СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Wagner Justin, Keskus Ayse G, Oshima Keisuke K, Ranallo-Benavidez T Rhyker, McDaniel Jennifer, Sikic Mile, Lin Dehui, Paulin Luis F, English Adam C, Sedlazeck Fritz J, Munding Elizabeth M, Sanborn J Zachary, Carroll Andrew, Chang Pi-Chuan, Cook Daniel E, Shafin Kishwar, de Ligt Joep, Hassaine Rayan, Cameron Daniel, Catreux Severine, Lee Yeonghun, Murray Lisa, Truong Sean, Brueffer Christian, Zimin Aleksey V, Cross Erin, McGowan Matthew, Vernich Michael, Liss Andrew S, Kocher Jean-Pierre, Stephens Zachary, Ahmad Tanveer, Bryant Asher, Dwarshuis Nathan, He Hua-Jun, He Zhiyong, Olson Nathan D, Thibaud-Nissen Francoise, Antipov Dmitry, Koren Sergey, Phillippy Adam, Musunuri Rajeeva Lochan, Narzisi Giuseppe, Jain Miten, Wenger Aaron M, Eacker Stephen, Sahraeian Sayed Mohammad Ebrahim, Boutros Paul C, Patel Yash, Yamaguchi Takafumi N, McConnell Joseph, Borchers Matthew, Gerton Jennifer L, Kostos Paxton, Guarracino Andrea, Jehangir Maryam, Benjamin Hila, Mootor Mohammed Faizal Eeman, Xu Yuan, Asri Mobin, Miga Karen H, Park Jimin, Paten Benedict, Luo Ruibang, Zheng Zhenxian, Choi Jae Young, Nguyen Linh, Vats Pankaj, Robinson Dan R, Vo Josh N, Gao Shenghan, Murtaza Ghulam, Mason Christopher E, Cheng Haoyu, Barthel Floris P, Xiao Chunlin, Logsdon Glennis A, Kolmogorov Mikhail, Zook Justin M
Аннотация
Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine.1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions.1-3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres.4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.