenner tumors with paired mucinous tumors, two Brenner tumors not associated with a mucinous neoplasm, and two atypical proliferative (borderline) Brenner tumors was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced using a 358-gene next-generation sequencing assay. Variant calls were compared within tumor groups to assess somatic mutation profiles. There was high concordance of the variants between paired samples (40% to 75%; P < 0.0001). Four of the six tumor pairs showed KRAS hotspot driver mutations specifically in the mucinous tumor. In the two paired samples that lacked KRAS mutations, MYC amplification was detected in both of the mucinous and the Brenner components; MYC amplification also was detected in a third Brenner tumor. Five of the Brenner tumors had no reportable potential driver alterations. The two atypical proliferative (borderline) Brenner tumors both had RAS mutations. The high degree of coordinate variants between paired Brenner and mucinous tumors supports a shared origin or progression. Differences observed in affected genes and pathways, particularly involving RAS and MYC, may point to molecular drivers of a divergent phenotype and progression of these tumors.

show abstract

Section: Discussionsupporting

confidence: 44%

Molecular Genetic Analysis of Ovarian Brenner Tumors and Associated Mucinous Epithelial Neoplasms

Tafe

Muller

Ananda

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Ovarian endometrioid carcinomas (OECs) constitute 10–15% of ovarian carcinomas, and closely resemble their uterine counterparts, being mostly low‐grade, with frequent squamous differentiation, and unusual morphological patterns such as mucinous differentiation . High‐grade OECs are relatively uncommon, and their repertoire of somatic genetic alterations has yet to be fully characterized . Rarer is the coexistence of low‐grade and high‐grade areas within OECs…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of a morphologically heterogeneous ovarian endometrioid carcinoma

et al. 2017

View full text Add to dashboard Cite

Aims Low-grade ovarian endometrioid carcinomas may be associated with high-grade components. Whether the latter are clonally-related to and originate from the low-grade endometrioid carcinoma remains unclear. Here we employed massively parallel sequencing to characterize the genomic landscape and clonal relatedness of an ovarian endometrioid carcinoma containing low- and high-grade components. Methods and Results DNA samples extracted from each tumor component (low-grade endometrioid, high-grade anaplastic and high-grade squamous) and matched normal tissue were subjected to targeted massively parallel sequencing using the 410 gene Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing assay. Somatic single nucleotide variants, small insertions and deletions, and copy number alterations were detected by state-of-the-art bioinformatics algorithms, and validated with orthogonal methods. The endometrioid carcinoma and the associated high-grade components shared copy number alterations and four clonal mutations, including SMARCA4 mutations, which resulted in loss of BRG1 protein expression. Subclonal mutations and mutations restricted to single components were also identified, such as distinct TP53 mutations restricted to each histologic component. Conclusions Histologically distinct components of ovarian endometrioid carcinomas may display intra-tumor genetic heterogeneity but be clonally related, harboring a complex clonal composition. In the present case, SMARCA4 mutations were likely early events, whereas TP53 somatic mutations were acquired later in evolution.

show abstract

“…One study recently showed that as many as 37% of the patients who received broad-based NGS testing have at least one clinically relevant mutation that could be targeted with either an off-label therapy or through a registered clinical trial (9). Another recent study revealed that nearly 200 cancers of unknown primary site harbored at least one clinically relevant molecular alteration (10). Furthermore, disease-specific studies have shown that up to 83% of the biliary cancers have clinically relevant genomic alterations, 67 actionable mutations were detected from 48 ovarian epithelial carcinomas, and over 40% of HER2-negative breast cancers had potentially targetable genomic alterations when NGS-based testing is used to identify tumor-derived genomic alterations [9][10][11][12].…”

Section: Next-generation Sequencing For Targeted Therapies and Immunomentioning

confidence: 99%

“…Another recent study revealed that nearly 200 cancers of unknown primary site harbored at least one clinically relevant molecular alteration (10). Furthermore, disease-specific studies have shown that up to 83% of the biliary cancers have clinically relevant genomic alterations, 67 actionable mutations were detected from 48 ovarian epithelial carcinomas, and over 40% of HER2-negative breast cancers had potentially targetable genomic alterations when NGS-based testing is used to identify tumor-derived genomic alterations [9][10][11][12]. These studies indicate that NGS-based molecular profiling is broadly applicable to numerous tumor types and support the notion that NGS testing can elucidate potential treatment options for patients with metastatic disease.…”

Section: Next-generation Sequencing For Targeted Therapies and Immunomentioning

confidence: 99%

“…As discussed above, one report shows as many as 37% of the patients who received broad-based NGS testing have at least one clinically relevant mutation that could be targeted with either an off-label therapy or through a registered clinical trial, and numerous tumor typesincluding cancers of unknown primarycan harbor potentially actionable mutations [9][10][11][12]16,28]. Recent, albeit small, studies have also investigated not only the identification of potentially actionable mutations by NGS-based tests but also the associated patient outcomes.…”

Section: Barriers To Adopting Next-generation Sequencing For All Cancmentioning

confidence: 99%

See 1 more Smart Citation

Should next-generation sequencing tests be performed on all cancer patients?

McKenzie

Dilks

Jones

et al. 2019

Expert Review of Molecular Diagnostics

View full text Add to dashboard Cite

Comprehensive Genomic Profiling of Epithelial Ovarian Cancer by Next Generation Sequencing-Based Diagnostic Assay Reveals New Routes to Targeted Therapies

Cited by 8 publications

References 0 publications

Molecular Genetic Analysis of Ovarian Brenner Tumors and Associated Mucinous Epithelial Neoplasms

Molecular Genetic Analysis of Ovarian Brenner Tumors and Associated Mucinous Epithelial Neoplasms

Genetic analysis of a morphologically heterogeneous ovarian endometrioid carcinoma

Should next-generation sequencing tests be performed on all cancer patients?

Contact Info

Product

Resources

About