Cell-lineage heterogeneity and driver mutation recurrence in pre-invasive breast neoplasia.
BACKGROUND
All cells in an individual are related to one another by a bifurcating lineage tree, in which each node is an ancestral cell that divided into two, each branch connects two nodes, and the root is the zygote. When a somatic mutation occurs in an ancestral cell, all its descendants carry the mutation, which can then serve as a lineage marker for the phylogenetic reconstruction of tumor progression. Using this concept, we investigate cell lineage relationships and genetic heterogeneity of pre-invasive neoplasias compared to invasive carcinomas.


METHODS
We deeply sequenced over a thousand phylogenetically informative somatic variants in 66 morphologically independent samples from six patients that represent a spectrum of normal, early neoplasia, carcinoma in situ, and invasive carcinoma. For each patient, we obtained a highly resolved lineage tree that establishes the phylogenetic relationships among the pre-invasive lesions and with the invasive carcinoma.


RESULTS
The trees reveal lineage heterogeneity of pre-invasive lesions, both within the same lesion, and between histologically similar ones. On the basis of the lineage trees, we identified a large number of independent recurrences of PIK3CA H1047 mutations in separate lesions in four of the six patients, often separate from the diagnostic carcinoma.


CONCLUSIONS
Our analyses demonstrate that multi-sample phylogenetic inference provides insights on the origin of driver mutations, lineage heterogeneity of neoplastic proliferations, and the relationship of genomically aberrant neoplasias with the primary tumors. PIK3CA driver mutations may be comparatively benign inducers of cellular proliferation.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA ; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA.
Ziming
Z
Weng
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA ; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA.
Noah
N
Spies
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA.
Shirley X
SX
Zhu
Biomedical Informatics Training Program, Stanford University, Stanford, CA 94305 USA.
Daniel E
DE
Newburger
Department of Computer Science, Stanford University, Stanford, CA 94305 USA.
Dorna
D
Kashef-Haghighi
Department of Computer Science, Stanford University, Stanford, CA 94305 USA.
Serafim
S
Batzoglou
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA ; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA.
Arend
A
Sidow
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305 USA.
Robert B
RB
West