Large-scale analysis of acquired chromosomal alterations in non-tumor samples from patients with cancer

Jakubek, Yasminka A.; Chang, Kyle; Sivakumar, Smruthy; Yu, Yao; Giordano, Mirella; Fowler, Jerry; Huff, Chad; Kadara, Humam; Vilar, Eduardo; Scheet, Paul

doi:10.1038/s41587-019-0297-6

Cited by 38 publications

(26 citation statements)

References 48 publications

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“…Positive selection was further evidenced by recurrent peaks of subclonal amplifications, enriched for established oncogenes, subclonal losses resulting in LOH, even after genome doubling, and parallel evolution of SCNAs. These data are consistent with previously documented parallel and convergent evolution of SCNAs 3, [24][25][26] Finally, recurrent focal subclonal SCNAs, encompassing oncogenic events including CCND1…”

Section: Discussionsupporting

confidence: 92%

Pervasive chromosomal instability and karyotype order in tumour evolution

Watkins

Lim

Petković

et al. 2020

Nature

292

300

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Cancer chromosomal instability (CIN) results from dynamic changes to chromosome number and structure. The resulting diversity in somatic copy number alterations (SCNA) may provide the variation necessary for cancer evolution. Multi-sample phasing and SCNA analysis of 1421 samples from 394 tumours across 24 cancer types revealed ongoing CIN resulting in pervasive SCNA heterogeneity. Parallel evolutionary events, causing disruption to the same genes, such as BCL9, ARNT/HIF1B, TERT and MYC, within separate subclones were present in 35% of tumours. Most recurrent losses occurred prior to whole genome doubling (WGD), a clonal event in 48% of tumours. However, loss of heterozygosity at the human leukocyte antigen locus and loss of 8p to a single haploid copy recurred at significant subclonal frequencies, even in WGD tumours, likely reflecting ongoing karyotype remodeling. Focal amplifications affecting 1q21 (BCL9, ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal and exhibited an illusion of clonality within single samples. Analysis of an independent series of 1024 metastatic samples revealed enrichment for 14 focal SCNAs in metastatic samples, including late gains of 8q24.1 (MYC) in clear cell renal carcinoma and 11q13.3 (CCND1) in HER2-positive breast cancer. CIN may enable ongoing selection of SCNAs, manifested as ordered events, often occurring in parallel, throughout tumour evolution.

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Section: Discussionsupporting

confidence: 92%

Pervasive chromosomal instability and karyotype order in tumour evolution

Watkins

Lim

Petković

et al. 2020

Nature

292

300

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“…The mapping of the normal mucosa from patients with UC revealed that the fields were highly heterogenous, indicating an ongoing genomic evolution and genetic divergence. This finding has recently been shown to be true also for other tumor types 8 . Similar detailed molecular analyses of pathologically normal sections of the bladder from patients with NMI tumors remains scarce, as these patients rarely are subjected to cystectomy.…”

supporting

confidence: 61%

Recurring urothelial carcinomas show genomic rearrangements incompatible with a direct relationship

Marzouka

Lindgren

Eriksson

et al. 2020

Sci Rep

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We used the fact that patients with non-muscle invasive bladder tumors show local recurrences and multiple tumors to study re-initiation of tumor growth from the same urothelium. By extensive genomic analyses we show that tumors from the same patient are clonal. We show that gross genomic chromosomal aberrations may be detected in one tumor, only to be undetected in a recurrent tumor. By analyses of incompatible changes i.e., genomic alterations that cannot be reversed, we show that almost all tumors from a single patient may show such changes, thus the tumors cannot have originated from each other. As recurring tumors share both genomic alterations and driver gene mutations, these must have been present in the urothelium in periods with no tumor growth. We present a model that includes a growing and evolving field of urothelial cells that occasionally, and locally, produce bursts of cellular growth leading to overt tumors.

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“…CNAs are found in <5% of nonmalignant cells with a median of 1.8% 24 – 26 and are diagnostically used to differentiate normal and malignant cells 27 . We therefore performed combined genome and transcriptome analysis and isolated genomic DNA and mRNA from the same single cell 5 , 14 .…”

Section: Resultsmentioning

confidence: 99%

Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency

et al. 2020

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Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.

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Large-scale analysis of acquired chromosomal alterations in non-tumor samples from patients with cancer

Cited by 38 publications

References 48 publications

Pervasive chromosomal instability and karyotype order in tumour evolution

Pervasive chromosomal instability and karyotype order in tumour evolution

Recurring urothelial carcinomas show genomic rearrangements incompatible with a direct relationship

Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency

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