Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma

Abstract

In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non-endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low-grade, non-ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE-positive endometrioid endometrial carcinomas (EECs). We performed exome-sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling-related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA-repair-related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co-occurrence (RAD50-KMT2D and RAD50-SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.

Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications

“…45 KMT2 genes code for a homonymous family of methyltransferases, which are the effectors of histone H3 methylation, one of the epigenetic mechanisms regulating gene transcription. 46 In case of mutations, both JAK and KMT2 genes have been already described as potential drivers in MSI/dMMR tumours of other sites, 45 46 and we highlighted their potential involvement also in MSI/dMMR PDAC, further refining the knowledge on the genetic landscape of this tumour entity. Regarding survival of MSI/dMMR patients with PDAC, this systematic review revealed that there are no significant improvements in survival outcomes for this subgroup of patients.…”

SET domain containing 1B gene is mutated in primary hepatic neuroendocrine tumors

“…revealed a synergistic role of hSET1 and NURF in regulating the USF‐bound barrier insulator that prevents erythroid genes from encroaching upon heterochromatin . Chromatin remodeling related genes ( KMT2D , KMT2C , SETD1B and BCOR ) is frequently mutated in endometrioid endometrial carcinoma . Collectively, we concluded that gene‐oriented ( SETD1B ) and pathway‐oriented networks are dependent and cooperative and require further investigation in PHNETs.…”

EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells

“…From clinical data we extracted the worst prognosis when both, ZEB1 and SETD1B were highly expressed whereas in the low/low group nearly all colorectal cancer patients survived the first 5 years after surgery. For endometrial carcinomas it was reported that for SETD1B mutant cases a higher myometrial invasion can be predicted 36 . In clear cell renal cell carcinomas SETD1B overexpression could discriminate metastatic from non-metastatic tumors 37 .…”