Publisher Correction: Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Quinton, Ryan J.; DiDomizio, Amanda; Vittoria, Marc A.; Kotýnková, Kristýna; Ticas, Carlos J.; Patel, Sheena; Koga, Yusuke; Vakhshoorzadeh, Jasmine; Hermance, Nicole; Kuroda, Taruho S.; Parulekar, Neha; Taylor, Alison M.; Manning, Amity L.; Campbell, Joshua D.; Ganem, Neil J.

doi:10.1038/s41586-021-03591-3

Cited by 5 publications

(4 citation statements)

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“…This raises the possibility that polyploidy may promote primary tumor growth in the absence of an adaptive immune system, but slow primary tumor growth in immunocompetent mice, which would be consistent with previous findings 8 , 28 . Indeed, recent studies examining human tumors have shown that established aneuploid tumors actually have fewer adaptive immune cells and diminished host immune responses 41 , 42 suggesting that these tumors evolve immune escape mechanisms. Together these results suggest the consequences of polyploidy, including aneuploidy, shape interactions between tumors and the microenvironment, leading to changes in gene expression that are likely to influence tumor growth and characteristics.…”

Section: Discussionmentioning

confidence: 99%

Context-dependent effects of whole-genome duplication during mammary tumor recurrence

Newcomb

Dean

McKinney

et al. 2021

Sci Rep

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Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.

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Section: Discussionmentioning

confidence: 99%

Context-dependent effects of whole-genome duplication during mammary tumor recurrence

Newcomb

Dean

McKinney

et al. 2021

Sci Rep

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“…The presence of chromothripsis appears to be buffered by WGD and tumours with the most severe events may suffer increased immunogenicity or compromised metabolism, leading to longer OS (Figure 6). Nevertheless, the frequent occurrence of WGD has clinical significance, since WGD itself has been reported to be a targetable vulnerability 75,76 . This highlights the potential for new therapeutic opportunities in patients with WGD tumours which are generally HR proficient and currently more challenging to treat.…”

Section: Discussionmentioning

confidence: 99%

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Ewing,

Meynert,

Silk

et al. 2024

Preprint

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Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.

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“…Moreover, aneuploidy generates replication stress-mediated DNA DSBs, activating the DDR pathway (Ohashi et al, 2015). Failure of cell-cycle control can lead to WGD(Dewhurst et al, 2014; Goyal et al, 2011; Quinton et al, 2021a). Cancer cells with high replication stress are subjected to ploidy abnormalities such greater focal amplifications.…”

Section: Discussionmentioning

confidence: 99%

Replicative stress in gastroesophageal adenocarcinoma is associated with chromosomal instability and sensitivity to DNA damage response inhibitors

Sahgal

Patil

Sztupinszki

et al. 2023

Preprint

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Gastroesophageal adenocarcinoma (GEA) is an aggressive, often lethal, malignancy that displays marked chromosomal instability (CIN). To understand adaptive responses that enable CIN, we analyzed paired normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DNA damage response (DDR), and cell cycle regulator p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, including high-level focal amplifications and whole-genome duplication (WGD). Moreover, high expression of DNA damage marker H2AX correlated with CIN, WGD, and inferior patient survival. By developing and implementing a composite diagnostic score that incorporates TP53 mutation status, ploidy abnormalities, and H2AX expression, among other genomic information, we can identify GEA cell lines with enhanced sensitivity to DDR pathway inhibitors targeting Chk1/2 and Wee1. Anti-tumor properties were further augmented in combination with irinotecan (SN38) but not gemcitabine chemotherapy. These results implicate specific DDR biomarkers and ploidy abnormalities as diagnostic proxy that may predict premalignant progression and response to DDR pathway inhibitors.

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Publisher Correction: Whole-genome doubling confers unique genetic vulnerabilities on tumour cells

Cited by 5 publications

References 0 publications

Context-dependent effects of whole-genome duplication during mammary tumor recurrence

Context-dependent effects of whole-genome duplication during mammary tumor recurrence

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Replicative stress in gastroesophageal adenocarcinoma is associated with chromosomal instability and sensitivity to DNA damage response inhibitors

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