Explosive beginnings

the authors propose a ‘Big Bang’ model of tumour initiation in colorectal cancer

Understanding intratumoural heterogeneity (ITH) might provide information about tumour initiation as well as identify so-called ‘driver mutations’ that might be therapeutic targets. Sottoriva et al. sought to understand the spatial patterns of ITH and the underlying clonal dynamics by analysing multiple single glands and bulk tumour regions from colorectal tumours. Sottoriva et al. profiled 349 colorectal tumour glands (comprising fewer than 10,000 cells) and bulk samples taken from 2 opposing sides of 15 colorectal tumours. Given the glandular structure of colorectal tumours, it can be considered that cells within a gland share a common ancestry and have not been ‘mixed’, allowing the detection of subclonal alterations. Using whole-genome single-nucleotide polymorphism (SNP) array-based profiling of copy number alterations (CNAs), the authors observed several patterns of spatial variation, including CNAs found in all samples, those found in one side and not the other, CNAs found in some glands on one side only and CNAs found in only one gland. Adenomas (n = 4), which were more genomically stable than the carcinomas (n = 11), had many side-specific CNAs. Conversely, most carcinomas had the same CNAs — to varying extents — on both sides of the tumour, indicating that CNAs occurring early in tumorigenesis become spread out to distant regions as the tumour grows (referred to as varie­ gation). Thus, an important finding is

that one region does not represent the entirety of the tumour. Next, the authors assessed the mutational hetero­geneity of the bulk tumour samples using whole-exome sequencing. On the basis of the patientspecific mutations identified, they carried out deep targeted sequencing in the glands and fragments of the bulk samples. Twelve of the tumours had nonsense mutations in adenomatous polyposis coli (APC), and they also found KRAS mutations in five of the tumours and TP53 mutations in three of the carcinomas. Like the CNA data, the mutation analysis showed clonal spatial segregation in the adenomas and variegation in the carcinomas. To assess whether there was heterogeneity within the glands, the authors carried out fluorescence in situ hybridization (FISH) for ERBB2 amplification of single adjacent cells in 65 glands. There were substantial differences in the CNAs between adjacent cells in all of the glands, which may be the result of chromosome instability — a common feature of colorectal cancer. Furthermore, epigenetic passenger mutations were also highly hetero­ geneous. This heterogeneity indicates an absence of a selective sweep and that the alterations occurred early in tumorigenesis.


/ row aC Lar

Finally, the authors used a mathe­ matical model to quantitatively simulate the expansion of a tumour. Interestingly, the simulation revealed that subclones from the adenomas did not exhibit differences in fitness, whereas carcinoma subclones did. The simulation also confirmed that the alterations that occurred in more than one gland mostly occurred early when the tumour was small (and was unlikely to be clinically detectable). It is important to note that in the simulation the tumour micro­environment was assumed not to have an active role in clonal selection; this issue needs to be addressed specifically. On the basis of these data, the authors propose a ‘Big Bang’ model of tumour initiation in colorectal cancer. This model suggests that after an initial oncogenic mutation, which is present in most subsequent cells, the progeny then acquire further mutations, which are present in discrete populations of cells that then expand as the tumour grows, leading to spatial heterogeneity. Gemma K. Alderton ORIGINAL RESEARCH PAPER Sottoriva, A. et al. A Big Bang model of human colorectal tumor growth. Nature Genet. 47, 209–216 (2015)

VOLUME 15 | APRIL 2015 © 2015 Macmillan Publishers Limited. All rights reserved


Heterogeneity: Explosive beginnings.

Heterogeneity: Explosive beginnings. - PDF Download Free
90KB Sizes 2 Downloads 5 Views

Recommend Documents

Student life - Outstanding beginnings.
The Cavell nursing student awards are given to recognise exceptional nursing and midwifery students. Each year, five scholarships are offered for placements in the UK or abroad.

The beginnings of long QT syndrome.
The purpose of this study is to update the perinatal cardiologist and obstetrical care provider on the presentation and management of the fetus with long QT syndrome (LQTS).