BRCA2-branching out too?
BRCA2-branching out too?
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BRCA2-也分支出来吗？
DOI：
10.1093/jnci/djv066
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Amos,ChristopherI
中科院分区：
文献类型：
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作者：
Spitz,MargaretR;Liu,Yanhong;Amos,ChristopherI
在本期杂志中，Delahaye-Sourdeix等人(1)报告了BRCA2基因变异K3326X(Rs11571833)截断的罕见(次要等位基因频率[MAF]<；0.01)与上消化道(UADT)癌症风险之间具有统计学意义的关联(优势比[OR]=2.53)。他们的数据是综合九项国际研究得出的。这一发现是基于已发表的K3326X与肺癌的关联(2)，主要是由于与鳞癌而不是腺癌组织学的关系。K3326X最近也被证明会使乳腺癌风险增加1.26倍(3)，以前曾被认为是食道癌(4)和胰腺癌(5)的风险因素。这项研究之所以令人感兴趣，有几个原因。它证实了BRCA2的一个变异与吸烟相关的癌症之间有很强的相关性。此外，这些与吸烟相关的癌症，特别是肺癌、UADT、胰腺癌和食道癌(都在两倍以上)的关联强度，远远超过了乳腺癌风险和优势比的温和26%的增幅，这些风险和优势比与几乎所有其他疾病的GWA报告的最高命中率相关。Delahaye-Sourdeix等人(1)估计，每个K3326X变异等位基因患UADT癌症的风险增加2.5倍(OR=2.53，95%可信区间[CI]=1.89至3.38，P=3x10-10)，这对遗传因素的影响很大。这种关联强度几乎与先前发现的与鳞状细胞肺癌风险的关联相同(OR=2.47，P=4.74×10-20)(2)。目前的研究发现，在吸烟者中，UADT的风险效应要强得多，而在从不吸烟的人中，对风险没有明显的影响。另一方面，肺脏研究报告了在从不吸烟的人中存在微弱但积极的关联，BRCA2的主要功能是促进同源重组，执行双链断裂的高保真修复，并且是保护增殖细胞中基因组完整性的主要机制(6)。BRCA2抑癌基因表现出相当大的等位基因多样性。BRCA2特异性突变体K3326X是由BRCA2基因序列第27外显子上的腺苷突变为胸腺嘧啶所致，导致该蛋白C末端93个氨基酸被截断。该区域有一个高度保守的RAD51结合域，在双链断裂修复过程中，如在活性氧诱导下，它在DNA同源重组中起着重要作用。另一个有趣的事实是，之前描述的Fanconi基因FANCD1已被鉴定为BRCA2(7)。正如Delahaye-Sourdeix等人(1)指出的那样，患有Fanconi贫血(FA)的老年患者患头颈部(最常见的实体肿瘤)以及食道癌和胃肠癌的风险很高。如果FA途径的中断被假设为一种致病机制，这将是一种不同于其他BRCA2突变携带者易患乳腺癌或卵巢癌的机制(8)。仍然没有足够的证据来充分描述K3326X变体的功能效应。在计算机分析表明，突变被预测为蛋白质损伤的PolyPhen-2，有害的SIFT，和高功能的突变检测细胞表达截短的BRCA2蛋白，缺乏C末端外显子27编码区，不显示FANCD2，BRCA2和RAD51在染色质上共定位，并对交联剂如丝裂霉素C(9，10)，但一项早期研究未能发现该区域对RAD51结合的影响(11)。外显子27纯合子缺失的小鼠表现出对各种实体肿瘤的易感性增加，但对乳腺肿瘤没有影响(12)。IT与…
In this issue of the Journal, Delahaye-Sourdeix et al.(1) report a statistically significant association (odds ratio [OR]= 2.53) between a rare (minor allele frequency [MAF]< 0.01) truncating BRCA2 genetic variant, K3326X (rs11571833) and risk of upper aero-digestive tract (UADT) cancer. Their data are derived from combining nine international studies. This finding follows on the published association of K3326X with lung cancer (2), driven primarily by a relationship with squamous rather than adenocarcinoma histology. K3326X was recently also shown to confer a 1.26-fold increased breast cancer risk (3) and has been suggested previously as a risk factor for both esophageal (4) and pancreatic cancers (5). This study is of interest for several reasons. It confirms a robust association between a variant in BRCA2 and smokingrelated cancers. Furthermore, the strength of the associations noted for these smoking-related cancers, specifically lung, UADT, pancreatic, and esophageal (all above two-fold), far exceeds the modest 26% increase in breast cancer risk and odds ratios associated with the top hits reported for virtually all GWAS of other conditions. Delahaye-Sourdeix et al.(1) estimated a 2.5-fold increase in risk for UADT cancer per variant allele of K3326X (OR= 2.53, 95% confidence interval [CI]= 1.89 to 3.38, P= 3X10-10), a very large effect size for a genetic factor. This strength of association is nearly identical to the previously identified association with squamous cell lung cancer risk (OR= 2.47, P= 4.74 X10-20)(2). The current study finds a much stronger effect of risk for UADT among smokers with no evident effect on risk among never smokers. On the other hand, the lung study reported a weak but positive association in never smokers, The primary function of BRCA2 is to facilitate homologous recombination that carries out high fidelity repair of doublestrand breaks and is a major mechanism for protecting the integrity of the genome in proliferating cells (6). The BRCA2 tumor suppressor gene displays substantial allelic diversity. The specific BRCA2 variant, K3326X, results from mutation of adenosine to thymine at exon 27 in the BRCA2 mRNA sequence, resulting in truncation of 93 amino acids from the C terminus of the protein. This region has a highly conserved RAD51 binding domain, which plays a major role in homologous recombination of DNA during double-strand break repair, such as induced by reactive oxygen species. Of added interest is the fact that the previously described Fanconi gene, FANCD1, has been identified to be BRCA2 (7). As Delahaye-Sourdeix et al.(1) point out, older patients with Fanconi anemia (FA) are at high risk of developing head and neck (the most common solid tumor) as well as esophageal and gastrointestinal cancers. If interruption of the FA pathway is hypothesized as an etiologic mechanism, this would be a different mechanism from that predisposing carriers of other BRCA2 mutations to breast or ovarian cancer (8). There is still insufficient evidence to fully characterize the functional effect of the K3326X variant. In silico analysis shows that the mutation is predicted to be protein damaging by PolyPhen-2, deleterious by SIFT, and highly functional by Mutation Tester Cells that express truncated BRCA2 protein, that lack the C terminal exon 27 coding region, do not show colocalization of FANCD2, BRCA2, and RAD51 on chromatin and are hypersensitive to crosslinking agents like mitomycin C (9, 10), but one early study failed to find an effect of this region on RAD51 binding (11). Mice with a homozygous deletion of exon 27 exhibit increased susceptibility to various types of solid tumors but not mammary tumors (12). It …