TY - JOUR
T1 - Mutational Landscape and Outcomes of Conjunctival Melanoma in 101 Patients
AU - Lally, Sara E.
AU - Milman, Tatyana
AU - Orloff, Marlana
AU - Dalvin, Lauren A.
AU - Eberhart, Charles G.
AU - Heaphy, Christopher M.
AU - Rodriguez, Fausto J.
AU - Lin, Chun Chieh
AU - Dockery, Philip W.
AU - Shields, Jerry A.
AU - Shields, Carol L.
N1 - Funding Information:
Support provided by the Eye Tumor Research Foundation , Philadelphia, Pennsylvania (to S.E.L., J.A.S., C.L.S.). The funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. Sara E. Lally, MD, has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2022 American Academy of Ophthalmology
PY - 2022/6
Y1 - 2022/6
N2 - Purpose: To evaluate targetable mutations and molecular genetic pathways in conjunctival melanoma with clinical correlation. Design: Observational case series. Participants: Patients with conjunctival melanoma. Main Outcome Measures: Mutational profile of the tumor by next-generation sequencing (NGS), alternative lengthening of telomeres (ALT) by fluorescence in situ hybridization (FISH), and ATRX immunohistochemistry. Outcomes at 2 years and 5 years of tumor-related metastasis and death were recorded. Results: Of the 101 patients, mean age at presentation was 60 years, 52% were male, and 88% were White. The NGS panels initially targeted BRAF only (n = 6, 6%), BRAF/NRAS (n = 17, 17%), and BRAF/NRAS/NF1 (n = 10, 10%). Sixty-eight tumors were tested with the expanded 592-gene panel. Next-generation sequencing identified high-frequency mutations in NF1 (29/74, 39%), BRAF (31/101, 31%), NRAS (25/95, 26%), and ATRX (17/68, 25%). Of those with an ATRX mutation, 12 (71%) had an additional NF1 mutation. A subset analysis of 21 melanomas showed that the ATRX mutation was associated with loss of ATRX protein expression and ALT. Loss of ATRX expression and ALT were present in both intraepithelial and invasive tumors, suggesting that an ATRX mutation is an early event in conjunctival melanoma progression. The NF1 and ATRX mutations were associated with tarsal (vs. nontarsal) tumors (NF1: 28% vs. 9%, P = 0.035, ATRX: 41% vs. 14%, P = 0.021) and orbital (vs. nonorbital) tumors (ATRX: 24% vs. 2%, P = 0.007). ATRXMUT (vs. ATRXWT) tumors were associated with a lower 2-year rate of metastasis (0% vs. 24%, P = 0.005). NRASMUT (vs. NRASWT) tumors were associated with a greater 2-year rate of metastasis (28% vs. 14%, P = 0.07) and death (16% vs. 4%, P = 0.04), with a 5-fold increased risk of death (relative risk, 5.45 [95% confidence interval, 1.11–26.71], P = 0.039). Conclusions: This study confirms the high frequency of previously documented BRAF and NRAS mutations and recently reported ATRX and NF1 mutations in conjunctival melanoma. An NRAS mutation implied increased risk for metastasis and death. Loss of ATRX and ALT may be early events in conjunctival melanoma development.
AB - Purpose: To evaluate targetable mutations and molecular genetic pathways in conjunctival melanoma with clinical correlation. Design: Observational case series. Participants: Patients with conjunctival melanoma. Main Outcome Measures: Mutational profile of the tumor by next-generation sequencing (NGS), alternative lengthening of telomeres (ALT) by fluorescence in situ hybridization (FISH), and ATRX immunohistochemistry. Outcomes at 2 years and 5 years of tumor-related metastasis and death were recorded. Results: Of the 101 patients, mean age at presentation was 60 years, 52% were male, and 88% were White. The NGS panels initially targeted BRAF only (n = 6, 6%), BRAF/NRAS (n = 17, 17%), and BRAF/NRAS/NF1 (n = 10, 10%). Sixty-eight tumors were tested with the expanded 592-gene panel. Next-generation sequencing identified high-frequency mutations in NF1 (29/74, 39%), BRAF (31/101, 31%), NRAS (25/95, 26%), and ATRX (17/68, 25%). Of those with an ATRX mutation, 12 (71%) had an additional NF1 mutation. A subset analysis of 21 melanomas showed that the ATRX mutation was associated with loss of ATRX protein expression and ALT. Loss of ATRX expression and ALT were present in both intraepithelial and invasive tumors, suggesting that an ATRX mutation is an early event in conjunctival melanoma progression. The NF1 and ATRX mutations were associated with tarsal (vs. nontarsal) tumors (NF1: 28% vs. 9%, P = 0.035, ATRX: 41% vs. 14%, P = 0.021) and orbital (vs. nonorbital) tumors (ATRX: 24% vs. 2%, P = 0.007). ATRXMUT (vs. ATRXWT) tumors were associated with a lower 2-year rate of metastasis (0% vs. 24%, P = 0.005). NRASMUT (vs. NRASWT) tumors were associated with a greater 2-year rate of metastasis (28% vs. 14%, P = 0.07) and death (16% vs. 4%, P = 0.04), with a 5-fold increased risk of death (relative risk, 5.45 [95% confidence interval, 1.11–26.71], P = 0.039). Conclusions: This study confirms the high frequency of previously documented BRAF and NRAS mutations and recently reported ATRX and NF1 mutations in conjunctival melanoma. An NRAS mutation implied increased risk for metastasis and death. Loss of ATRX and ALT may be early events in conjunctival melanoma development.
KW - ATRX
KW - Alternative lengthening of telomeres
KW - BRAF
KW - Biomarker
KW - Conjunctiva
KW - Fluorescence in situ hybridization
KW - Melanoma
KW - Mutation
KW - NF1
KW - NRAS
KW - Next-generation sequencing
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U2 - 10.1016/j.ophtha.2022.01.016
DO - 10.1016/j.ophtha.2022.01.016
M3 - Article
C2 - 35085662
AN - SCOPUS:85126559828
SN - 0161-6420
VL - 129
SP - 679
EP - 693
JO - Ophthalmology
JF - Ophthalmology
IS - 6
ER -