Abstract 2244: SPOP mutations in prostate cancer across demographically diverse patient cohorts
Cancer Research(2014)
摘要
Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
Background
Recurrent mutations in the Speckle-Type POZ Protein (SPOP) gene have been reported in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unclear. In addition, detection of point mutations in archival samples can be technically challenging, making mutational analysis of well annotated archival tissue difficult. We set out to investigate SPOP mutations across diverse cohorts, and validate a series of assays employing High Resolution Melting Analysis (HRM) and Sanger sequencing for mutational analysis of FFPE material.
Methods:
An assay employing HRM and Sanger sequencing was optimized to screen for somatic mutations in recurrently altered areas of the SPOP gene. 720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both PSA-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features (ERG rearrangement, PTEN deletion, CHD1 deletion) as well as clinical and pathologic features.
Results:
The overall frequency of SPOP mutations was 8.1% in 720 patient's samples, ranging from 4.6% in the African American cohort to 14.4% in the WCMC cohort. There were no significant differences in frequency between ethnicities or cohorts (p=0.14). SPOP mutation was inversely associated with ERG rearrangement (p<0.01), and SPOP mutant cancers had higher rates of CHD1 deletions (p<0.01). There were no significant differences in rates or time to biochemical recurrence (BCR) in SPOP wild-type (wt) vs mutants (p=0.18, 0.30 respectively). The mutational assays showed excellent sensitivity and specificity in high quality samples. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes.
Conclusions:
In this study we were able to show the high sensitivity of HRM followed by Sanger Sequencing to detect mutated SPOP in 720 cases consisting of fresh frozen as well as FFPE material. Using next generation sequencing did not rescue samples which were determined as “assay failure” by HRM and or Sanger Sequencing. SPOP is mutated in 4.6-14.4% of prostate cancer patients across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.
Citation Format: Mirjam Blattner, Daniel Lee, Catherine O´Reilly, Kyung Park, Theresa Y. MacDonald, Francesca Khani, Kevin Turner, Peter J. Wild, Haley Hieronymus, Charles L. Sawyers, Ashutosh K. Tewari, Holger Moch, Ghil Suk Yoon, Ove Andren, Katja Fall, Juan Miguel Mosquera, Brian D. Robinson, Andrea Sboner, Christopher E. Barbierie, Mark A. Rubin. SPOP mutations in prostate cancer across demographically diverse patient cohorts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2244. doi:10.1158/1538-7445.AM2014-2244
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关键词
spop mutations,prostate cancer,diverse patient cohorts
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