Whole-exome sequencing for ocular adnexal sebaceous carcinoma suggests PCDH15 as a novel mutation associated with metastasis

Xu, Shi-Qiong; Moss, Tyler J.; Rubin, Maria Laura; Ning, Jing; Eterovic, Karina; Yu, Hong; Jia, Renbing; Fan, Xianqun; Tetzlaff, Michael T.; Esmaeli, Bita

doi:10.1038/s41379-020-0454-y

Cited by 16 publications

(19 citation statements)

References 19 publications

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“…TP53 mutations were only identified in OA tumors, and the frequency in our group was similar to that reported in prior studies [11,24,35]. One previous study reported aberrant immunolabeling, potentially corresponding to TP53 mutations in 19/29 (66%) of OA sebaceous carcinomas; in another series, TP53 mutations were detected in 23/31 (71%) of cases [11,35]. Additionally, overexpression of Has-miR-34a, part of the TP53 suppressor complex, has been reported in both nodular and pagetoid sebaceous carcinomas, and nuclear expression has been observed in 68% of intraepithelial tumor cells in OA cases [10,22].…”

Section: Discussionsupporting

confidence: 90%

“…In this cohort, 77% and 54% of all sebaceous carcinomas harbored these mutations, respectively. TP53 mutations were only identified in OA tumors, and the frequency in our group was similar to that reported in prior studies [11,24,35]. One previous study reported aberrant immunolabeling, potentially corresponding to TP53 mutations in 19/29 (66%) of OA sebaceous carcinomas; in another series, TP53 mutations were detected in 23/31 (71%) of cases [11,35].…”

Section: Discussionsupporting

confidence: 89%

“…Additionally, overexpression of Has-miR-34a, part of the TP53 suppressor complex, has been reported in both nodular and pagetoid sebaceous carcinomas, and nuclear expression has been observed in 68% of intraepithelial tumor cells in OA cases [10,22]. RB1 mutations were reported in 14/29 (48%) and 12/31 (39%) of OA tumors in two studies [11,35].…”

Section: Discussionmentioning

confidence: 99%

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NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas

Peterson

Moore

Hicks

et al. 2021

IJMS

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Ocular adnexal (OA) sebaceous carcinomas generally demonstrate more aggressive clinical and histopathological phenotypes than extraocular cases, but the molecular drivers implicated in their oncogenesis remain poorly defined. A retrospective review of surgical and ocular pathology archives identified eleven primary resection specimens of OA sebaceous carcinomas with adequate tissue for molecular analysis; two extraocular cases were also examined. Next-generation sequencing was used to evaluate mutations and copy number changes in a large panel of cancer-associated genes. Fluorescence in situ hybridization (FISH) confirmed MYC copy number gain in select cases, and immunohistochemistry to evaluate MYC protein expression. The commonest mutations occurred in TP53 (10/13) and RB1 (7/13). Additional mutations in clinically actionable genes, or mutations with a frequency of at least 25%, included the NF1 (3/12), PMS2 (4/12), ROS1 (3/12), KMT2C (4/12), MNX1 (6/12), NOTCH1 (4/12), PCLO (3/12), and PTPRT (3/12) loci. Low level copy number gain suggestive of amplification of the MYC locus was seen in two cases, and confirmed using FISH. MYC protein expression, as assessed by immunohistochemistry, was present in almost all sebaceous carcinoma cases. Our findings support the concept that alterations in TP53 and RB1 are the commonest alterations in sebaceous carcinoma, and suggest that MYC may contribute to the oncogenesis of these tumors.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas

Peterson

Moore

Hicks

et al. 2021

IJMS

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“…In fact, recent work shows that of the mutations identified by WES, mutations in RB1 were some of the most common and unique to ocular SC. 17,18 Given the high incidence of RB1 mutation found in SC, the propagation of the mutation into BP50 supports its use as a RB1-specific SC model.…”

Section: Discussionmentioning

confidence: 99%

“…Otherwise, somatic mutations within the ZNF750, PCDH15, or NOTCH1 genes or related pathways were not identified in the tumor or cell line. [16][17][18]…”

Section: Mutational Analysis Of Primary Tumor and Derived Cell Linementioning

confidence: 99%

Establishment and Characterization of a Novel Human Ocular Adnexal Sebaceous Carcinoma Cell Line

Rong

Gallo

Zhang

et al. 2021

Trans. Vis. Sci. Tech.

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Sebaceous carcinoma (SC) is a malignant eyelid tumor of the ocular adnexa that is primarily treated via surgical excision. Few therapies exist in advanced cases, and medical therapy is limited because of our incomplete understanding of SC biology. Herein, we describe a technique to culture human ocular adnexal SC for use as an in vitro model. Methods: Human ocular adnexal SC tumor cells were isolated from a patient undergoing orbital exenteration surgery and named Bascom Palmer 50 (BP50). They were cultured in Dulbecco's modified Eagle medium/nutrient mixture F-12 supplemented with 10% fetal bovine serum and antibiotics and were maintained at 37°C in humidified 5% CO 2 . The cells were characterized by immunohistochemistry, exome sequencing, and short tandem repeats analysis. In vitro drug screening against mitomycin-C (MMC) was performed using a cell viability assay.Results: BP50 grew past 40 passages with a doubling time of 52.3 hours. Immunocytochemical staining revealed expression of SC-associated markers adipophilin, epithelial membrane antigen, p53, and androgen receptor. Whole exome sequencing showed a significant carryover in somatic mutations between the tumor tissue and corresponding cell line, revealing genetic markers consistent with SC. MMC affected cell viability in a dose-dependent manner.Conclusions: BP50 displays characteristics of ocular adnexal SC and therefore may facilitate improved understanding of SC biology and the high throughput assessment of novel therapeutic compounds and new drug combinatorial approaches targeted for this disease.Translational Relevance: Drug screening with MMC against these cells shows in vitro evidence to support its continued clinical use in SC.

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Prognostic Significance of Tumor-Infiltrating Lymphocytes and High-Risk Human Papillomavirus in Ocular Sebaceous Carcinoma: A Comprehensive Analysis

Jeong,

Song,

Lee

et al. 2024

Modern Pathology

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Whole-exome sequencing for ocular adnexal sebaceous carcinoma suggests PCDH15 as a novel mutation associated with metastasis

Cited by 16 publications

References 19 publications

NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas

NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas

Establishment and Characterization of a Novel Human Ocular Adnexal Sebaceous Carcinoma Cell Line

Prognostic Significance of Tumor-Infiltrating Lymphocytes and High-Risk Human Papillomavirus in Ocular Sebaceous Carcinoma: A Comprehensive Analysis

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