美国纽约基因组中心Marcin Imieliński团队近期取得重要工作进展，他们研究提出，无需长读数即可检测到癌症基因组中的大多数大型结构变异。相关研究成果2023年11月9日在线发表于《自然—遗传学》杂志上。

据介绍，短读测序是癌症基因组学的主力，但被认为错过了许多结构变异（SV），尤其是大的染色体改变。

为了表征短读全基因组中缺失的SV，研究人员分析了“松散末端”—相邻DNA片段之间质量平衡的局部破坏。在1330个高纯度癌症全基因组的松散末端中，大多数大的（>10kb）克隆SV通过在87%的人类基因组中被短读完全解析，拷贝数可以可靠地测量。一些松散端代表新端粒，研究人员认为这是端粒表型替代性延长的标志。38例乳腺癌和黑色素瘤病例的长分子图谱证实了这些泛癌症的发现。

总之，这一结果表明，异常同源重组不太可能驱动大多数大型癌症SV。此外，在短读全基因组数据中的质量平衡分析提供了癌症染色体结构的完整图像。

附：英文原文

Title: Most large structural variants in cancer genomes can be detected without long reads

Author: Choo, Zi-Ning, Behr, Julie M., Deshpande, Aditya, Hadi, Kevin, Yao, Xiaotong, Tian, Huasong, Takai, Kaori, Zakusilo, George, Rosiene, Joel, Da Cruz Paula, Arnaud, Weigelt, Britta, Setton, Jeremy, Riaz, Nadeem, Powell, Simon N., Busam, Klaus, Shoushtari, Alexander N., Ariyan, Charlotte, Reis-Filho, Jorge, de Lange, Titia, Imieliski, Marcin

Issue&Volume: 2023-11-09

Abstract: Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed ‘loose ends’—local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure. JaBbA v1 pinpoints the ‘loose ends’ of large (>10-kb) unmapped structural variants in short-read DNA sequencing, suggesting that about 90% of cancer chromosomal alterations outside centromeres are resolvable with short reads and that long reads will primarily improve calling of smaller somatic variants.

DOI: 10.1038/s41588-023-01540-6

Source: https://www.nature.com/articles/s41588-023-01540-6