Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

Abstract

PurposeThe extent to which the developmental transcription factor SOX9 functions as an oncogene or tumor suppressor in colorectal carcinoma (CRC) is debatable. We aimed to clarify the effect of SOX9 mutations on SOX9 protein expression and their association with known molecular subtypes and clinical characteristics in advanced CRC.Experimental DesignNext generation sequencing data (MSK-IMPACT) from CRC patients was used to interrogate SOX9, KRAS, NRAS, BRAF, TP53, APC, and PIK3CA. Mutant and wild type (WT) SOX9 cases underwent immunohistochemical (IHC) staining to assess protein expression. SOX9 allele-specific copy number was assessed by Affymetrix Oncoscan array.ResultsSOX9 was mutated in 38 of 353 (10.7%) CRC, of which 82% were frameshift or nonsense. Compared to SOX9 WT, SOX9 mutation was strongly associated with coexistent mutant KRAS (p=0.0001) and WT TP53 (p=0.0004). SOX9 was overexpressed in both SOX9 mutant and WT CRC. Among SOX9 mutants, the highest expression was noted for truncating exon 3 mutants (mean H scores 239±105 versus 147±119, p value=0.02). Further, SOX9 truncating mutants with loss of the WT allele demonstrated protein overexpression indicating the WT protein was not required for protein stabilization.ConclusionsSOX9 is overexpressed in CRC, including those with recurrent distal truncating mutations. The latter has structural similarity to the oncogenic isoform MiniSOX9, which is distally truncated due to aberrant splicing. This information suggests that truncated SOX9 has oncogenic features. SOX9 mutations are highly enriched in KRAS mutant and TP53 wild type CRC; and may provide a therapeutic target in approximately 11% of CRC.

<p>Long Non-Coding RNA LEF1-AS1 Promotes Migration, Invasion and Metastasis of Colon Cancer Cells Through miR-30-5p/SOX9 Axis</p>

“…43 Moreover, a variety of studies demonstrated that SOX9 was overexpressed in colon cancer tissues and cell lines compared with healthy colon epithelia, suggesting that SOX9 was inclined to be oncogenic in colon cancer. 36,37,42,44,45 In our study, we found that SOX9 was a downstream target for miR-30-5p, and LEF1-AS1 overexpression increased the expression level of SOX9 in colon cancer cells. Moreover, restoration of SOX9 attenuated the effects caused by LEF1-AS1 knockdown.…”

“…41 However, study of the truncating mutations of SOX9 indicating that these mutations were likely oncogenic and overexpressed in colon cancer. 42 Besides, data across TCGA showed that SOX9 was mutated and amplified in multiple cancers and whole gene deletion was rarely detected, a pattern typically seen in oncogenes. 43 Moreover, a variety of studies demonstrated that SOX9 was overexpressed in colon cancer tissues and cell lines compared with healthy colon epithelia, suggesting that SOX9 was inclined to be oncogenic in colon cancer.…”

The effects of lncRNA MALAT1 on proliferation, invasion and migration in colorectal cancer through regulating SOX9

“…More importantly, SOX9 with up-regulated expression was indicated poor prognosis in colorectal cancer, glioma and lung cancer (Liu et al 2017 ; Bruun et al 2014 ; Zhou et al 2012 ). SOX9 over-expressed in colorectal cancer was reported by (Javier et al 2016 ; Montorsi et al 2016 and Shi et al 2015 ). However, the mechanisms underlying SOX9 mediated tumorigenesis remain elusive.…”

Transcriptional Regulation of the Intestinal Cancer Stem Cell Phenotype

“…SOX9 displays missense or frameshift mutations in almost 10% of CRC [29]. SOX9 mutation rate is higher in more advanced tumors and is correlated with activated KRAS, an oncogene frequently mutated during CRC development, thus facilitating transformation and tumor progression [29]. Furthermore, a SOX9 splice variant (MiniSOX9) that contains the HMG domain responsible for binding to DNA but devoid of the trans-activating domain has been discovered [30].…”