Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML.
Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML.
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DOI：
10.1001/jama.2011.473
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发表时间：
2011-04-20
影响因子：
120.7
通讯作者：
Mardis, Elaine R.
中科院分区：
文献类型：
--
作者：
Link, Daniel C.;Schuettpelz, Laura G.;Shen, Dong;Wang, Jinling;Walter, Matthew J.;Kulkarni, Shashikant;Payton, Jacqueline E.;Ivanovich, Jennifer;Goodfellow, Paul J.;Le Beau, Michelle;Koboldt, Daniel C.;Dooling, David J.;Fulton, Robert S.;Bender, R. Hugh F.;Fulton, Lucinda L.;Delehaunty, Kimberly D.;Fronick, Catrina C.;Appelbaum, Elizabeth L.;Schmidt, Heather;Abbott, Rachel;O'Laughlin, Michelle;Chen, Ken;McLellan, Michael D.;Varghese, Nobish;Nagarajan, Rakesh;Heath, Sharon;Graubert, Timothy A.;Ding, Li;Ley, Timothy J.;Zambetti, Gerard P.;Wilson, Richard K.;Mardis, Elaine R.
遗传性癌症易感综合征患者的识别有助于早期诊断、预防和治疗。然而，在许多疑似癌症易感性的病例中，家族史不清楚，常见癌症易感基因的基因测试也无法揭示情况。将全基因组测序应用于疑似癌症易感性的患者(没有明确的癌症家族史，也没有BRCA1和BRCA2突变)，以识别癌症易感基因中罕见或新的种系变异。从1例早发性乳腺癌、卵巢癌和与治疗相关的急性髓系白血病(t-AML)患者的皮肤(正常)和骨髓(白血病)DNA中提取DNA，并进行以下分析：1)成对末端读数全基因组测序；2)SNP基因分型；3)RNA表达谱分析；4)光谱核型分析。利用上述平台检测和验证了结构变异、拷贝数改变、单核苷酸变异和小插入和小缺失(INDELs)。全基因组测序显示，患者正常皮肤DNA中有一个新的杂合性3kb缺失，去除了TP53的第7-9外显子，由于单亲二体，白血病DNA中的TP53是纯合的。此外，在患者的白血病基因组中共检测到28个编码基因的体细胞单核苷酸变异或INDELs，8个体细胞结构变异和12个体细胞拷贝数改变。全基因组测序除了提供关于癌症基因组突变谱的公正信息外，还可以识别癌症易感基因中的新的、神秘的变异。
The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing. To apply whole-genome sequencing to a patient with suspected cancer susceptibility (and lacking a clear family history of cancer and no BRCA1 and BRCA2 mutations) to identify rare or novel germline variants in cancer susceptibility genes. Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer and therapy-related acute myeloid leukemia (t-AML), and analyzed with: 1) whole genome sequencing using paired end reads; 2) SNP genotyping; 3) RNA expression profiling; and 4) spectral karyotyping. Structural variants, copy number alterations, single nucleotide variants and small insertions and deletions (indels) were detected and validated using the above platforms. Whole genome sequencing revealed a novel, heterozygous 3 Kb deletion removing exons 7-9 of TP53 in the patient’s normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient’s leukemia genome. Whole genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.
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影响因子：
7.2
作者：
Khoury, Marie P.;Bourdon, Jean-Christophe
通讯作者：
Bourdon, Jean-Christophe
影响因子：
39.2
作者：
LI, FP;FRAUMENI, JF
通讯作者：
FRAUMENI, JF
影响因子：
30.8
作者：
Iafrate, AJ;Feuk, L;Lee, C
通讯作者：
Lee, C
影响因子：
120.7
作者：
Walsh, T;Casadei, S;King, MC
通讯作者：
King, MC
影响因子：
56.9
作者：
MALKIN, D;LI, FP;FRIEND, SH
通讯作者：
FRIEND, SH