Frequent breakpoints of focal deletion and uniparental disomy in 22q11.1 or 11.2 segmental duplication region reveal distinct tumorigenesis in rhabdoid tumor of the kidney
Frequent breakpoints of focal deletion and uniparental disomy in 22q11.1 or 11.2 segmental duplication region reveal distinct tumorigenesis in rhabdoid tumor of the kidney
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DOI：
10.1002/gcc.22952
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发表时间：
2021-05-04
影响因子：
3.7
通讯作者：
Kaneko，Yasuhiko
中科院分区：
文献类型：
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作者：
Haruta，Masayuki;Arai，Yasuhito;Kaneko，Yasuhiko
SMARCB 1在肾脏（RTK）和各种其他器官中发生的大多数横纹肌样肿瘤（RT）中发生突变。在22q11.2缺失综合征患者中发现的局灶性缺失显示了节段性重复（SD）簇内的断点，并且在一些RT中显示了22 q11-q12区域的断点。已知SD会引起由非等位基因同源重组介导的局灶性缺失。本研究使用SNP阵列CGH、MLPA和序列分析在所有30个RTK中鉴定SMARCB 1改变。28例肿瘤共有51个断裂点，形成局灶性22 q缺失和/或单亲二体（22 qUPD），另外2例有复合突变，22 q无断裂点。51个折点中有24个（47.1%）在SD范围内，发生在30个肿瘤中的16个（53.3%）中。不仅在病灶缺失中发现了断裂点与SD的关联，而且在22 qUPD中也发现了断裂点与SD的关联，表明SD介导SMARCB 1改变的第一次和第二次命中（病灶缺失）以及第二次命中（22 qUPD）。在51个断点中，14个是复发性的，14个断点中有10个在SD内，这表明在22q11.2区域存在热点。SD外的一个复发性断点位于SMARCB 1中，表明该基因通过框外融合失活。SD和局灶性缺失之间的关联已在其他两种类型的癌症中报道。RTK可能是SD相关肿瘤的第三个例子。因此，本研究表明RTK利用22q11.1 - 11.2 SDs区域的基因组不稳定性，并且由有丝分裂重组引起的22 qUPD也可能由SDs介导。
SMARCB1is mutated in most rhabdoid tumors (RTs) developing in the kidney (RTK) and various other organs. Focal deletions found in patients with 22q11.2 deletion syndrome show breakpoints within clusters of segmental duplications (SDs), and those in some RTs show breakpoints in the 22q11‐q12 region. SDs are known to cause focal deletion mediated by non‐allelic homologous recombination. The present study identifiedSMARCB1alterations in all 30 RTKs, using SNP array CGH, MLPA, and sequence analyses. Twenty‐eight tumors had a total of 51 breakpoints forming focal 22q deletion and/or uniparental disomy (22qUPD), and the other two had compound mutation with no breakpoints in 22q. Twenty‐four (47.1%) of the 51 breakpoints were within SDs, and occurred in 16 (53.3%) of the 30 tumors. The association of breakpoints with SDs was found not only in focal deletion, but also in 22qUPD, indicating that SDs mediate the first and second hits (focal deletion) and the second hit (22qUPD) ofSMARCB1alteration. Of the 51 breakpoints, 14 were recurrent, and 10 of the 14 were within SDs, suggesting the presence of hotspots in the 22q11.2 region. One recurrent breakpoint outside SDs resided inSMARCB1, suggesting inactivation of the gene by out‐of‐frame fusion. The association between SDs and focal deletion has been reported in two other types of cancer. RTKs may be the third example of SD‐associated tumors. Thus, the present study indicated that RTKs exploit genomic instability in the 22q11.1‐11.2 SDs region, and 22qUPD caused by mitotic recombination may also be mediated by SDs.