A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications.
A common copy-number breakpoint of ERBB2 amplification in breast cancer colocalizes with a complex block of segmental duplications.
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DOI：
10.1186/bcr3362
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发表时间：
2012-11-26
期刊：
影响因子：
--
通讯作者：
Tanaka H
中科院分区：
文献类型：
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作者：
Marotta M;Chen X;Inoshita A;Stephens R;Budd GT;Crowe JP;Lyons J;Kondratova A;Tubbs R;Tanaka H
片段重复（英语：Segmental duplications）是人类基因组中最近重复的基因组片段，其序列几乎相同（> 90%），约占常染色质区域的5%。在生殖系中，重复片段介导非等位基因同源重组，从而导致非致病性拷贝数变异和基因组疾病。重复片段在癌症中的体细胞DNA重排中发挥何种作用仍然是难以捉摸的。重复片段通常聚集并形成富含正向和反向重复序列的基因组块（复杂基因组区域）。这种复杂的区域可能是脆弱的，并在乳腺肿瘤中ERBB2基因的扩增中发挥机械作用，因为已知重复序列在模型系统中启动基因扩增。我们对原发性乳腺肿瘤进行了基于聚合酶链反应（PCR）的检测，并分析了实验室可用的阵列比较基因组杂交数据，以绘制ERBB2扩增的原发性乳腺肿瘤中常见的拷贝数断点。我们进一步使用分子、生物信息学和群体遗传学方法来定义共同断点内的重复内容、结构变体和单倍型。我们发现了一个大的（> 300 kb）块的重复片段，与ERBB2扩增的共同拷贝数断点共定位。可能启动ERBB2扩增的断点位于ERBB2端粒侧1.5 Mb区域。该区域非常复杂，KRTAP基因大量重复，结构变异，因此缺乏单核苷酸多态性（SNP）标记。重复片段的大小和序列同源性程度各不相同，表明重复在基因组进化过程中反复发生。乳腺肿瘤中ERBB2基因的扩增可能是由一个复杂的区域启动的，该区域具有不寻常的基因组特征，因此需要进行严格的劳动密集型研究。我们提供的单倍型可能是有用的，以确定复杂的区域和ERBB2扩增之间的潜在关联。
Segmental duplications (low-copy repeats) are the recently duplicated genomic segments in the human genome that display nearly identical (> 90%) sequences and account for about 5% of euchromatic regions. In germline, duplicated segments mediate nonallelic homologous recombination and thus cause both non-disease-causing copy-number variants and genomic disorders. To what extent duplicated segments play a role in somatic DNA rearrangements in cancer remains elusive. Duplicated segments often cluster and form genomic blocks enriched with both direct and inverted repeats (complex genomic regions). Such complex regions could be fragile and play a mechanistic role in the amplification of the ERBB2 gene in breast tumors, because repeated sequences are known to initiate gene amplification in model systems. We conducted polymerase chain reaction (PCR)-based assays for primary breast tumors and analyzed publically available array-comparative genomic hybridization data to map a common copy-number breakpoint in ERBB2-amplified primary breast tumors. We further used molecular, bioinformatics, and population-genetics approaches to define duplication contents, structural variants, and haplotypes within the common breakpoint. We found a large (> 300-kb) block of duplicated segments that was colocalized with a common-copy number breakpoint for ERBB2 amplification. The breakpoint that potentially initiated ERBB2 amplification localized in a region 1.5 megabases (Mb) on the telomeric side of ERBB2. The region is very complex, with extensive duplications of KRTAP genes, structural variants, and, as a result, a paucity of single-nucleotide polymorphism (SNP) markers. Duplicated segments are varied in size and degree of sequence homology, indicating that duplications have occurred recurrently during genome evolution. Amplification of the ERBB2 gene in breast tumors is potentially initiated by a complex region that has unusual genomic features and thus requires rigorous, labor-intensive investigation. The haplotypes we provide could be useful to identify the potential association between the complex region and ERBB2 amplification.
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