Germline genetic determination of cancer progression and survival
Open accessPreprint — published as 10.1038/s41591-020-0879-3 · Paper page
Abstract
We report the surprising finding that common germline polymorphisms of APOE , present in approximately 39% of Caucasians, predict survival outcomes in human melanoma. Analysis of The Cancer Genome Atlas revealed that carriers of the APOE2 variant experienced shorter survival relative to APOE3 homozygotes, while APOE4 variant carriers exhibited increased survival. Consistent with this, melanoma growth in human APOE knock-in mice followed the order of APOE2 > APOE3 > APOE4 , revealing causal regulation of progression by APOE variants. Mechanistically, recombinant ApoE protein variants differentially suppressed melanoma cell invasion and endothelial recruitment phenotypes. Moreover, tumors in APOE4 mice exhibited greater immune cell infiltration and activation relative to tumors of APOE2 mice. These findings support the notion that human germline genetic makeup can impact the trajectory of a future malignancy.
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Cites
Detection of Mycoplasma in cell cultures
Young, L., Sung, J., Stacey, G., & Masters, J. R. (2010) · Nature Protocols · doi:10.1038/nprot.2010.43 · Cited by 437 · cited 1× · see citing works
“Contamination with mycoplasma was ruled out by PCR testing according to standard protocols (29).”
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- Authors
- Ostendorf, B. N., Tafreshian, K. N., Adaku, N., Bilanovic, J., Tavora, B., & Tavazoie, S. F.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- Tavazoie, Sohail F.
- Venue
- Nature Medicine
- Publisher
- openRxiv
- Published
- 2019-03-13
- Volume
- 26
- Issue
- 7
- Pages
- 1048-1053
- ISSN
- 1078-8956 (ISSN-L)
- PMC
- PMC8058866
- OpenAlex
- W3026412257
- Cited by
- 108
- References
- 1
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 18 · 2023: 15 · 2022: 22 · 2021: 10 · 2020: 5
- FWCI
- 4.70
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Hope Funds for Cancer Research
- Deutsche Forschungsgemeinschaft (OS 498/1-1)
- Studienstiftung des Deutschen Volkes
- National Institutes of Health (UL1TR001866)
- National Cancer Institute (R01CA184804)
- National Institute of General Medical Sciences (T32GM007739)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- APOE gene, APOE ε4, APOE2, melanoma, germline mutations, antitumor immunity, T cells, metastasis, melanoma progression, survival, PD-1 immune checkpoint blockade, anti-PD-1 therapy, liver X receptor, genetic biomarkers, cancer immunotherapy response
- MeSH terms
- Animals, Brain, Female, Genotype, Humans, Melanoma, Mice, Transgenic, Germ-Line Mutation, Disease Progression, Disease-Free Survival, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Programmed Cell Death 1 Receptor
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