Single-Nucleus Genome Sequencing Shows Early Aneuploid Rearrangement and Gradual Clonal Evolution in Breast Cancer

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In a study reported in Nature, Wang and colleagues developed a whole-genome and exome single-cell sequencing approach (nuc-seq) using G2/M nuclei and used the method to sequence single normal and tumor nuclei from an estrogen receptor–positive breast cancer and a triple-negative ductal carcinoma. The investigators found that aneuploid rearrangements occurred early in tumor evolution and remained highly stable as clonal expansion, reflecting gradual evolution of point mutations, occurred within tumor masses.

Use of targeted single-molecule sequencing showed that many of the point mutations occurred at low frequencies (< 10%) in tumor masses. Mathematical modeling showed that the triple-negative tumor cells had a 13-fold increased mutation rate, whereas the increased mutation rate was not observed in estrogen receptor–positive tumor cells.

The investigators concluded: “These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.” ■

Wang Y, et al: Nature 512:155-160, 2014.




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