短读长测序是癌症基因组学的主力，但被认为会遗漏许多结构变异（SV），特别是大的染色体改变。为了表征短读长全基因组中缺失的 SV，我们分析了“松散末端”——相邻 DNA 片段之间质量平衡的局部违反。在 1,330 个高纯度癌症全基因组的松散末端景观中，大多数大型 (>10-kb) 克隆 SV 可以通过 87% 的人类基因组中的短读段完全解析，其中可以可靠地测量拷贝数。一些松散的末端代表新端粒，我们建议将其作为端粒表型替代延长的标志。这些泛癌研究结果得到了 38 例乳腺癌和黑色素瘤病例的长分子谱的证实。我们的结果表明，异常同源重组不太可能驱动大多数大型癌症 SV。此外，短读长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令人惊讶的完整图像。© 2023。作者。

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.© 2023. The Author(s).