Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs)

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dc.contributor.author Kjällquist, Una
dc.contributor.author Erlandsson, Rikard
dc.contributor.author Tobin, Nicholas P
dc.contributor.author Alkodsi, Amjad
dc.contributor.author Ullah, Ikram
dc.contributor.author Stålhammar, Gustav
dc.contributor.author Karlsson, Eva
dc.contributor.author Hatschek, Thomas
dc.contributor.author Hartman, Johan
dc.contributor.author Linnarsson, Sten
dc.contributor.author Bergh, Jonas
dc.date.accessioned 2018-02-18T04:19:58Z
dc.date.available 2018-02-18T04:19:58Z
dc.date.issued 2018-02-12
dc.identifier.citation BMC Cancer. 2018 Feb 12;18(1):174
dc.identifier.uri http://hdl.handle.net/10138/232545
dc.description.abstract Abstract Background Tumor heterogeneity in breast cancer tumors is today widely recognized. Most of the available knowledge in genetic variation however, relates to the primary tumor while metastatic lesions are much less studied. Many studies have revealed marked alterations of standard prognostic and predictive factors during tumor progression. Characterization of paired primary- and metastatic tissues should therefore be fundamental in order to understand mechanisms of tumor progression, clonal relationship to tumor evolution as well as the therapeutic aspects of systemic disease. Methods We performed full exome sequencing of primary breast cancers and their metastases in a cohort of ten patients and further confirmed our findings in an additional cohort of 20 patients with paired primary and metastatic tumors. Furthermore, we used gene expression from the metastatic lesions and a primary breast cancer data set to study the gene expression of the AKAP gene family. Results We report that somatic mutations in A-kinase anchoring proteins are enriched in metastatic lesions. The frequency of mutation in the AKAP gene family was 10% in the primary tumors and 40% in metastatic lesions. Several copy number variations, including deletions in regions containing AKAP genes were detected and showed consistent patterns in both investigated cohorts. In a second cohort containing 20 patients with paired primary and metastatic lesions, AKAP mutations showed an increasing variant allele frequency after multiple relapses. Furthermore, gene expression profiles from the metastatic lesions (n = 120) revealed differential expression patterns of AKAPs relative to the tumor PAM50 intrinsic subtype, which were most apparent in the basal-like subtype. This pattern was confirmed in primary tumors from TCGA (n = 522) and in a third independent cohort (n = 182). Conclusion Several studies from primary cancers have reported individual AKAP genes to be associated with cancer risk and metastatic relapses as well as direct involvement in cellular invasion and migration processes. Our findings reveal an enrichment of mutations in AKAP genes in metastatic breast cancers and suggest the involvement of AKAPs in the metastatic process. In addition, we report an AKAP gene expression pattern that consistently follows the tumor intrinsic subtype, further suggesting AKAP family members as relevant players in breast cancer biology.
dc.publisher BioMed Central
dc.subject Breast cancer
dc.subject Metastasis
dc.subject Exome sequencing
dc.subject Somatic mutations
dc.subject AKAP
dc.subject A-kinase anchoring proteins
dc.title Exome sequencing of primary breast cancers with paired metastatic lesions reveals metastasis-enriched mutations in the A-kinase anchoring protein family (AKAPs)
dc.date.updated 2018-02-18T04:19:58Z
dc.language.rfc3066 en
dc.rights.holder The Author(s).
dc.type.uri http://purl.org/eprint/entityType/ScholarlyWork
dc.type.uri http://purl.org/eprint/entityType/Expression
dc.type.uri http://purl.org/eprint/type/JournalArticle

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