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Structural Variant Evolution After Telomere Crisis Dewhurst S.M1 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.29.318436; this version posted September 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Structural variant evolution after telomere crisis 2 3 Dewhurst S.M1,*, Yao X2,3,4*, Joel Rosiene3,4, Huasong Tian3,4, Julie Behr2,3,4, Nazario Bosco1,5, 4 Kaori K. Takai1,& de Lange T1,** & Imielinski M3,4 ** 5 6 1 Laboratory of Cell Biology and Genetics, Rockefeller University, New York, USA 7 2 Tri-Institutional Ph.D. Program in Computational Biology and Medicine, Weill Cornell Medicine, 8 New York, USA 9 3 Department of Pathology and Laboratory Medicine, Englander Institute for Precision Medicine, 10 and Meyer Cancer Center, Weill Cornell Medicine, New York, USA 11 4 New York Genome Center, New York, USA 12 5 Present address: Department of Biochemistry and Molecular Pharmacology, Institute for 13 Systems Genetics, NYU Langone Health, New York, USA 14 15 16 * Equal contribution 17 ** Corresponding authors: [email protected], [email protected] 18 Lead contact: Marcin Imielinski 19 20 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.29.318436; this version posted September 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 21 Abstract 22 Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display 23 breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of previous experimental 24 telomere crisis studies. We examine the spectrum of SVs instigated by natural telomere crisis. 25 Spontaneous post-crisis clones from prior studies had both complex and simple SVs without 26 BFB cycles or chromothripsis. In contrast, BFB cycles and chromothripsis occurred in clones 27 that escaped from telomere crisis after CRISPR-controlled telomerase activation in MRC5 28 fibroblasts. This system revealed convergent evolutionary lineages altering one allele of 12p, 29 where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and 30 BFB events were stabilized by independent fusions to 21. Telomere crisis can therefore 31 generate a wide spectrum of SVs, and lack of BFB patterns and chromothripsis does not 32 indicate absence of past crisis. 33 34 35 36 37 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.29.318436; this version posted September 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 38 Structural variation is a hallmark of cancer genomes. Recent pan-cancer whole genome 39 sequencing (WGS) studies have begun to reveal a more complete picture of the spectrum of 40 structural variants (SVs) found in cancer genomes, ranging from simple deletions, duplications 41 and translocations to complex and often multi-chromosomal rearrangements1–3. The PCAWG 42 consortium catalogued WGS variants across >2,500 cases spanning 38 tumor types4 to 43 nominate novel classes of complex SVs and cluster these into signatures, mirroring previous 44 work in the categorization of single nucleotide variants (SNVs) into distinct mutational 45 processes5–8. The analysis of genome graphs provides a rigorous and unified framework to 46 classify simple and complex SVs (including chromothripsis, breakage-fusion-bridge (BFB) 47 cycles, and double minutes), nominate novel event classes, and study the rearranged structure 48 of aneuploid alleles3. 49 50 However, despite advances in the identification and classification structural variations, a 51 mechanistic understanding of the underlying causes is often still lacking. SV mutational 52 processes may have a more complex etiology than those driving the formation of SNVs and 53 generate a more complex spectrum of patterns: layers of simple SVs can reshape a locus 54 gradually and across multiple alleles, and complex SVs can rapidly rewire many genomic 55 regions. In addition, multiple underlying causes can lead to the same type of rearrangement, 56 and diverse outcomes can originate from a single cause. Further, it has been expensive and 57 technically challenging to delineate specific mechanisms, although some progress has been 58 made9–14. 59 60 Telomere crisis, which is thought to occur at an early stage of carcinogenesis before a telomere 61 maintenance mechanism is activated15, has been nominated as a cause of cancer genome SVs. 62 A priori, the genomic consequences of telomere crisis are predicted to be profound: critically 63 short telomeres in human cells can trigger a DNA damage response, and inappropriately 64 engage DNA repair pathways resulting in telomere to telomere fusions16,17. Subsequent cell 65 divisions in the presence of fused chromosomes has long been considered a mechanism driving 66 complex chromosomal rearrangements such as BFB cycles in tumors18,19. The characteristic 67 fold-back inversions of BFB cycles are known to contribute to tumorigenesis in ALL20 as well as 68 squamous cell cancers and esophageal adenocarcinoma3. Modeling of telomere crisis in late 69 generation telomerase-deficient mice lacking p53 showed that telomere dysfunction engenders 70 cancers with non-reciprocal translocations, as well as focal amplifications and deletions in bioRxiv preprint doi: https://doi.org/10.1101/2020.09.29.318436; this version posted September 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 71 regions relevant to human cancers21,22. Furthermore, mouse models of telomerase reactivation 72 after a period of telomere dysfunction showed that acquisition of specific copy number 73 aberrations and aneuploidy could drive malignant phenotypes23. 74 75 Studies in cultured human cells have also illuminated the genomic consequences of telomere 76 dysfunction. Even a single artificially deprotected telomere can fuse with multiple intra- and 77 inter-chromosomal loci leading to complex fusion products24 but it is unclear whether these 78 complex rearrangements are compatible with escape from telomere crisis. The resolution of 79 dicentric chromosomes induced by over-expression of a dominant negative allele of the 80 telomere binding protein TRF2 can lead to the dramatic chromosome re-shuffling phenomenon 81 of chromothripsis11,14,25. However, to date the only study directly investigating the consequences 82 of a sustained period of telomere dysfunction failed to identify any complex rearrangements in 83 wild-type HCT116 colon carcinoma cells26. This may be because these cells readily escaped 84 from the telomere dysfunction induced by expression of a dominant-negative hTERT 85 (telomerase reverse transcriptase) allele. In HCT116 cells with defective Non-Homologous End 86 Joining (NHEJ) pathways, which are already genetically unstable, complex chained SVs were 87 observed after telomere dysfunction, but the relevance of these types of rearrangements to 88 human cancer remains unclear26. 89 90 Given the expanding repertoire of structural variation present in so many cancer types, and the 91 potential contribution of telomere dysfunction to many of these different aberrations, we set out 92 to characterize the extent and type of structural variation that can be unleashed by telomere 93 crisis and subsequent genome stabilization by telomerase expression. We approached this 94 problem in two ways. First, we performed whole genome sequencing (WGS) on a panel of 95 seven previously isolated cell lines that had escaped telomere crisis spontaneously through 96 telomerase activation. Secondly, we created a controlled in vitro telomere crisis system by 97 engineering an MRC5-derived cell line in which telomerase could be activated during telomere 98 crisis and analyzed the resulting post-crisis clones by WGS. The results indicate that the 99 consequences of telomere crisis are varied and not readily predictable. In many instances, the 100 post-crisis genomes did not feature BFB cycles or chromothripsis. Therefore, telomere crisis 101 may have occurred in cancers that lack these genomic scars of telomere dysfunction. 102 103 bioRxiv preprint doi: https://doi.org/10.1101/2020.09.29.318436; this version posted September 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 104 Results 105 106 Genomic complexity after spontaneous telomerase activation 107 In order to determine the SVs in post-telomere crisis genomes, we examined seven SV40 large 108 T-transformed cell lines that had undergone spontaneous telomerase activation after passage 109 into telomere crisis (Supplementary Table 1, Supplementary Figure 1). The cell lines represent 110 independent immortalization events in a variety of cell lineages27–29. We carried out whole 111 genome sequencing of these cell lines to a median depth of 41X (range: 17-55) and generated 112 junction balanced genome graphs3 via JaBbA from SvABA30 and GRIDSS31 junction calls (see 113 Methods). All genomes demonstrated some level of aneuploidy but there was a high variance in 114 the total number of junctions fit across each genome, ranging from 7 to 100. Analysis of 115 junction-balanced genome graphs3 revealed complex multi-chromosomal gains in four of seven 116 samples, with the remaining three lines harboring only broad arm level losses (Figure 1A). 117 118 Strikingly, genome graph-based categorization of complex SVs3 did not identify the classic 119 footprints of chromothripsis or BFB cycles in these genomes.
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