Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets.
Bioinformatics
Breast cancer
Genetics
Oncology
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
03 08 2020
03 08 2020
Historique:
received:
08
05
2019
accepted:
05
05
2020
pubmed:
14
7
2020
medline:
3
2
2021
entrez:
14
7
2020
Statut:
ppublish
Résumé
Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases - MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1 - 5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAQR8. PAQR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Our findings identify multiple therapeutic targets in metastatic recurrence that are not significantly mutated in primary cancers, implicate membrane progesterone signaling and nuclear PKA in metastatic recurrence, and provide genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer.
Identifiants
pubmed: 32657779
pii: 129941
doi: 10.1172/JCI129941
pmc: PMC7410083
doi:
pii:
Substances chimiques
Neoplasm Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4252-4265Subventions
Organisme : NCI NIH HHS
ID : R01 CA148774
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA223816
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA098371
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA143296
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208273
Pays : United States
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