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. 2014 Nov;67(11):968-73.
doi: 10.1136/jclinpath-2014-202514. Epub 2014 Jul 30.

Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

J S Ross  1 , K Wang  2 , J V Rand  3 , L Gay  2 , M J Presta  3 , C E Sheehan  3 , S M Ali  2 , J A Elvin  2 , E Labrecque  2 , C Hiemstra  2 , J Buell  2 , G A Otto  2 , R Yelensky  2 , D Lipson  2 , D Morosini  2 , J Chmielecki  2 , V A Miller  2 , P J Stephens  2
Affiliations

Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

J S Ross et al. J Clin Pathol. 2014 Nov.

Abstract

Aims: Adrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice.

Methods: DNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs).

Results: At least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial.

Conclusions: Next-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer.

Keywords: Cancer Genetics; Endocrine Pathology; Gene Amplification; Molecular Pathology; Oncology.

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Figures

Figure 1
Figure 1
Tile plot of genomic alterations identified in 29 adrenocortical carcinoma cases.
Figure 2
Figure 2
Case 13. A pleomorphic adrenocortical carcinoma liver metastasis derived from a 48-year-old man harboured CDK4 and MDM2 amplifications, CUL4A (V275M) and TP53 (S241Y) mutations.
Figure 3
Figure 3
Case 7. A Stage III Fuhrman Grade 3 adrenocortical carcinoma with extensive tumour necrosis derived from a 60-year-old man harboured PDGFRB amplification.
See this image and copyright information in PMC

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