br Lung squamous cell carcinoma Bladder transitional
Lung squamous cell carcinoma; Bladder transitional cell carcinoma
8 52 p.R4400Q Missense COSM5453041 Breast lobular carcinoma; Colon adenocarcinoma 
9 52 p.E4378K Missense COSM4943274 ER-positive breast carcinoma; Bladder transitional cell carcinoma [33,44]
COSMIC, the Catalogue of Somatic Mutations in Cancer; Mutation ID: come from COSMIC (https://cancer.sanger.ac.uk/cosmic); No., number; Exon.
# Exon position; p., protein sequence. * The translation stop codon; fs, Frame shift.
New mutation domains of KMT2C detected in GDPH cohort.
# Exon position; p., protein sequence. * the translation stop codon; fs, Frame shift.
= protein has not been analysed, RNA was, but no change is expected.
3.4. KMT2C mutations and clinical outcome
The data of TCGA and the METABRIC cohorts were subjected to Kaplan–Meier survival analysis to verify the influence of KMT2C mu-tation on the prognosis of patients with breast cancer. In the TCGA cohort, KMT2C mutation was associated with a poor prognosis in pa-tients with breast cancer [hazard ratio (HR), 2.00; 95% confidence in-terval (CI), 1.08–3.71; p = 0.027; Fig. 3A). In patients with HR + breast cancer, KMT2C mutation was associated with relatively shorter OS compared with the wild-type group (HR, 1.53; 95% CI, 1.12–1.78; p = 0.016; Fig. 3C). However, KMT2C mutation was not associated with the prognosis of patients with breast cancer in the METABRIC cohort (overall breast cancer HR, 2.03; 95% CI, 0.45–3.08; p = 0.419 vs. HR + breast cancer HR, 1.37; 95% CI, 0.36–2.58; p = 0.341; Fig. 3B and D). Univariate and multivariate analyses were performed to test the correlation between different clinicopathological features and OS in the TCGA cohort. In addition, TP53 and PIK3CA, the most commonly mu-tated SYBR Safe DNA Gel Stain in patients with breast cancer, were included in the factor analysis to further explore the correlation between clinicopathological characteristics and prognosis. Although the univariate analysis
indicated that KMT2C mutation was an independent risk factor for the OS of patients with breast cancer, the multivariate analysis suggested that KMT2C mutation (HR, 1.71; 95% CI, 0.88–3.31; p = 0.111) was not an independent prognostic factor for OS. Neither PIK3CA nor TP53 mutation was associated with OS (p > 0.05). Taken together, these results suggest that KMT2C mutation status might not be associated with the OS of patients with breast cancer (Table 5).
This retrospective study is the first comprehensive study on the clinicopathological characteristics of Chinese patients with KMT2C-mutant breast cancer. In this study, 411 breast cancer tissue samples from the GDPH cohort were evaluated by NGS, and the results were compared with those of the TCGA and METABRIC cohorts. The results demonstrated different mutation spectra of KMT2C between the GDPH, TCGA, and MATEBRIC cohorts, and the mutation rates among patients in the three cohorts was 8.0%, 7%, and 14.5%, respectively. Racial diversity has been considered to be closely associated with the patho-genesis of cancer . As only a few Asian (or Chinese) patients are included in the public databases, it is difficult to validate the effects of ethnic diversity in KMT2C mutation.
On the one side, nonsense and frameshift mutations were the most common types of mutations detected in the three cohorts, and these two types of mutations often truncate the majority of the protein and probably affect carboxy-terminal SET and PHD domain protein tran-scription. Associations of the SET and PHD domains with diseases have been reported previously , but the common mutation sites in these three cohorts have not been found. Although KMT2C appears to be mutated less frequently in breast cancer than in colon cancer, glio-blastoma multiforme, and pancreatic ductal adenocarcinoma [21,22], KMT2C mutations might nevertheless play a key role in the develop-ment of breast cancer. On the other side, 19 novel mutations in the GDPH cohort were found, but the mutant KMT2C core domains and hot-spot mutations were not observed in the three cohorts. KMT2C is one of the most frequently mutated genes in several types of human cancers, but studies on the function of KMT2C gene mutations are limited . This might be related to the absence of mutant hotspots and frequent mutant domains in the KMT2C gene. Thus, the present data provide clinical evidence for further functional studies of KMT2C mu-tation in the Chinese population with breast cancer.
The results suggested that KMT2C mutations are associated with clinicopathological characteristics of breast cancer in the three cohorts. In particular, female patients over 50 years of age appear to be more prone to KMT2C mutations. A previous study  found that epigenetic
Clinicopathologic characteristics of patients with breast cancer in TCGA, METABRIC, and GDPH cohorts.