Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma.
Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma.
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DOI：
10.1186/s12885-018-5079-x
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发表时间：
2018-11-26
期刊：
影响因子：
3.8
通讯作者：
Ganguly A
中科院分区：
文献类型：
--
作者：
Ewens KG;Lalonde E;Richards-Yutz J;Shields CL;Ganguly A
BAP 1的种系突变与BAP 1-肿瘤易感综合征（BAP 1-TPDS）相关，BAP 1-TPDS是一个家族中多种肿瘤的易感性，包括葡萄膜黑色素瘤（UM）、皮肤黑色素瘤、恶性间皮瘤和肾细胞癌。或者，UM中BAP 1的体细胞突变与转移的高风险相关。在这项研究中，我们比较了携带生殖系与体细胞BAP 1突变和突变阴性肿瘤的UM转移风险。使用桑格或下一代测序法对从142个UM和匹配血液样本中提取的DNA进行测序，以鉴定BAP 1基因突变。142例UM中有11例（8%）携带生殖系BAP 1突变，43例（30%）有体细胞突变，88例（62%）为突变阴性。在血液样本中鉴定的所有BAP 1突变也存在于匹配的UM中。在54个肿瘤中有52个独特的突变。所有病例均为致病性或可能致病性。携带体细胞突变与生殖系突变或无突变的肿瘤的比较显示，携带体细胞突变的肿瘤的转移频率更高：分别为74%与36%，P=0.03和74%与26%，P<0.001。与突变阴性肿瘤相比，体细胞突变肿瘤的诊断年龄更大（61.8 vs. 52.2岁，P=0.002），转移时间更短（16 vs. 26个月，P=0.04）。Kaplan-Meier分析进一步显示，具有体细胞（与种系）突变的肿瘤显示出更大的转移风险（P=0.03）。考克斯多变量分析显示，除了3号染色体单体性和较大的肿瘤直径外，BAP 1体细胞突变的存在与转移风险显著相关（P=0.02），而非生殖系突变。79例病例有BAP 1-TPDS的个人或家族史。所有8例具有生殖系突变的病例均报告了BAP 1-TPDS病史，其显著高于在具有体细胞突变的病例（23例中的10例，P=0.009）或突变阴性病例（48例中的11例，P<0.001）中观察到的情况。确定UM中BAP 1突变的种系与体细胞性质可以告知个体转移的风险和转移时间，这对个体来说是至关重要的结果。这些信息也可以改变对家庭成员的级联筛查和监测。本文的在线版本（10.1186/s12885-018-5079-x）包含补充材料，可供授权用户使用。
Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors. DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations. Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic. A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02). Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001). Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members. The online version of this article (10.1186/s12885-018-5079-x) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Pilarski, Robert;Cebulla, Colleen M.;Massengill, James B.;Rai, Karan;Rich, Thereasa;Strong, Louise;McGillivray, Barbara;Asrat, Mary-Jill;Davidorf, Frederick H.;Abdel-Rahman, Mohamed H.
通讯作者：
Abdel-Rahman, Mohamed H.
DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
影响因子：
8.1
作者：
Decatur CL;Ong E;Garg N;Anbunathan H;Bowcock AM;Field MG;Harbour JW
通讯作者：
Harbour JW
影响因子：
16.6
作者：
Field MG;Durante MA;Anbunathan H;Cai LZ;Decatur CL;Bowcock AM;Kurtenbach S;Harbour JW
通讯作者：
Harbour JW
影响因子：
8.1
作者：
Gupta, Mrinali P.;Lane, Anne Marie;Kim, Ivana K.
通讯作者：
Kim, Ivana K.