Feasibility of analyzing DNA copy number variation in breast cancer tumor specimens from 1950 to 2010: how old is too old?
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The purpose of the study was to assess the feasibility of quantifying long-term trends in breast tumor DNA copy number variation (CNV) profiles.
We evaluated CNV profiles in formalin-fixed paraffin-embedded (FFPE) tumor specimens from 30 randomly selected Kaiser Permanente Northern California health plan women members diagnosed with breast cancer from 1950 to 2010. Assays were conducted for five cases per decade who had available tumor blocks and pathology reports.
As compared to the tumors from the 1970s to 2000s, the older tumors dating back to the 1950s and 1960s were much more likely to (1) fail quality control, and (2) have fewer CNV events (average 23 and 31 vs. 58 to 69), fewer CNV genes (average 5.1 and 3.7k vs. 8.1 to 10.3k), shorter CNV length (average 2,440 and 3,300k vs. 5,740 to 9,280k), fewer high frequency Del genes (37 and 25% vs. 54 to 76%), and fewer high frequency high_Amp genes (20% vs. 56 to 73%). On average, assay interpretation took an extra 60 min/specimen for cases from the 1960s versus 20 min/specimen for the most recent tumors.
Assays conducted in the mid-2010s for CNVs may be feasible for FFPE tumor specimens dating back to the 1980s, but less feasible for older specimens.
KeywordsArchival specimen Breast cancer Biomarker DNA copy number variation Epidemiology Historical trend
We also would like to thank Marvella A. Villasenor, BA (Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612; email: Marvella.A.Villasenor@kp.org) for her administrative assistance with study logistics.
NK led design of the study, arranged for the assays, oversaw the analyses, and led manuscript preparation. SN interpreted the assay results and contributed to text on the methods and results. LH oversaw the initial selection of cases and retrieval of the tumor specimens, and assisted in all logistics pertaining to handling of the specimens at KPNC, as carried out by LA and NA. PDW assisted with all logistics pertaining to the handling of the specimens and with arranging the assays, once the specimens were at Harvard. SJS oversaw the histological characterization of the tumor specimens and the extraction of tumor DNA for the study assay. All authors contributed to manuscript preparation and reviewed and approved the final manuscript prior to submission.
This study was funded by NIH grant 5R03CA193078 (PI: Krieger), which was supported by the National Cancer Institute (NCI) and the NIH Office of Behavioral and Social Sciences Research, in the Office of the Director, National Institutes of Health (OD). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article; and decision to submit the article for publication.
Compliance with ethical standards
Conflicts of interest
The authors declare they have no conflicts of interest to declare.
Human Subjects and Informed Consent
This study was approved by the Institutional Review Boards (IRBs) of the Harvard T.H. Chan School of Public Health (#CR-20929-02) and Kaiser Permanente Northern California (#CN-13Labe-O3-H). All procedures involving human subjects were in accordance with the ethical standards of these IRBs and the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For the type of retrospective study conducted, formal consent was not required for inclusion in this study.
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