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TTN/OBSCN 'Double-Hit' predicts favourable prognosis, 'immune-hot' subtype and potentially better immunotherapeutic efficacy in colorectal cancer.

ABSTRACT: Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide. Although treatment strategies for solid tumours have been revolutionized by immunotherapy, only a small subset of CRC patients benefit. Using two-independent cohorts, we found the common frequently mutated genes TTN and OBSCN had the significant correlation with higher tumour mutation burden (TMB) and favourable overall survival. TTN and OBSCN also displayed significant commutation phenomenon. Therefore, based on the status of TTN and OBSCN, we stratified patients into 'Double-WT' phenotype, 'Single-Hit' phenotype and 'Double-Hit' phenotype. Importantly, the 'Double-Hit' phenotype had favourable prognosis, low malignant events propensity, and highest TMB, immune cells infiltration abundance, POLE mutation rate, microsatellite instability ratio, as well as immune checkpoints expression compared with the other two phenotypes. These results indicated that the 'Double-Hit' phenotype suggested 'immune-hot' tumours and potentially better immunotherapeutic efficacy. Bioinformatic algorithm assessment of immunotherapy responses also confirmed this conclusion, and the 'Double-Hit' phenotype was found to be a better predictor of immunotherapy than PD-L1, PD-1, CTLA-4, TMB and microsatellite status. This study revealed CRC patients with TTN/OBSCN 'Double-Hit' was significantly associated favourable prognosis, 'immune-hot' subtype and potentially better immunotherapeutic efficacy.

SUBMITTER: Liu Z

PROVIDER: S-EPMC8034451 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsYin Yang 1 (YY1) is a multifunctional transcription factor that plays an important role in tumour development and progression, while its clinical significance in diffuse large B-cell lymphoma (DLBCL) remains largely unexplored. This study aimed to investigate the expression and clinical implications of YY1 in DLBCL.MethodsYY1 expression in 198 cases of DLBCL was determined using immunohistochemistry. The correlation between YY1 expression and clinicopathological parameters as well as the overall survival (OS) and progression-free survival (PFS) of patients was analyzed.ResultsYY1 protein expression was observed in 121 out of 198 (61.1 %) DLBCL cases. YY1 expression was significantly more frequent in cases of the GCB subgroup than in the non-GCB subgroup (P = 0.005). YY1 was positively correlated with the expression of MUM1, BCL6, pAKT and MYC/BCL2 but was negatively associated with the expression of CXCR4. No significant relationships were identified between YY1 and clinical characteristics, including age, sex, stage, localization, and B symptoms. Univariate analysis showed that the OS (P = 0.003) and PFS (P = 0.005) of patients in the YY1-negative group were significantly worse than those in the YY1-positive group. Multivariate analysis indicated that negative YY1 was a risk factor for inferior OS (P < 0.001) and PFS (P = 0.017) independent of the international prognostic index (IPI) score, treatment and Ann Arbor stage. Furthermore, YY1 is more powerful for stratifying DLBCL patients into different risk groups when combined with MYC/BCL2 double-expression (DE) status.ConclusionsYY1 was frequently expressed in DLBCL, especially in those of GCB phenotype and with MYC/BCL2-DE. As an independent prognostic factor, YY1 expression could predict a favourable outcome in DLBCL. In addition, a complex regulatory mechanism might be involved in the interactions between YY1 and MYC, pAKT as well as CXCR4 in DLBCL, which warrants further investigation.

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TTN/OBSCN 'Double-Hit' predicts favourable prognosis, 'immune-hot' subtype and potentially better immunotherapeutic efficacy in colorectal cancer.

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