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4. Iris melanoma in an Australian cohort.

Author

McGrath, Lindsay A., Warrier, Sunil K., Glasson, William J., D'Mellow, Matthew G., Hamilton, Hayley R., Palmer, Jane M., Brooks, Kelly M., Johansson, Peter A., and Hayward, Nicholas K.

Subjects
*IRIS (Eye), *GENETIC profile, *ULTRAVIOLET radiation, *INDIVIDUAL development, *HOBBIES
Abstract

Background: To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. Methods: This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age‐adjusted incidence and relative survival. Results: Eighty‐six patients (63% female) were included. Mean age was 54 years (range 17–82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low‐risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1–21 years) after diagnosis, and only one case of metastasis was documented. Conclusions: The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR‐related uveal melanoma. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Author

Johansson, Peter A., Brooks, Kelly, Newell, Felicity, Palmer, Jane M., Wilmott, James S., Pritchard, Antonia L., Broit, Natasa, Wood, Scott, Carlino, Matteo S., Leonard, Conrad, Koufariotis, Lambros T., Nathan, Vaishnavi, Beasley, Aaron B., Howlie, Madeleine, Dawson, Rebecca, Rizos, Helen, Schmidt, Chris W., Long, Georgina V., Hamilton, Hayley, Kiilgaard, Jens F., Isaacs, Timothy, Gray, Elin S., Rolfe, Olivia J., Park, John J., Stark, Andrew, Mann, Graham J., Scolyer, Richard A., Pearson, John V., van Baren, Nicolas, Waddell, Nicola, Wadt, Karin W., McGrath, Lindsay A., Warrier, Sunil K., Glasson, William, and Hayward, Nicholas K.

Published
2020
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6. Conjunctival Lymphoma

Author

McGrath, Lindsay A., primary, Ryan, David A., additional, Warrier, Sunil K., additional, Coupland, Sarah E., additional, and Glasson, William J., additional

Published
2022
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7. Loss-of-function variants in POT1 predispose to uveal melanoma

Author

Nathan, Vaishnavi, primary, Palmer, Jane M, additional, Johansson, Peter A, additional, Hamilton, Hayley R, additional, Warrier, Sunil K, additional, Glasson, William, additional, McGrath, Lindsay A, additional, Kahl, Vivian F S, additional, Vasireddy, Raja S, additional, Pickett, Hilda A, additional, Brooks, Kelly M, additional, Pritchard, Antonia L, additional, and Hayward, Nicholas K, additional

Published
2020
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10. Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Author

Johansson, Peter A, Brooks, Kelly, Newell, Felicity, Palmer, Jane M, Wilmott, James S, Pritchard, Antonia L, Broit, Natasa, Wood, Scott, Carlino, Matteo S, Leonard, Conrad, Koufariotis, Lambros T, Nathan, Vaishnavi, Beasley, Aaron B, Howlie, Madeleine, Dawson, Rebecca, Rizos, Helen, Schmidt, Chris W, Long, Georgina V, Hamilton, Hayley, Kiilgaard, Jens F, Isaacs, Timothy, Gray, Elin S, Rolfe, Olivia J, Park, John J, Stark, Andrew, Mann, Graham J, Scolyer, Richard A, Pearson, John V, van Baren, Nicolas, Waddell, Nicola, Wadt, Karin W, McGrath, Lindsay A, Warrier, Sunil K, Glasson, William, Hayward, Nicholas K, Johansson, Peter A, Brooks, Kelly, Newell, Felicity, Palmer, Jane M, Wilmott, James S, Pritchard, Antonia L, Broit, Natasa, Wood, Scott, Carlino, Matteo S, Leonard, Conrad, Koufariotis, Lambros T, Nathan, Vaishnavi, Beasley, Aaron B, Howlie, Madeleine, Dawson, Rebecca, Rizos, Helen, Schmidt, Chris W, Long, Georgina V, Hamilton, Hayley, Kiilgaard, Jens F, Isaacs, Timothy, Gray, Elin S, Rolfe, Olivia J, Park, John J, Stark, Andrew, Mann, Graham J, Scolyer, Richard A, Pearson, John V, van Baren, Nicolas, Waddell, Nicola, Wadt, Karin W, McGrath, Lindsay A, Warrier, Sunil K, Glasson, William, and Hayward, Nicholas K

Abstract

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).

Published
2020

11. A Panel of Circulating MicroRNAs Detects Uveal Melanoma With High Precision

Author

Stark, Mitchell S., primary, Gray, Elin S., additional, Isaacs, Timothy, additional, Chen, Fred K., additional, Millward, Michael, additional, McEvoy, Ashleigh, additional, Zaenker, Pauline, additional, Ziman, Melanie, additional, Soyer, H. Peter, additional, Glasson, William J., additional, Warrier, Sunil K., additional, Stark, Andrew L., additional, Rolfe, Olivia J., additional, Palmer, Jane M., additional, and Hayward, Nicholas K., additional

Published
2019
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12. A panel of circulating MicroRNAs detects uveal melanoma with high precision

Author

Stark, Mitchell S., Gray, Elin S., Isaacs, Timothy, Chen, Fred K., Millward, Michael, McEvoy, Ashleigh, Zaenker, Pauline, Ziman, Melanie, Soyer, H. Peter, Glasson, William J., Warrier, Sunil K., Stark, Andrew L., Rolfe, Olivia J., Palmer, Jane M., Hayward, Nicholas K., Stark, Mitchell S., Gray, Elin S., Isaacs, Timothy, Chen, Fred K., Millward, Michael, McEvoy, Ashleigh, Zaenker, Pauline, Ziman, Melanie, Soyer, H. Peter, Glasson, William J., Warrier, Sunil K., Stark, Andrew L., Rolfe, Olivia J., Palmer, Jane M., and Hayward, Nicholas K.

Abstract

Purpose: To determine if a circulating microRNA (miRNA) panel could be used to distinguish between uveal melanoma and uveal nevi. Methods: We report on a multicenter, cross-sectional study conducted between June 2012 and September 2015. The follow-up time was approximately 3 to 5 years. Blood was drawn from participants presenting with a uveal nevus (n = 10), localized uveal melanoma (n = 50), or metastatic uveal melanoma (n = 5). Levels of 17 miRNAs were measured in blood samples of study participants using a sensitive real-time PCR system. Results: A panel of six miRNAs (miR-16, miR-145, miR-146a, miR-204, miR-211, and miR-363-3p) showed significant differences between participants with uveal nevi compared with patients with localized and metastatic uveal melanoma. Importantly, miR-211 was able to accurately distinguish metastatic disease from localized uveal melanoma (P < 0.0001; area under the curve = 0.96). When the six-miRNA panel was evaluated as a group it had the ability to identify uveal melanoma when four or more miRNAs (93% sensitivity and 100% specificity) reached or exceeded their cut-point. Conclusions: This miRNA panel, in tandem with clinical findings, may be suited to confirm benign lesions. In addition, due to the panel’s high precision in identifying malignancy, it has the potential to augment melanoma detection in subsequent clinical follow-up of lesions with atypical clinical features. Translational Relevance: Uveal nevi mimic the appearance of uveal melanoma and their transformation potential cannot be definitively determined without a biopsy. This panel is most relevant at the nevus stage and in lesions with uncertain malignant potential as a companion diagnostic tool to assist in clinical decision-making.

Published
2019

13. Sutureless vitrectomy

Author

Warrier, Sunil K, Jain, Rajeev, Gilhotra, Jagjit Singh, and Newland, Henry S

Subjects
Review Article, 20 gauge, 23 gauge, sutureless vitrectomy, transconjunctival, 25 gauge
Abstract

Sutureless vitrectomy has rapidly been accepted as an essential part of a vitreoretinal surgical setup. The size and structure of the wound along with near intact conjunctival covering makes the incision self-sealing and safe. This allows the vitrectomy instruments to be used without creating an initial limited peritomy to expose bare sclera, and obviates the need for sutures at the end of the procedure. Wound construction is the essential step in ensuring postoperative wound stability. Both one-step and two-step wound constructions have been described. Key points include an oblique, tunneled approach to ensure a valve-like effect as well as misalignment of conjunctival and scleral wounds by displacing conjunctiva during construction. Advantages include decreased operative times in certain cases and decreased postoperative inflammation, early postoperative rehabilitation, improved patient comfort, and minimal conjunctival damage. Complications are based around wound competence, hypotony, and its relationship to endophthalmitis rates. Early reports highlighted an increase in endophthalmitis though further studies are required to accurately assess the incidence. Endophthalmitis has not been reported in cases that underwent fluid/air exchange. This review focuses on techniques, benefits, complications, personal experiences, and the safety profiles of sutureless vitrectomy systems. A literature review was undertaken using ′Medline′ and ′Pubmed′. Search terms included sutureless vitrectomy, 20 gauge, 23 gauge, 25 gauge, and transconjunctival and small gauge vitrectomy.

Published
2008

15. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

Author

Johansson, Peter, Aoude, Lauren G, Wadt, Karin, Glasson, William J, Warrier, Sunil K, Hewitt, Alex W, Kiilgaard, Jens Folke, Heegaard, Steffen, Isaacs, Tim, Franchina, Maria, Ingvar, Christian, Vermeulen, Tersia, Whitehead, Kevin J, Schmidt, Christopher W, Palmer, Jane M, Symmons, Judith, Gerdes, Anne-Marie, Jönsson, Göran, Hayward, Nicholas K, Johansson, Peter, Aoude, Lauren G, Wadt, Karin, Glasson, William J, Warrier, Sunil K, Hewitt, Alex W, Kiilgaard, Jens Folke, Heegaard, Steffen, Isaacs, Tim, Franchina, Maria, Ingvar, Christian, Vermeulen, Tersia, Whitehead, Kevin J, Schmidt, Christopher W, Palmer, Jane M, Symmons, Judith, Gerdes, Anne-Marie, Jönsson, Göran, and Hayward, Nicholas K

Abstract

Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

Published
2016

16. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

Author

Johansson, Peter, primary, Aoude, Lauren G., additional, Wadt, Karin, additional, Glasson, William J., additional, Warrier, Sunil K., additional, Hewitt, Alex W., additional, Kiilgaard, Jens Folke, additional, Heegaard, Steffen, additional, Isaacs, Tim, additional, Franchina, Maria, additional, Ingvar, Christian, additional, Vermeulen, Tersia, additional, Whitehead, Kevin J., additional, Schmidt, Christopher W., additional, Palmer, Jane M., additional, Symmons, Judith, additional, Gerdes, Anne-Marie, additional, Jönsson, Göran, additional, and Hayward, Nicholas K., additional

Published
2015
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19. Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Author

<p>Funding information available at https://doi.org/10.1007/s00429-020-02071-1</p>, Johansson, Peter A., Brooks, Kelly, Newell, Felicity, Palmer, Jane M., Wilmott, James S., Pritchard, Antonia L., Broit, Natasa, Wood, Scott, Carlino, Matteo S., Leonard, Conrad, Koufariotis, Labros T., Nathan, Vaishnavi, Beasley, Aaron B., Howlie, Madeleine, Dawson, Rebecca, Rizos, Helen, Schmidt, Chris W., Long, Georgina V., Hamilton, Hayley, Kiilgaard, Jens F., Isaacs, Timothy, Gray, Elin S., Rolfe, Olivia J., Park, John J., Stark, Andrew, Mann, Graham J., Scolyer, Richard A., Pearson, John V., van Baren, Nicolas, Waddell, Nicola, Wadt, Karin W., McGrath, Lindsay A., Warrier, Sunil K., Glasson, William, Hayward, Nicholas K., <p>Funding information available at https://doi.org/10.1007/s00429-020-02071-1</p>, Johansson, Peter A., Brooks, Kelly, Newell, Felicity, Palmer, Jane M., Wilmott, James S., Pritchard, Antonia L., Broit, Natasa, Wood, Scott, Carlino, Matteo S., Leonard, Conrad, Koufariotis, Labros T., Nathan, Vaishnavi, Beasley, Aaron B., Howlie, Madeleine, Dawson, Rebecca, Rizos, Helen, Schmidt, Chris W., Long, Georgina V., Hamilton, Hayley, Kiilgaard, Jens F., Isaacs, Timothy, Gray, Elin S., Rolfe, Olivia J., Park, John J., Stark, Andrew, Mann, Graham J., Scolyer, Richard A., Pearson, John V., van Baren, Nicolas, Waddell, Nicola, Wadt, Karin W., McGrath, Lindsay A., Warrier, Sunil K., Glasson, William, and Hayward, Nicholas K.

Abstract

Johansson, P. A., Brooks, K., Newell, F., Palmer, J. M., Wilmott, J. S., Pritchard, A. L., ... & Koufariotis, L. T. (2020). Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours. Nature communications, 11(1), Article number: 2408. https://doi.org/10.1038/s41467-020-16276-8

20. A panel of circulating MicroRNAs detects uveal melanoma with high precision

Author

Stark, Mitchell S., Gray, Elin S., Isaacs, Timothy, Chen, Fred K., Millward, Michael, McEvoy, Ashleigh, Zaenker, Pauline, Ziman, Melanie, Soyer, H. Peter, Glasson, William J., Warrier, Sunil K., Stark, Andrew L., Rolfe, Olivia J., Palmer, Jane M., Hayward, Nicholas K., Stark, Mitchell S., Gray, Elin S., Isaacs, Timothy, Chen, Fred K., Millward, Michael, McEvoy, Ashleigh, Zaenker, Pauline, Ziman, Melanie, Soyer, H. Peter, Glasson, William J., Warrier, Sunil K., Stark, Andrew L., Rolfe, Olivia J., Palmer, Jane M., and Hayward, Nicholas K.

Abstract

Stark, M. S., Gray, E. S., Isaacs, T., Chen, F. K., Millward, M., McEvoy, A., ... Hayward, N. K. (2019). A panel of circulating microRNAs detects uveal melanoma with high precision. Translational Vision Science and Technology, 8(6), Article 12. Available here

21. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4.

Author

Johansson P, Aoude LG, Wadt K, Glasson WJ, Warrier SK, Hewitt AW, Kiilgaard JF, Heegaard S, Isaacs T, Franchina M, Ingvar C, Vermeulen T, Whitehead KJ, Schmidt CW, Palmer JM, Symmons J, Gerdes AM, Jönsson G, and Hayward NK

Subjects
Humans, Neoplasm Staging, Prognosis, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Uveal Melanoma, Biomarkers, Tumor genetics, High-Throughput Nucleotide Sequencing methods, Melanoma diagnosis, Melanoma genetics, Phospholipase C beta genetics, Uveal Neoplasms diagnosis, Uveal Neoplasms genetics
Abstract

Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM&#95;000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.

Published
2016
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