Melanoma Unit, Dermatology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques d'August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red en Enfermedades Raras, Valencia, Spain3Melanoma Unit, Molecular Biology and Genetics Department, Hospital Clínic de Barcelona, Spain.
JAMA Dermatol. 2016 Apr;152(4):405-12. doi: 10.1001/jamadermatol.2015.4356.
The main high-penetrance melanoma susceptibility gene is CDKN2A, encoding p16INK4A and p14ARF. The gene MITF variant p.E318K also predisposes to melanoma and renal cell carcinoma. To date, the prevalence of MITF p.E318K and its clinical and phenotypical implications has not been previously assessed in a single cohort of Spanish patients with melanoma or in p16INK4A mutation carriers.
To evaluate the prevalence of MITF p.E318K in Spanish patients with melanoma and assess the association with clinical and phenotypic features.
DESIGN, SETTING, AND PARTICIPANTS: A hospital-based, case-control study was conducted at the Melanoma Unit of Hospital Clinic of Barcelona, with MITF p.E318K genotyped in all patients using TaqMan probes. We included 531 patients: 271 patients with multiple primary melanoma (MPM) without mutations affecting p16INK4A (wild-type p16INK4A); 191 probands from melanoma-prone families with a single melanoma diagnosis and without mutations affecting p16INK4A, and 69 probands from different families carrying CDKN2A mutations affecting p16INK4A. A population-based series of 499 age- and sex-matched cancer-free individuals from the Spanish National Bank of DNA were included as controls. Patients were recruited between January 1, 1992, and June 30, 2014; data analysis was conducted from September 1 to November 30, 2014.
The genetic results of the MITF p.E318K variant were correlated with clinical and phenotypic features.
Among the 531 patients, the prevalence of the MITF p.E318K variant was calculated among the different subsets of patients included and was 1.9% (9 of 462) in all melanoma patients with wild-type p16INK4A, 2.6% (7 of 271) in those with MPM, and 2.9% (2 of 69) in the probands of families with p16INK4A mutations. With results reported as odds ratio (95% CI), the MITF p.E318K was associated with an increased melanoma risk (3.3 [1.43-7.43]; P < .01), especially in MPM (4.5 [1.83-11.01]; P < .01) and high nevi count (>200 nevi) (8.4 [2.14-33.19]; P < .01). Two fast-growing melanomas were detected among 2 MITF p.E318K carriers during dermatologic digital follow-up.
In addition to melanoma risk, MITF p.E318K is associated with a high nevi count and could play a role in fast-growing melanomas. Testing for MITF p.E318K should not exclude patients with known mutations in p16INK4A. Strict dermatologic surveillance, periodic self-examination, and renal cell carcinoma surveillance should be encouraged in this context.
重要性：主要的高外显率黑色素瘤易感基因是 CDKN2A，其编码 p16INK4A 和 p14ARF。MITF 变体 p.E318K 也易导致黑色素瘤和肾细胞癌。迄今为止，MITF p.E318K 的流行率及其在单一队列的西班牙黑色素瘤患者或 p16INK4A 突变携带者中的临床和表型意义尚未得到评估。
目的：评估 MITF p.E318K 在西班牙黑色素瘤患者中的流行率，并评估其与临床和表型特征的关联。
设计、地点和参与者：在巴塞罗那临床医院的黑色素瘤科进行了一项基于医院的病例对照研究，使用 TaqMan 探针对所有患者进行 MITF p.E318K 基因分型。我们纳入了 531 名患者：271 名患有多发性原发性黑色素瘤（MPM）且 p16INK4A 无突变（野生型 p16INK4A）的患者；191 名有单个黑色素瘤诊断且 p16INK4A 无突变的黑色素瘤易感家族的先证者，和 69 名携带影响 p16INK4A 的 CDKN2A 突变的不同家族的先证者。从西班牙国家 DNA 银行纳入了一个与病例对照年龄和性别匹配的 499 名无癌个体的人群作为对照组。患者于 1992 年 1 月 1 日至 2014 年 6 月 30 日期间招募；数据分析于 2014 年 9 月 1 日至 11 月 30 日进行。
主要结局和测量：MITF p.E318K 变体的遗传结果与临床和表型特征相关联。
结果：在 531 名患者中，计算了不同亚组患者的 MITF p.E318K 变体的流行率，在所有野生型 p16INK4A 的黑色素瘤患者中为 1.9%（462 例中的 9 例），在多发性原发性黑色素瘤患者中为 2.6%（271 例中的 7 例），在有 p16INK4A 突变的家族的先证者中为 2.9%（69 例中的 2 例）。MITF p.E318K 与黑色素瘤风险增加相关（比值比 [95%CI]，3.3[1.43-7.43]；P<.01），尤其是在多发性原发性黑色素瘤（比值比 [95%CI]，4.5[1.83-11.01]；P<.01）和高痣计数（>200 颗痣）（比值比 [95%CI]，8.4[2.14-33.19]；P<.01）。在皮肤学数字随访期间，在 2 名 MITF p.E318K 携带者中发现了 2 例快速生长的黑色素瘤。
结论和相关性：除了黑色素瘤风险外，MITF p.E318K 还与高痣计数相关，并可能在快速生长的黑色素瘤中发挥作用。检测 MITF p.E318K 不应排除已知 p16INK4A 突变的患者。在这种情况下，应鼓励进行严格的皮肤学监测、定期自我检查和肾细胞癌监测。
