Prevalence of the CHEK2 R95* germline mutation.
Prevalence of the CHEK2 R95* germline mutation.
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DOI：
10.1186/s13053-016-0059-0
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发表时间：
2016
影响因子：
1.7
通讯作者：
Lønning PE
中科院分区：
文献类型：
--
作者：
Knappskog S;Leirvaag B;Gansmo LB;Romundstad P;Hveem K;Vatten L;Lønning PE
虽然种系 CHEK2 突变与中度升高的癌症风险有关，但迄今为止，已发现的此类突变数量有限。最近，我们报道了两名被诊断患有局部晚期乳腺癌的挪威患者存在种系无义突变（C283T；R95*），引入了早期终止密码子。两名患者均对蒽环类药物治疗产生耐药性，类似于 TP53 突变所观察到的情况。在本研究中，我们筛选了基于大量人群的样本，包括 3748 个非癌症个体和 7081 个癌症病例（乳腺癌，n = 1717；前列腺癌 n = 2501，肺癌 n = 1331 和结直肠癌 n = 1532），以了解 CHEK2 R95* 的分布。我们发现 12 名个体 (0.11 %) 携带 R95* 变异：4 名非癌症个体 (0.11 %)、4 名乳腺癌病例 (0.23 %) 和 4 名前列腺癌病例 (0.16 %)。尽管观察数量较少，无法进行正式的统计评估，但我们的数据可能表明与 CHEK2 R95* 相关的乳腺癌（OR：2.19，95% CI：0.55–8.75）和前列腺癌（OR：1.5，95% CI：0.36–6.00）风险升高。通过挖掘国际数据库，我们没有发现携带 R95* 突变的个体，这表明该突变仅限于挪威人群。我们提供了概念验证，证明以前未知的 CHEK2 种系突变可能存在于某些人群中。值得注意的是，当代大规模并行测序策略通常会漏掉肿瘤中的种系突变，因为肿瘤突变通常会针对种系进行过滤。 CHEK2 R95* 突变可能与癌症患者对蒽环类药物的耐药性相关，这一事实强调了其可能的临床重要性。
While germline CHEK2 mutations have been linked to a moderately elevated cancer risk, to date, a limited number of such mutations have been identified. Recently, we reported a germline nonsense mutation (C283T; R95*), introducing an early stop-codon, in two Norwegian patients diagnosed with locally advanced breast cancer. Both patients were resistant to anthracycline therapy, resembling what has been observed for TP53 mutations. In the present study, we screened a large population based sample, including 3748 non-cancer individuals and 7081 incident cancer cases (breast cancer, n = 1717; prostate cancer n = 2501, lung cancer n = 1331 and colorectal cancer n = 1532), for the distribution of CHEK2 R95*. We found that 12 individuals (0.11 %) carried the R95* variant: 4 non-cancer individuals (0.11 %), 4 breast cancer cases (0.23 %), and 4 prostate cancer cases (0.16 %). Although the low number of observations precluded formal statistical assessment, our data may indicate an elevated risk for breast (OR: 2.19, 95 % CI: 0.55–8.75) and prostate cancer (OR: 1.5, 95 % CI: 0.36–6.00) associated with CHEK2 R95*. By mining international databanks, we found no individuals carrying the R95* mutation, indicating it to be restricted to the Norwegian population. We provide proof-of-concept that previously unknown CHEK2 germline mutations may be present in certain populations. Notably, germline mutations in tumours are in general missed by contemporary massive parallel sequencing strategies, since tumour mutations are usually filtered against the germline. The fact that the CHEK2 R95* mutation may be associated with resistance to anthracyclines in cancer patients emphasizes its possible clinical importance.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1186/bcr3147
发表时间：
2012-03-15
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Knappskog S;Chrisanthar R;Løkkevik E;Anker G;Østenstad B;Lundgren S;Risberg T;Mjaaland I;Leirvaag B;Miletic H;Lønning PE
通讯作者：
Lønning PE
影响因子：
7.7
作者：
Naess, Oyvind;Sogaard, Anne Johanne;Aamodt, Geir
通讯作者：
Aamodt, Geir
影响因子：
120.7
作者：
Walsh, T;Casadei, S;King, MC
通讯作者：
King, MC
影响因子：
45.3
作者：
Cybulski, Cezary;Wokolorczyk, Dominika;Lubinski, Jan
通讯作者：
Lubinski, Jan