Whole exome profiling and mutational analysis of Ocular Surface Squamous Neoplasia

Ramos-Betancourt, Nallely; Field, Matthew G.; Davila-Alquisiras, Jesus H.; Karp, Carol L.; Hernández-Zimbrón, Luis Fernando; Garcia-Vazquez, R; Vázquez-Romo, K.A.; Wang, Gaofeng; Fromow-Guerra, Jans; Hernández-Quíntela, Everardo

doi:10.1016/j.jtos.2020.07.011

Cited by 11 publications

(11 citation statements)

References 27 publications

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“…The predominant cytosine to thymine base substitution at pyrimidine sites is unique to UV-insults, and is therefore known as the ‘UV-signature’ [ 46 ]. OSSN and squamous cell carcinoma of the skin exhibit this molecular signature, especially in the TP53 gene [ 46 , 47 , 48 ]. One study defined the mutation spectrum of the TP53 gene in pterygium, and one out of six missense mutations encompassed a cytosine to thymine transversion (exon 5, codon 179, CAT) [ 49 ].…”

Section: Uv-induced Damagementioning

confidence: 99%

Pterygium—The Good, the Bad, and the Ugly

Acker

Bogerd

Haagdorens

et al. 2021

Cells

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Pterygium is a multifaceted pathology that displays apparent conflicting characteristics: benign (e.g., self-limiting and superficial), bad (e.g., proliferative and potentially recurrent) and ugly (e.g., signs of preneoplastic transformation). The natural successive question is: why are we lacking reports showing that pterygium lesions become life-threatening through metastasis, especially since pterygium has considerable similarities with UV-related malignancies on the molecular level? In this review, we consider how our pathophysiological understanding of the benign pterygium pathology overlaps with ocular surface squamous neoplasia and skin cancer. The three UV-related disorders share the same initial insult (i.e., UV radiation) and responsive repair mechanisms to the ensuing (in)direct DNA damage. Their downstream apoptotic regulators and other cellular adaptations are remarkably alike. However, a complicating factor in understanding the fine line between the self-limiting nature of pterygium and the malignant transformation in other UV-related diseases is the prominent ambiguity in the pathological evaluation of pterygium biopsies. Features of preneoplastic transformation (i.e., dysplasia) are used to define normal cellular reactions (i.e., atypia and metaplasia) and vice versa. A uniform grading system could help in unraveling the true nature of this ancient disease and potentially help in identifying the earliest intervention point possible regarding the cellular switch that drives a cell’s fate towards cancer.

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Section: Uv-induced Damagementioning

confidence: 99%

Pterygium—The Good, the Bad, and the Ugly

Acker

Bogerd

Haagdorens

et al. 2021

Cells

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“…Series from the USA ( n = 60), Thailand ( n = 30), and Australia ( n = 288) have reported that 30%–50% of the patients synchronously presented with other ocular diseases related to UVR exposure: pterygium, pinguecula, solar elastosis, or nuclear sclerosis (Lee & Hirst, 1997 ; Tulvatana et al, 2003 ; Tunc et al, 1999 ). A few studies have investigated the genomic profile of conjunctival SCC and the precursor lesions (Galor et al, 2016 ; Lazo de la Vega et al, 2020 ; Ramos‐Betancourt et al, 2020 ). One study reported a UVR mutational signature in 10 out of 10 conjunctival CIN investigated by whole‐exome sequencing (Ramos‐Betancourt et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…A few studies have investigated the genomic profile of conjunctival SCC and the precursor lesions (Galor et al, 2016 ; Lazo de la Vega et al, 2020 ; Ramos‐Betancourt et al, 2020 ). One study reported a UVR mutational signature in 10 out of 10 conjunctival CIN investigated by whole‐exome sequencing (Ramos‐Betancourt et al, 2020 ). A few studies have reported C > T and CC > TT variants in selected genes, such as TP53 (Ateenyi‐Agaba et al, 2004 ) and the TERT promoter (Scholz et al, 2015 ; Starita et al, 2018 ), indicative of UVR‐induced damage; however, caution must be paid when deducing the mutagen from genetic patterns in few loci.…”

Section: Introductionmentioning

confidence: 99%

“…Frequent pathogenic variants in TP53 and the TERT promoter have been reported in conjunctival CIN and SCC (Ateenyi‐Agaba et al, 2004 ; Scholz et al, 2015 ; Starita et al, 2018 ). However, the genomic profile of conjunctival SCC has only been addressed in one previous study (Lazo de la Vega et al, 2020 ), and two additional studies have performed whole‐exome sequencing of pre‐invasive tumors (Galor et al, 2016 ; Ramos‐Betancourt et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Loss of heterozygosity in CDKN2A and TP53 were evident also in the pre‐invasive tumors, indicating that these are early events in conjunctival SCC development (Lazo de la Vega et al, 2020 ). In the two studies assessing the genetic profile of conjunctival CIN, frequent variants in cancer‐related genes were detected in TP53 , HGF , and CREBBP (Galor et al, 2016 ; Ramos‐Betancourt et al, 2020 ). As for now, no genomic biomarker has been incorporated into conjunctival CIN and SCC diagnostics, prognostication, or prediction.…”

Section: Introductionmentioning

confidence: 99%

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Human papillomavirus‐related neoplasia of the ocular adnexa

Ramberg

2022

Acta Ophthalmologica

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SummaryHuman papillomaviruses (HPV) are involved in approximately 5% of solid cancers worldwide. The mucosotropic genotypes infect the stratified epithelium of various locations, where persistent infection may lead to invasive carcinomas. While the causative role of HPV in certain anogenital and head and neck carcinomas is well established, the role of HPV in carcinomas arising in the mucosal membranes of the ocular adnexal tissue (the lacrimal drainage system and the conjunctiva) has been a topic of great uncertainty. Therefore, we conducted a series of studies to assess the correlation between HPV and carcinomas arising in the mucosa of the ocular adnexal tissue and characterize the clinical, histopathological, and genomic features of the tumors in the context of HPV status in a Danish nationwide cohort.We collected clinical and histopathological data and tumor specimens from patients with carcinomas of the conjunctiva and the lacrimal drainage system, and their potential precursors, identified in Danish nationwide registries. The HPV status of the tumors was determined by the combined use of HPV DNA polymerase chain reaction (PCR), HPV E6/E7 mRNA in‐situ hybridization, and p16 immunohistochemistry. The genomic profile was investigated by high‐throughput DNA sequencing targeting 523 cancer‐relevant genes. The literature to date on carcinomas of the lacrimal drainage system and the conjunctiva was summarized.In the Danish cohort, 67% of all carcinomas of the lacrimal drainage system and 21% of all conjunctival carcinomas were HPV‐positive. HPV16 was the most frequently implicated genotype. A full‐thickness expression of the viral oncogenes E6 and E7 was evident in almost all HPV DNA‐positive cases. The HPV‐positive carcinomas of the conjunctiva and the lacrimal drainage system shared histopathological and genomic features distinct from their HPV‐negative counterparts. The HPV‐positive carcinomas were characterized by a non‐keratinizing morphology, p16 overexpression, high transcriptional activity of HPV E6/E7, and frequent pathogenic variants in the PI3K‐AKT signaling cascade. In contrast, the HPV‐negative carcinomas were characterized by a keratinizing morphology, lack of p16 and E6/E7 expression, and frequent somatic pathogenic variants in TP53, CDKN2A, and RB1. Among the patients with conjunctival tumors, HPV positivity was associated with a younger age at diagnosis and a higher risk of recurrence.In conclusion, the results support an etiological role of HPV in a subset of conjunctival and LDS carcinomas and their precursor lesions. Our investigations have shown that the HPV‐positive carcinomas of the ocular adnexa share genomic and phenotypic characteristics with HPV‐positive carcinomas of other anatomical locations. Therefore, these patients may be eligible for inclusion in future basket trials and future treatment regimens tailored to the more frequently occurring HPV‐positive carcinomas of other locations. Future research will further elucidate the diagnostic, prognostic, and predictive role of HPV in these carcinomas.

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