Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer

Abstract

Background: Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types.

Methods: The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)).

Results: Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7%; Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5%; Gly44Cys, Ala67Val).

Conclusion: Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.

Figure 1

Mutations in MED12 exon 2. The whole MED12 exon 2 with the amino acids and codon numbers is shown at the top, and multispecies alignment of the regions with the detected mutations is shown below. Mutations observed in uterine leiomyosarcoma and CRC samples are marked with black and red, respectively. Mutations G44C and G44V in ULMS were reported by Pérot et al (2012). Mutation G44C in CRC was observed in this study and also in the study by The Cancer Genome Atlas Network (2012). Mutation D34Y in CRC has been reported by Je et al (2012). Amino acids at the top are color-coded according to their side-chains' pK_as (acid dissociation constant) and charge at physiological pH 7.4. Red = negatively charged, green = hydrophobic, yellow = small non-polar, magenta = polar, blue = positively charged.