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Abstract P1-06-06: Evidence for tumor heterogeneity and clonal evolution during invasive progression of breast cancer

Publication ,  Conference
Ding, Y; Marks, JR; King, LM; Hall, AH; Mardis, ER; Rodrigo, AG; Maley, CC; Hwang, E-S
Published in: Cancer Research
February 15, 2017

Purpose: Intratumoral heterogeneity is well recognized to be an important driver of treatment resistance and metastasis. We undertook this N of one study to measure the degree of heterogeneity in a single large preinvasive lesion with an invasive component to determine the relationship between tumor heterogeneity, spatial distribution, clonal evolution, and invasive progression.Methods: We identified a patient with extensive DCIS measuring 7.5 cm, associated with 1.5 cm of an invasive component. We segregated the tumor sample into 32 unique blocks with precise geospatial localization; invasive cancer was identified in 3 of 32 blocks. NGS libraries were made from FFPE derived DNA (20-40ng) for full exome sequencing and hybridization to a 4.8 million element SNP array. All data were analyzed and a phylogentic tree was constructed.Results: The sequence data was analyzed with Platypus[1] and 3922 somatic mutation sites were found in total. These sites were concatenated into one sequence for each sample. Then a Neighbor-Joining tree was built with a Jukes-Cantor model and 1000 bootstrap replicates using FastME 2.0[2], to assess the reliability of the tree (Figure 1). Phylogenetic analysis revealed that invasive cancer evolved twice, independently. Dense sampling allowed reconstruction of the temporal order of mutations that accumulated in the cell lineage of the invasive cancers. Furthermore, the phylogeny revealed that distant regions may be closely genetically related, the oldest parts of the tumor were in the interior of the tumor, and that the invasive tumors evolved near the oldest parts of the tumor, rather than at the expanding front.Conclusions: Extensive sampling and sequencing of a single tumor yields important insights about tumor heterogeneity and tumor progression for DCIS to invasive cancer. Foci of invasion were geospatially associated with preinvasive regions of progressively higher mutational load.1. Rimmer A, Phan H, Mathieson I, Iqbal Z, Twigg SR, Wilkie AO, McVean G, Lunter G, Consortium W: Integrating mapping-, assembly-and haplotype-based approaches for calling variants in clinical sequencing applications. Nature genetics 2014, 46(8):912-918.2. Lefort V, Desper R, Gascuel O: FastME 2.0: a comprehensive, accurate, and fast distance-based phylogeny inference program. Molecular biology and evolution 2015:msv150.Citation Format: Ding Y, Marks JR, King LM, Hall AH, Mardis ER, Rodrigo AG, Maley CC, Hwang E-S. Evidence for tumor heterogeneity and clonal evolution during invasive progression of breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-06-06.

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

February 15, 2017

Volume

77

Issue

4_Supplement

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
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Ding, Y., Marks, J. R., King, L. M., Hall, A. H., Mardis, E. R., Rodrigo, A. G., … Hwang, E.-S. (2017). Abstract P1-06-06: Evidence for tumor heterogeneity and clonal evolution during invasive progression of breast cancer. In Cancer Research (Vol. 77). American Association for Cancer Research (AACR). https://doi.org/10.1158/1538-7445.sabcs16-p1-06-06
Ding, Y., J. R. Marks, L. M. King, A. H. Hall, E. R. Mardis, A. G. Rodrigo, C. C. Maley, and E. -. S. Hwang. “Abstract P1-06-06: Evidence for tumor heterogeneity and clonal evolution during invasive progression of breast cancer.” In Cancer Research, Vol. 77. American Association for Cancer Research (AACR), 2017. https://doi.org/10.1158/1538-7445.sabcs16-p1-06-06.
Ding Y, Marks JR, King LM, Hall AH, Mardis ER, Rodrigo AG, et al. Abstract P1-06-06: Evidence for tumor heterogeneity and clonal evolution during invasive progression of breast cancer. In: Cancer Research. American Association for Cancer Research (AACR); 2017.
Ding, Y., et al. “Abstract P1-06-06: Evidence for tumor heterogeneity and clonal evolution during invasive progression of breast cancer.” Cancer Research, vol. 77, no. 4_Supplement, American Association for Cancer Research (AACR), 2017. Crossref, doi:10.1158/1538-7445.sabcs16-p1-06-06.
Ding Y, Marks JR, King LM, Hall AH, Mardis ER, Rodrigo AG, Maley CC, Hwang E-S. Abstract P1-06-06: Evidence for tumor heterogeneity and clonal evolution during invasive progression of breast cancer. Cancer Research. American Association for Cancer Research (AACR); 2017.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

February 15, 2017

Volume

77

Issue

4_Supplement

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis