Abstract P6-07-09: Somatic mutations in A kinase anchoring proteins (AKAPs) in metastatic tumors - A potential characteristic of breast cancer metastasis
Authors: Kjällquist U , Erlandsson R , Alkodsi A , Tobin N , Karlsson E , Hatschek T , Hartman J , Linnarsson S , Bergh J 
Published: May 2016

Abstract
Introduction
Genomic heterogeneity in primary solid tumors has been extensively studied using deep sequencing technologies during the last decade. The heterogeneity of cancer tumors is today a well-established concept partly reflected in the low number of genes being recurrently mutated in over 10% of the tumors. However, most available data relates to the primary breast cancer tumors and little has been described about the mutational profiles of the metastatic lesions and their relation to its original malignant cell population. Prospective and retrospective studies have demonstrated that altered receptor status in the metastatic lesion occurs at high rates during cancer progression and is additionally affected by adjuvant therapy with major implications for management of the metastatic disease. Here, we report the exome sequences of paired primary and metastatic lesions from ten breast cancer patients.
Results
We found a marked heterogeneity of somatic mutations as well as chromosomal aberrations in the metastatic lesions. A number of mutated genes were enriched in the metastases including, significantly, members of the A-kinase anchoring protein family (AKAPs), p &lt; 0.02; Fisher's exact test.
The enrichment of AKAP mutations in metastatic lesions was confirmed in an independent cohort containing 20 patients with paired primary and metastatic lesions, which showed the same mutational pattern. In total, 14 nonsynonymous mutations were found in ten of the fourteen AKAP family members. Out of the totally 30 patients examined, ten (30%) carried one or more mutations in AKAP genes either in primary tumor, metastasis, or both. In seven of these ten patients, the AKAP mutation was found uniquely in the metastatic lesion.
Several copy number variations (CNV), mostly deletions in regions containing AKAP genes were detected. For example, the down-regulation of AKAP12 is often associated with promoter hypermethylation or loss of its locus 6q24-25.2 and has been associated with tumor progression and metastasis. In our data deletion of the AKAP12 locus is present in six out of twenty patients.
Discussion
AKAPs are members of a protein family acting as anchors for Protein Kinase A (PKA) by specifically associate PKA regulatory subunits to cellular organelles and direct its active signal transduction spatially and temporally. Several of the AKAP members have been associated to cancer development and metastatic spread, mostly based on differential expression and effects on migration in in vitro assays but both polymorphisms and somatic mutations have been reported in human tumors.
Our findings indicate that in metastatic lesions, the primary tumor genome is extensively transformed, with enrichment of mutations in a distinct set of genes. Together, these findings suggest the involvement of AKAPs in the metastatic process and provide a potential avenue for targeted therapy directed at metastatic breast cancer. Molecular and genetic characterization of the metastatic lesions is not only important in the clinical setting but should also provide the means to reveal genetic patterns specific for the disseminated malignancy.
Citation Format: Kjällquist U, Erlandsson R, Alkodsi A, Tobin N, Karlsson E, Hatschek T, Hartman J, Linnarsson S, Bergh J. Somatic mutations in A kinase anchoring proteins (AKAPs) in metastatic tumors - A potential characteristic of breast cancer metastasis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-07-09.