Dynamic clonal equilibrium and predetermined cancer risk in Barrett’s oesophagus

Martinez, Pierre; Timmer, Margriet R.; Lau, Chiu Ting; Calpe, Silvia; Sancho-Serra, Maria del Carmen; Straub, Daniëlle; Baker, Ann‐Marie; Meijer, Sybren L.; Kate, Fiebo J.W. ten; Mallant-Hent, Rosalie C.; Naber, A.H.J.; Oijen, Arnoud H A M van; Baak, Lubbertus C.; Scholten, Pieter; Böhmer, Clarisse J M; Fockens, Paul; Bergman, Jacques; Maley, Carlo C.; Graham, Trevor A.; Krishnadath, Kausilia K.

doi:10.1038/ncomms12158

Cited by 82 publications

(95 citation statements)

References 32 publications

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“…For example, early driver mutations may become obsolete once the tumor is established, or may even hinder the tumor at later stages so their loss becomes positively selected for. Hints of changing selective pressures on particular aberrations have recently been observed for Barrett's esophagus (Martinez et al 2016). Loss of a copy of CDKN2A seemed to provide a fitness advantage for clones experiencing acid reflux but a disadvantage when the acid is suppressed under treatment.…”

Section: Discussionmentioning

confidence: 99%

Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors

et al. 2017

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Intra-tumor heterogeneity poses substantial challenges for cancer treatment. A tumor's composition can be deduced by reconstructing its mutational history. Central to current approaches is the infinite sites assumption that every genomic position can only mutate once over the lifetime of a tumor. The validity of this assumption has never been quantitatively assessed. We developed a rigorous statistical framework to test the infinite sites assumption with single-cell sequencing data. Our framework accounts for the high noise and contamination present in such data. We found strong evidence for the same genomic position being mutationally affected multiple times in individual tumors for 11 of 12 single-cell sequencing data sets from a variety of human cancers. Seven cases involved the loss of earlier mutations, five of which occurred at sites unaffected by large-scale genomic deletions. Four cases exhibited a parallel mutation, potentially indicating convergent evolution at the base pair level. Our results refute the general validity of the infinite sites assumption and indicate that more complex models are needed to adequately quantify intra-tumor heterogeneity for more effective cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors

et al. 2017

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“…However, fewer than 20% of specific variants overlap between adjacent BE and EA, so either the cancer clone diverged at an early stage or originated separately 53,70 . Analysis BE patients suggested that the genetic diversity of different clones did not change significantly over time, but the extent of divergence of clones at baseline was the strongest predictor of progression 77 .…”

Section: Somatic Mutations That Affect Be Progressionmentioning

confidence: 99%

The Evolving Genomic Landscape of Barrett’s Esophagus and Esophageal Adenocarcinoma

et al. 2017

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We have recently gained unprecedented insight into genetic factors that determine risk for Barrett’s esophagus (BE) and progression to esophageal adenocarcinoma (EA). Next-generation sequencing technologies have allowed us to identify somatic mutations that initiate BE and track genetic changes during development of tumors and invasive cancer. These technologies led to identification of mechanisms of tumorigenesis that challenge the current multi-step model of progression to EA. Newer, cost-effective technologies create opportunities to rapidly translate the analysis of DNA into tools that can identify patients with BE at high risk for cancer, detect dysplastic lesions at earlier stages, and uncover mechanisms of carcinogenesis.

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“…Two studies measured the SCNA rate and clonal dynamics of Barrett’s esophagus (34,45) – a dysplastic condition that has a risk of transforming into invasive carcinoma. In the first study, multiple biopsies from four or more timepoints were subject to analysis with SNP arrays – phylogenetic methods were used to estimate the SCNA rate.…”

Section: Somatic Copy Number Alteration Ratementioning

confidence: 99%

Genomic Instability in Cancer: Teetering on the Limit of Tolerance

2017

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Cancer genomic instability contributes to the phenomenon of intratumoral genetic heterogeneity, provides the genetic diversity required for natural selection and enables the extensive phenotypic diversity that is frequently observed among patients. Genomic instability has previously been associated with poor prognosis. However, we have evidence that for solid tumors of epithelial origin, extreme levels of genomic instability, where more than 75% of the genome is subject to somatic copy number alterations, are associated with a potentially better prognosis compared to intermediate levels under this threshold. This has been observed in clonal subpopulations of larger size, especially when genomic instability is shared among a limited number of clones. We hypothesize that cancers with extreme levels of genomic instability may be teetering on the brink of a threshold where so much of their genome is adversely altered that cells rarely replicate successfully. Another possibility is that tumors with high levels of genomic instability are more immunogenic than other cancers with a less extensive burden of genetic aberrations. Regardless of the exact mechanism, but hinging on our ability to quantify how a tumor’s burden of genetic aberrations is distributed among coexisting clones – genomic instability has important therapeutic implications. Herein, we explore the possibility that a high genomic instability could be the basis for a tumor’s sensitivity to DNA damaging therapies. We primarily focus on studies of epithelial-derived solid tumors.

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Dynamic clonal equilibrium and predetermined cancer risk in Barrett’s oesophagus

Cited by 82 publications

References 32 publications

Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors

Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors

The Evolving Genomic Landscape of Barrett’s Esophagus and Esophageal Adenocarcinoma

Genomic Instability in Cancer: Teetering on the Limit of Tolerance

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