Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma

Abdel‐Rahman, Mohamed H.; Sample, Klarke M.; Pilarski, Robert; Walsh, Tom; Grosel, Timothy; Kinnamon, Daniel D.; Boru, Getachew; Massengill, James B.; Schoenfield, Lynn; Kelly, Ben; Gordon, David; Johansson, Peter; DeBenedictis, Meghan J; Singh, Arun D.; Casadei, Silvia; Davidorf, Frederick H.; White, Peter; Stacey, Andrew W.; Scarth, James; Fewings, Eleanor; Tischkowitz, Marc; King, Mary Claire; Hayward, Nicholas K.; Cebulla, Colleen M.

doi:10.1016/j.ophtha.2019.11.009

Cited by 33 publications

(28 citation statements)

References 57 publications

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“…Other cancer genes reported in patients with UM include BRCA2, BRCA1, CHEK2, PALB2, SMARCE1, MBD4, MSH6 and MLH1. 12 17 CHEK2 mutations predispose to papillary thyroid, prostate and breast cancers. 18 PALB2 mutations show an association with breast, ovarian and pancreatic cancers.…”

Section: Discussionmentioning

confidence: 99%

Uveal melanoma-associated cancers revisited

et al. 2020

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BackgroundUveal melanoma (UM) is the most common primary ocular malignancy of adults. A small group of patients was found to express familial predisposition. Moreover, it may be preceded or followed by other malignancies elsewhere in the body. We aim to compare the incidence of UM and other associated cancers and study the factors that may influence each condition.Patients and methodsWe have collected the data from the Surveillance, Epidemiology and End Results database of nine US cancer registries for UM patients between 1973 and 2015. We calculated the standardised incidence ratios for single primary UM, first primary and second primary UM, and compared the groups for multiple factors.ResultsA total of 4946 patients were included in the study; 3863 with single primary UM, 646 developed a second primary malignancy following UM, and 437 patients developed second primary UM following a previous primary malignancy. The risk of developing UM increased after leukaemia, melanoma of the skin and prostate. On the other side, the risk of developing melanoma of the skin, thyroid, renal and other eye and orbit malignancies has increased significantly after initial UM. This risk was more evident in the age group between 50 and 70 years old. Cancer-specific survival was significantly higher in UM associated with other malignancies group compared with single primary UM.ConclusionOur study showed a different behaviour of the UM when associated with other tumours that exceed the known spectrum of hereditary UM. Further studies are required to dissect the genetic background of this behaviour.

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Section: Discussionmentioning

confidence: 99%

Uveal melanoma-associated cancers revisited

et al. 2020

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“…In this review, the cases of pregnant women with UM were notably younger at presentation than unselected UM patients (median age 29.5 vs. 62 years, respectively) [12]. Recent research by Abdel-Rahman et al [53-57] on genetic causes of UM has shown that germline mutation in BAP1 and other genes can predispose patients to UM and other cancers, and that their cancers may present at an earlier age than in the general population. In UM, younger patients (<age 30) have a higher incidence of BAP1 germline mutation compared to unselected UM patients (∼7 vs. ∼1–2%) [57].…”

Section: Evidence For Sex Hormone Receptor Expression In Nevi/um Tumorsmentioning

confidence: 97%

Is Uveal Melanoma a Hormonally Sensitive Cancer? A Review of the Impact of Sex Hormones and Pregnancy on Uveal Melanoma

Miller¹,

Schoenfield²,

Abdel-Rahman³

et al. 2021

Ocul Oncol Pathol

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Background: Despite a higher incidence and worse prognosis of uveal melanoma (UM) in men, there have been many case reports of pregnant patients with aggressive UM. This has led researchers to explore the influence of sex hormones and pregnancy on the development and progression of UM and hormones as potential therapeutic targets. Summary: A systematic literature review was conducted. More work is needed to elucidate the basis of sex differences in UM incidence and survival. The evaluation of germline BAP1 mutation would be beneficial in patients with UM presenting at a young age. Importantly, multiple studies reported no significant difference between the 5-year survival and 5-year metastasis-free survival rates between nonpregnant women with UM and pregnant women with UM. Multiple case-control studies disagree on how parity affects risk of UM. However, most studies agree that oral contraceptives and hormone replacement therapy have no effect on the incidence of UM. Current treatment strategies for pregnant patients with UM are discussed. Looking forward, this review reports recent research on targeted receptor-based chemotherapy, which is based on evidence of estrogen receptor (ER), estrogen-related receptor alpha (ERRα), and luteinizing hormone-releasing hormone (LHRH) receptor expression in UM. Key Messages: Based on review of the literature, UM is not a contraindication to oral contraceptives, hormone replacement therapy, or pregnancy. Globe-sparing radiation can be used as a treatment option for pregnant patients. Due to the presence of ER on a subset of unselected UM, its potential for adjunctive targeted therapy with agents like tamoxifen should be explored. Lessons from cutaneous melanoma regarding tissue ratios of estrogen receptors (ERα:ERβ) should be applied to assess their therapeutic predictive value. In addition, ERRα-targeted therapeutics and LHRH analogs are worthy of further exploration in UM.

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“…Examples are represented by mutations in the MLH1 and MSH2 genes that belong to the MMR pathway. When these genes are mutated, the resulting dysfunctional MMR leads to failure in properly recognizing and resolving errors arising from physiological processes, such as DNA replication, therefore priming malignant outcomes [ 84 ] or predisposing to cancer [ 85 ]. However, alteration in DDR can trigger disorders other than cancer.…”

Section: Dna Repair Defectsmentioning

confidence: 99%

DNA Damage: From Threat to Treatment

Carusillo

Mussolino

2020

Cells

152

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DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.

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Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma

Cited by 33 publications

References 57 publications

Uveal melanoma-associated cancers revisited

Uveal melanoma-associated cancers revisited

Is Uveal Melanoma a Hormonally Sensitive Cancer? A Review of the Impact of Sex Hormones and Pregnancy on Uveal Melanoma

DNA Damage: From Threat to Treatment

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