Deep sequencing of the X chromosome reveals the proliferation history of colorectal adenomas
- PMID: 25175524
- PMCID: PMC4181412
- DOI: 10.1186/s13059-014-0437-8
Deep sequencing of the X chromosome reveals the proliferation history of colorectal adenomas
Abstract
Background: Mismatch repair deficient colorectal adenomas are composed of transformed cells that descend from a common founder and progressively accumulate genomic alterations. The proliferation history of these tumors is still largely unknown. Here we present a novel approach to rebuild the proliferation trees that recapitulate the history of individual colorectal adenomas by mapping the progressive acquisition of somatic point mutations during tumor growth.
Results: Using our approach, we called high and low frequency mutations acquired in the X chromosome of four mismatch repair deficient colorectal adenomas deriving from male individuals. We clustered these mutations according to their frequencies and rebuilt the proliferation trees directly from the mutation clusters using a recursive algorithm. The trees of all four lesions were formed of a dominant subclone that co-existed with other genetically heterogeneous subpopulations of cells. However, despite this similar hierarchical organization, the growth dynamics varied among and within tumors, likely depending on a combination of tumor-specific genetic and environmental factors.
Conclusions: Our study provides insights into the biological properties of individual mismatch repair deficient colorectal adenomas that may influence their growth and also the response to therapy. Extended to other solid tumors, our novel approach could inform on the mechanisms of cancer progression and on the best treatment choice.
Figures





References
-
- Otter R. The number of trees. Ann Math. 1948;49:583–599. doi: 10.2307/1969046. - DOI
-
- Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461:809–813. doi: 10.1038/nature08489. - DOI - PubMed
Publication types
MeSH terms
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical