DNAH7 mutations benefit colorectal cancer patients receiving immune checkpoint inhibitors

Abstract

Background: Colorectal cancer (CRC) is a malignant tumor associated with a high mortality rate. While the advent of immune checkpoint inhibitors (ICIs) has been a gamechanger, only a small percentage of CRC patients benefit from ICIs. The pathological mechanism of CRC is not well understood, but somatic mutations, especially missense mutations, are believed to play an important role. This study examined the relationship between ICIs in colorectal cancer and missense mutations in the axonemal dynein heavy chain gene 7 (DNAH7).Methods: A clinical cohort (n=690) and the CRC data from the publicly available Cancer Genome Atlas (TCGA) were examined. Gene Set Enrichment Analysis, ESTIMATE analysis, and clinical correlation analysis were performed to explore the effects and mechanisms of DNAH7 mutation on immunotherapy in colorectal cancer. Results:The results showed that CRC patients with DNAH7 mutations can benefit more from ICIs (P<0.05). Patients with DNAH7 mutation had higher ESTIMATE scores, immune scores, and matrix scores, compared to patients without the DNAH7 mutation (P<0.001). The transport of small molecules, keratinization, asthma, autoimmune thyroid disease, allograft rejection, and other pathways were significantly enriched in DNAH7 mutated tissues (P<0.05). The top key genes associated with the DNAH7 mutation included AQP8, MS4A12, GUCA2B, and ZG16 (P<0.01). Conclusions:The current study not only demonstrated the significance of DNAH7 as a risk factor and prognostic feature in CRC, but also revealed that DNAH7 mutations might affect the clinical efficacy of ICIs by impacting the tumor immune microenvironment.

A Subset of Microsatellite Unstable Cancer Genomes Prone to Short Insertions over Deletions Is Associated with Elevated Anticancer Immunity

“…When we investigated genes with high affinity, the MMRd-ins subtype exhibited notably high neoantigen frequency for the following genes: RYR2 , DNAH7 , MGAM , NAV3 , SYNE1 , and TTN ( Figure 5 C). Previously, RYR2 , DNAH7 , and SYNE1 were shown to be associated with the immune response to various cancer types [ 54 , 55 , 56 ]. The expression of neoantigens for all of these genes except DNAH7 was also higher in the MMRd-ins subtype ( Figure 5 D).…”

Guanylate cyclase-C Signaling Axis as a theragnostic target in colorectal cancer: a systematic review of literature

“…• GUCA2B emerges as a prominent key gene linked to the DNAH7 mutation. (67) To explore the molecular signatures causing CRC as receptors and drug agents as inhibitors by using integrated statistics and bioinformatics approaches.…”

“…Recently, Yang et al (67) performed a comprehensive in silico analysis and discovered that patients with DNAH7 missense mutations might benefit more from ICIs (Table 4). Through establishing the protein-protein interaction (PPI), they identified the top key genes associated with the DNAH7 mutation, including GUCA2B, AQP8, MS4A12, and ZG16 (67).…”