Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

Abstract

MLL genes encode histone methyltransferases that are required for proper expression of a variety of genes. The pathologic implications of MLL genes have been studied not only in leukemias, but also in some solid cancers. We found in a public database that MLL, MLL2, MLL3, MLL4 and MLL5 genes had mononucleotide repeats that might be mutated in cancers with microsatellite instability (MSI). Frameshift mutations in a repeat of MLL3 have been found in colorectal cancers (CRC), but there is no frameshift mutation data of the other genes. In this study, we analyzed these repeats in 32 gastric cancers (GC) with high MSI (MSI-H), 59 GC with low MSI (MSI-L)/stable MSI (MSS), 40 CRC with MSI-H and 59 CRC with MSI-L/MSS by single-strand conformation polymorphism and DNA sequencing. We also analyzed MLL3 expression in GC and CRC tissues using immunohistochemistry. We found MLL, MLL2, MLL3 and MLL5 frameshift mutations in two (one GC and one CRC), three (one GC and two CRC), 17 (14 GC and three CRC) and six (four GC and two CRC) cancers, respectively. They were detected exclusively in MSI-H cancers, but not in MSI-L/MSS cancers. All of the cancers with MLL3 mutations showed loss of MLL3 expression, and their values were significantly lower than in those without MLL3 mutation (50.9%). Of note, the GC with MSI-H had significantly higher incidences in both MLL mutations and MLL3 expression loss than the CRC with MSI-H. Our data indicate that frameshift mutations of MLL genes and loss of expression of MLL3 protein are common in GC and CRC with MSI-H.

Mutational Landscape of Aggressive Cutaneous Squamous Cell Carcinoma

“…Inactivating KMT2C mutations have been reported for a number of tumors, including cancers of the stomach (31), bladder (32), and breast (33). In the TCGA stomach cancer dataset there is a trend towards reduced overall survival in patients with KMT2C mutation compared to patients who are wild type (median 13 vs 59 months).…”

The miR-200 family is increased in dysplastic lesions in ulcerative colitis patients

“…Among these genes, KMT2C is a lysine methyltransferase found to be associated with colorectal cancer as well as acute myeloid leukemia. [28,29] KMT2C has also been implicated in gastric cancer and could be useful as a marker of prognosis. [30] Table 4 summarises these results.…”

The Necessity for In Vivo Functional Analysis in Human Medical Genetics.

“…However, somatic mutations in KMT2D have been found in several types of human cancer, including medulloblastoma, breast, colon, gastric, and non-small cell lung cancer (Ford & Dingwall, 2015; Je, Lee, Yoo, & Lee, 2013; Natarajan et al, 2010; Rabello, de Moura, de Andrade, Motoyama, & Silva, 2013; S. Yin et al, 2014).…”