Extreme chromosomal instability forecasts improved outcome in ER-negative breast cancer: a prospective validation cohort study from the TACT trial

Jamal‐Hanjani, Mariam; A’Hern, Roger; Birkbak, Nicolai J.; Gorman, Patricia; Grönroos, Eva; Ngang, S.; Nicola, Patricia; Rahman, Loay; Thanopoulou, Eirini; Kelly, Gavin; Ellis, Paul; Barrett-Lee, Peter; Johnston, Stephen; Bliss, Judith; Roylance, Rebecca; Swanton, Charles

doi:10.1093/annonc/mdv178

Cited by 70 publications

(63 citation statements)

References 49 publications

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“…Analysis of chromosomal instability levels in patients echoed this work from model systems, demonstrating that patients with tumours exhibiting 'extreme' CIN showed better prognosis . This was supported by subsequent studies in breast cancer (Roylance et al 2011, Jamal-Hanjani et al 2015, and also more recently in a pan-cancer analysis (Andor et al 2016).…”

Section: :9mentioning

confidence: 55%

Role of chromosomal instability in cancer progression

McClelland

2017

Endocrine-Related Cancer

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Cancer cells often display chromosomal instability (CIN), a defect that involves loss or rearrangement of the cell's genetic material -chromosomes -during cell division. This process results in the generation of aneuploidy, a deviation from the haploid number of chromosomes, and structural alterations of chromosomes in over 90% of solid tumours and many haematological cancers. This trait is unique to cancer cells as normal cells in the body generally strictly maintain the correct number and structure of chromosomes. This key difference between cancer and normal cells has led to two important hypotheses: (i) cancer cells have had to overcome inherent barriers to changes in chromosomes that are not tolerated in non-cancer cells and (ii) CIN represents a cancer-specific target to allow the specific elimination of cancer cells from the body. To exploit these hypotheses and design novel approaches to treat cancer, a full understanding of the mechanisms driving CIN and how CIN contributes to cancer progression is required. Here, we will discuss the possible mechanisms driving chromosomal instability, how CIN may contribute to the progression at multiple stages of tumour evolution and possible future therapeutic directions based on targeting cancer chromosomal instability.

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Section: :9mentioning

confidence: 55%

Role of chromosomal instability in cancer progression

McClelland

2017

Endocrine-Related Cancer

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“…On the other hand, tumors would be vulnerable to either a decrease or an increase of CIN rates outside of the optimal range that supports clonal evolution. This is indeed supported by a number of clinical observations and experimental evidence (Bakhoum et al 2011;Birkbak et al 2011;Roylance et al 2011;Jamal-Hanjani et al 2015;Andor et al 2016). Among colorectal cancer-derived cell lines, chromosomally unstable cells are more resistant to targeted kinase inhibition as compared with their chromosomally stable counterparts (Lee et al 2011).…”

Section: The Dynamics Of Cin In Tumor Clonal Evolution and Therapeutimentioning

confidence: 68%

“…Among colorectal cancer-derived cell lines, chromosomally unstable cells are more resistant to targeted kinase inhibition as compared with their chromosomally stable counterparts (Lee et al 2011). In patients with breast cancer, the presence of moderate CIN is associated with inferior prognosis and resistance to taxanes whereas extreme CIN is associated with improved survival and reduced tumor relapse after primary therapy (Swanton et al 2009;Roylance et al 2011;Jamal-Hanjani et al 2015). Furthermore, in a pancancer genomic analysis of intratumor heterogeneity, patients that had tumors in the middle quartiles of chromosome copy number variations were at a significantly greater risk for death compared with those with tumors in the lowest or highest quartiles of chromosome copy number variations (Andor et al 2016).…”

Section: The Dynamics Of Cin In Tumor Clonal Evolution and Therapeutimentioning

confidence: 99%

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

Bakhoum

Landau

2017

Cold Spring Harb Perspect Med

125

103

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Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events.

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“…Patients whose tumor displayed either the lowest or highest instability (measured as the weighed Genome Instability Index, wGII) had better outcome than patients with intermediate levels of GIN in breast, ovarian, NSCLC, and gastric adenocarcinoma Roylance et al 2011). Extreme CIN was also linked to improved outcome in a multivariate analysis performed on a cohort of more than 1100 ER-negative breast cancer patients in which CIN was derived from centromeric FISH analysis (Jamal-Hanjani et al 2015). More recently, similar conclusions were reached in a pan-cancer analysis exploiting exome data from 1165 tumors across 12 tumor types and further validated with SNP-array data sets from more than 2000 samples (Andor et al 2016).…”

Section: Determinants Of Cin Propagation Sustainable Versus Lethal Lementioning

confidence: 99%

The Role of Aneuploidy in Cancer Evolution

Sansregret

Swanton

2016

Cold Spring Harb Perspect Med

215

163

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Chromosomal aberrations during cell division represent one of the first recognized features of human cancer cells, and modern detection methods have revealed the pervasiveness of aneuploidy in cancer. The ongoing karyotypic changes brought about by chromosomal instability (CIN) contribute to tumor heterogeneity, drug resistance, and treatment failure. Whole-chromosome and segmental aneuploidies resulting from CIN have been proposed to allow "macroevolutionary" leaps that may contribute to profound phenotypic change. In this review, we will outline evidence indicating that aneuploidy and CIN contribute to cancer evolution.

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Extreme chromosomal instability forecasts improved outcome in ER-negative breast cancer: a prospective validation cohort study from the TACT trial

Cited by 70 publications

References 49 publications

Role of chromosomal instability in cancer progression

Role of chromosomal instability in cancer progression

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

The Role of Aneuploidy in Cancer Evolution

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