Publication Date:
2014-08-01
Description:
Sequencing studies of breast tumour cohorts have identified many prevalent mutations, but provide limited insight into the genomic diversity within tumours. Here we developed a whole-genome and exome single cell sequencing approach called nuc-seq that uses G2/M nuclei to achieve 91% mean coverage breadth. We applied this method to sequence single normal and tumour nuclei from an oestrogen-receptor-positive (ER(+)) breast cancer and a triple-negative ductal carcinoma. In parallel, we performed single nuclei copy number profiling. Our data show that aneuploid rearrangements occurred early in tumour evolution and remained highly stable as the tumour masses clonally expanded. In contrast, point mutations evolved gradually, generating extensive clonal diversity. Using targeted single-molecule sequencing, many of the diverse mutations were shown to occur at low frequencies (〈10%) in the tumour mass. Using mathematical modelling we found that the triple-negative tumour cells had an increased mutation rate (13.3x), whereas the ER(+) tumour cells did not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158312/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158312/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Yong -- Waters, Jill -- Leung, Marco L -- Unruh, Anna -- Roh, Whijae -- Shi, Xiuqing -- Chen, Ken -- Scheet, Paul -- Vattathil, Selina -- Liang, Han -- Multani, Asha -- Zhang, Hong -- Zhao, Rui -- Michor, Franziska -- Meric-Bernstam, Funda -- Navin, Nicholas E -- 1R01CA169244-01/CA/NCI NIH HHS/ -- CA016672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50 CA098258/CA/NCI NIH HHS/ -- R01 CA169244/CA/NCI NIH HHS/ -- R01 CA172652/CA/NCI NIH HHS/ -- R01CA172652/CA/NCI NIH HHS/ -- R21 CA174397/CA/NCI NIH HHS/ -- R21CA174397-01/CA/NCI NIH HHS/ -- U24CA143883/CA/NCI NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- UL1 TR000371/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Aug 14;512(7513):155-60. doi: 10.1038/nature13600. Epub 2014 Jul 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The University of Texas MD Anderson Cancer Center, Department of Genetics, Houston, Texas 77030, USA. ; 1] The University of Texas MD Anderson Cancer Center, Department of Genetics, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA. ; The University of Texas MD Anderson Cancer Center, Department of Bioinformatics and Computational Biology, Houston, Texas 77030, USA. ; 1] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA [2] The University of Texas MD Anderson Cancer Center, Department of Epidemiology, Houston, Texas 77030, USA. ; The University of Texas MD Anderson Cancer Center, Department of Pathology, Houston, Texas 77030, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02215, USA. ; The University of Texas MD Anderson Cancer Center Department of Investigational Cancer Therapeutics, Houston, Texas 77030, USA. ; 1] The University of Texas MD Anderson Cancer Center, Department of Genetics, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030, USA [3] The University of Texas MD Anderson Cancer Center, Department of Bioinformatics and Computational Biology, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079324" target="_blank"〉PubMed〈/a〉
Keywords:
Breast Neoplasms/*genetics
;
Cell Line, Tumor
;
*Clonal Evolution
;
DNA Fingerprinting
;
Female
;
Genetic Variation
;
Genome/*genetics
;
Humans
;
Models, Theoretical
;
Mutation/genetics
;
Sequence Analysis, DNA
;
Single-Cell Analysis
;
Triple Negative Breast Neoplasms/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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