Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden

Anglesio, Michael S.; Bashashati, Ali; Wang, Yi Kan; Senz, Janine; Ha, Gavin; Yang, Winnie; Aniba, Mohamed Radhouane; Prentice, Leah M; Farahani, Hossein; Chang, Hector Li; Karnezis, Anthony N.; Marra, Marco A.; Yong, Paul J.; Hirst, Martin; Gilks, Blake; Shah, Sohrab P.; Huntsman, David G.

doi:10.1002/path.4516

Cited by 148 publications

(125 citation statements)

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“…Additionally, most of the cases that fall within this category are admixed CCC and EC, two histotypes that are largely accepted to arise from the same cell of origin, i.e. glandular epithelial cells of endometriosis (18, 19, 45–48). The mutational data, where informative, indicate that in such cases, the morphologically and molecularly distinct regions have arisen from the same initiation event.…”

Section: Discussionmentioning

confidence: 99%

“…The mutational data, where informative, indicate that in such cases, the morphologically and molecularly distinct regions have arisen from the same initiation event. The sequencing panel employed in this study is limited to hotspot regions of 50 genes and, in cases such as MX2 with only a single CTNNB1 mutation in EC component and no detectable mutations in the CCC, many ancestral mutations, such as ARID1A (48) may have been missed.…”

Section: Discussionmentioning

confidence: 99%

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Morphologic and Molecular Characteristics of Mixed Epithelial Ovarian Cancers

Mackenzie¹,

Talhouk²,

Eshragh

et al. 2015

American Journal of Surgical Pathology

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Epithelial ovarian cancer consists of 5 major histotypes: high-grade serous carcinoma (HGSC), endometrioid carcinoma (EC), clear cell carcinoma (CCC), mucinous carcinoma (MC) and low-grade serous (LGSC). Each can have a broad spectrum of morphological appearances, and one histotype can closely mimic histopathological features more typical of another. Historically, there has been a relatively high frequency of mixed, defined by 2 or more distinct histotypes present based on routine histopathological assessment, histotype carcinoma diagnoses (3–11%), however recent immunohistochemical studies identifying histotype specific markers and allowing more refined histotype diagnoses suggests a much lower incidence. We reviewed hematoxylin and eosin stained slides from 871 cases of epithelial ovarian cancer and found the frequency of mixed carcinomas to be 1.7% when modern diagnostic criteria are applied. Through international collaboration, we established a cohort totaling 22 mixed epithelial ovarian cancers, consisting of 9 EC/CCC, 4 EC/LGSC, 3 HGSC/CCC, 2 CCC/MC and 4 other combinations. We interrogated the molecular differences between the different components of each case using immunohistochemistry, gene expression and hotspot sequencing analyses. Immunohistochemical data alone suggested 9 of the 22 cases were not mixed tumors as they presented a uniform immuno-phenotype throughout, and these cases most probably represent morphological mimicry and variation within tumors of a single histotype. Synthesis of molecular data further reduces the incidence of mixed carcinomas. Based on these results, true mixed carcinomas with both morphological and molecular support for the presence of more than one histotype within a given tumor represent less than 1% of epithelial ovarian cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Morphologic and Molecular Characteristics of Mixed Epithelial Ovarian Cancers

Mackenzie¹,

Talhouk²,

Eshragh

et al. 2015

American Journal of Surgical Pathology

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“…Whole-genome sequencing of ovarian clear cell carcinomas and endometriotic lesions from multiple patients reveals that there may be multiple classes of endometriosis with a specific high mutational subset serving as the precursor lesion for malignancy. 22 Dr Huntsman also briefly touched on recent work demonstrating cystathionine F-lyase as a novel clear cell carcinoma biomarker. 23 Finally, the mutational profile of HGSOC and the investigation into the site(s) of origin were discussed, and the implication on clinical strategies for risk reducing surgeries again highlighted.…”

Section: The Origins and Early Development Of Ovarian Cancermentioning

confidence: 99%

Tumor Microenvironment and Models of Ovarian Cancer

McLean

Mehta

2017

International Journal of Gynecological Cancer

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Rapid advances continue in our understanding of the influence of the tumor microenvironment on ovarian cancer progression and metastasis. Vascular endothelial cells, stromal cells, and immune cells all modulate epithelial tumor cell biology and therefore serve as potential targets for improved treatment responses either in conjunction with or instead of current treatment modalities. Characterization of the underlying genetic alterations in both the tumor cells and surrounding microenvironment cells enhances our understanding of tumor biology. Model systems including both in vitro and in vivo approaches allow novel advances. Technological advances including sequencing strategies, use of mass spectrometry for metabolomics and other studies, and bioengineering approaches all complement conventional methodologies to push forward our understanding and ultimately the treatment of ovarian cancer.

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“…A series of seminal studies have used high-throughput sequencing to profile the intra-tumoral heterogeneity of kidney (Gerlinger et al 2012(Gerlinger et al , 2014Gulati et al 2014), prostate (Boutros et al 2015;Cooper et al 2015;Gundem et al 2015), breast Eirew et al 2015), lung (de Bruin et al 2014;Zhang et al 2014), ovarian (Bashashati et al 2013;Anglesio et al 2015), and other tumors. These studies have universally shown that individual tumors are comprised of myriad cell types present at different frequencies in different spatial sites.…”

Section: Reproducibility Of Analysesmentioning

confidence: 99%

The path to routine use of genomic biomarkers in the cancer clinic

Boutros

2015

Genome Res.

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It has been almost 15 years since the first microarray-based studies creating multigene biomarkers to subtype and predict survival of cancer patients. This Perspective looks at why only a handful of genomic biomarkers have reached clinical application and what advances are needed over the next 15 years to grow this number. I discuss challenges in creating biomarkers and reproducing them at the genomic and computational levels, including the problem of spatio-genomic heterogeneity in an individual cancer. I then outline the challenges in translating newly discovered genome-wide or regional events, like trinucleotide mutation signatures, kataegis, and chromothripsis, into biomarkers, as well as the importance of incorporating prior biological knowledge. Lastly, I outline the practical problems of pharmaco-economics and adoption: Are new biomarkers viewed as economically rational by potential funders? And if they are, how can their results be communicated effectively to patients and their clinicians? Genomic-based diagnostics have immense potential for transforming the management of cancer. The next 15 years will see a surge of research into the topics here that, when combined with a stream of new targeted therapies being developed, will personalize the cancer clinic. The potential of clinical cancer genomicsCancer is, at its heart, a disease of the genome. Individual tumors harbor from hundreds to hundreds of thousands of point mutations . They can have global ploidy changes or local chromosomal abnormalities that alter as much as 50% of the genome (Zack et al. 2013). They can have dozens of genomic rearrangements of various types (Yang et al. 2013). Large-scale sequencing projects like the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) have been sequencing hundreds of tumors of different subtypes to try to create catalogs of those that are recurrent in any given cancer type (The Cancer Genome Atlas Research Network 2008;Hudson et al. 2010). These studies have led to the discovery of fundamental new properties of cancer genomes, such as mutational signatures (Alexandrov et al. 2013a,b), focal genomic abnormalities like kataegis and chromothripsis (Stephens et al. 2011), robust estimates of the distribution and number of driver genes (Lawrence et al. 2014), and classification of many tumor types into distinct subtypes (The Cancer Genome Atlas Network 2012a.However, these discoveries by themselves are not sufficient to impact patient care. Rather, bringing cancer genomics into the clinic requires two separate and generally orthogonal arms. First, genomic profiles need to be mined to identify candidate genes that can be targeted by novel drugs. By targeting vulnerabilities present in a tumor and not in normal cells, it is believed that drugs can be developed with greater specificity and sensitivity. Second, genomic profiles need to be used to create novel biomarkers that can be used to diagnose disease, to predict patient survival, to predict response to treatment (e.g., companion di...

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Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden

Cited by 148 publications

References 44 publications

Morphologic and Molecular Characteristics of Mixed Epithelial Ovarian Cancers

Morphologic and Molecular Characteristics of Mixed Epithelial Ovarian Cancers

Tumor Microenvironment and Models of Ovarian Cancer

The path to routine use of genomic biomarkers in the cancer clinic

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