Gold Heidi L, Wengrod Jordan, de Miera Eleazar Vega-Saenz, Wang Ding, Fleming Nathaniel, Sikkema Lisa, Kirchhoff Tomas, Hochman Tsivia, Goldberg Judith D, Osman Iman, Gardner Lawrence B
New York University School of Medicine, 550 1st Avenue, New York, NY 10016.
Mol Cancer Res. 2014 Mar;12(3):433-9. doi: 10.1158/1541-7786.MCR-13-0422. Epub 2013 Dec 12.
Recent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However, the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from patients with melanoma (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in patients with both primary and metastatic melanoma. Despite minimal association between stage and presence of PP6C mutations in patients with primary melanoma, a subpopulation of cells within each tumor did contain PP6C mutations, suggesting PP6C mutation is an early, but non-tumor-initiating event in melanoma. Among patients with primary melanoma with PP6C mutations, patients with stop mutations had significantly shorter recurrence-free survival compared with patients without stop mutations. In addition, PP6C mutations were independent of commonly observed BRAF and NRAS mutations. Biochemically, PP6C mutations could be classified as those that interact with PP6C regulatory subunits and those that do not. Mutations that did not bind to PP6C regulatory subunits were associated with increased phosphorylation of Aurora kinase, a PP6C substrate, and mitotic defects. However, both classes of PP6C mutations led to increased sensitivity to Aurora kinase inhibition. Together, these data support for the first time that PP6C mutations are molecularly, biochemically, and clinically heterogeneous.
PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors.
近期的黑色素瘤全基因组测序研究已在编码丝氨酸/苏氨酸磷酸酶6催化亚基（PPP6C/PP6C）的基因中鉴定出复发性突变。然而，这些突变的生化、功能及临床影响尚不清楚。对黑色素瘤患者（233例原发性和77例转移性样本）的PP6C进行测序，并对其进行长期前瞻性临床随访，结果显示原发性和转移性黑色素瘤患者中均存在大量热点突变。尽管原发性黑色素瘤患者的分期与PP6C突变的存在之间关联极小，但每个肿瘤内的一部分细胞确实含有PP6C突变，这表明PP6C突变是黑色素瘤中的一个早期但非肿瘤起始事件。在原发性黑色素瘤伴有PP6C突变的患者中，与无终止突变的患者相比，有终止突变的患者无复发生存期显著缩短。此外，PP6C突变独立于常见的BRAF和NRAS突变。在生化方面，PP6C突变可分为与PP6C调节亚基相互作用的突变和不相互作用的突变。不与PP6C调节亚基结合的突变与PP6C底物极光激酶的磷酸化增加及有丝分裂缺陷相关。然而，这两类PP6C突变均导致对极光激酶抑制的敏感性增加。总之，这些数据首次证明PP6C突变在分子、生化和临床方面具有异质性。
PP6C突变在黑色素瘤中具有独特的功能和临床后果，并赋予对极光A激酶抑制剂的敏感性。
