Germline mutations in HOXB13 and prostate-cancer risk.
Germline mutations in HOXB13 and prostate-cancer risk.
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DOI：
10.1056/nejmoa1110000
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发表时间：
2012-01-12
期刊：
影响因子：
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通讯作者：
Cooney KA
中科院分区：
文献类型：
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作者：
Ewing CM;Ray AM;Lange EM;Zuhlke KA;Robbins CM;Tembe WD;Wiley KE;Isaacs SD;Johng D;Wang Y;Bizon C;Yan G;Gielzak M;Partin AW;Shanmugam V;Izatt T;Sinari S;Craig DW;Zheng SL;Walsh PC;Montie JE;Xu J;Carpten JD;Isaacs WB;Cooney KA
家族史是前列腺癌的重要危险因素，尽管这种关联的分子基础尚不清楚。连锁研究暗示染色体17q21-22可能是前列腺癌易感基因的位置。我们通过对94名无亲缘关系的前列腺癌患者的生殖系DNA进行测序，筛选了17q21-22区域的200多个基因。我们测试了家庭成员、额外的病例受试者和对照受试者，以表征所识别的突变的频率。来自四个家族的先显子在HOXB13 （rs138213197）中发现了罕见但复发的突变（G84E），这是一种同源盒转录因子基因，在前列腺发育中很重要。这四个家族中所有18名前列腺癌患者和可用DNA都携带了这种突变。在5083名无血缘关系的欧洲裔前列腺癌患者中，G84E突变的携带率增加了约20倍，其中72名（1.4%）患者发现了G84E突变，而在1401名对照患者中发现了1名（0.1%）（P = 8.5×10−7）。该突变在早发性家族性前列腺癌患者中（3.1%）明显高于晚发性非家族性前列腺癌患者（0.6%）（P = 2.0×10−6）。新型HOXB13 G84E变异与遗传性前列腺癌风险显著增加相关。尽管这种变异只占所有前列腺癌的一小部分，但这一发现对前列腺癌风险评估具有重要意义，并可能为这种常见癌症提供新的机制见解。（由美国国立卫生研究院和其他机构资助。）
Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P = 8.5×10−7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0×10−6). The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.)