Abstract
While cancer cells gain aggressiveness by mutations, abundant mutations release neoantigens, attracting anti-cancer immune cells. We hypothesized that in breast cancer (BC), where mutation is less common, tumors with high mutation rates demonstrate aggressive phenotypes and attract immune cells simultaneously. High mutation rates were defined as the top 10% of the mutation rate, utilizing TCGA and METABRIC transcriptomic data. Mutation rate did not impact survival although high mutation BCs were associated with aggressive clinical features, such as more frequent in ER-negative tumors (p < 0.01), in triple-negative subtype (p = 0.03), and increased MKI-67 mRNA expression (p < 0.01) in both cohorts. Tumors with high mutation rates were associated with APOBEC3B and homologous recombination deficiency, increasing neoantigen loads (all p < 0.01). Cell proliferation and immune activity pathways were enriched in BCs with high mutation rates. Furthermore, there were higher lymphocytes and M1 macrophage infiltration in high mutation BCs. Additionally, T-cell receptor diversity, cytolytic activity score (CYT), and T-cell exhaustion marker expression were significantly elevated in BCs with high mutation rates (all p < 0.01), indicating strong immunogenicity. In conclusion, enhanced immunity due to neoantigens can be one of possible forces to counterbalance aggressiveness of a high mutation rate, resulting in similar survival rates to low mutation BCs.
Highlights
Accumulation of somatic mutations, or somatic genome instability, has been the principle of carcinogenesis; cancer cells stem from a clone that has gained the somatically acquired genetic abnormalities, leading to malignant transformation and further progression[1]
The etiology of hypermutation varies between cancer types; ultraviolet (UV) light is the significant cause of mutations in melanoma, while smoking causes the mutations in non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (SCC)[7,8]
The majority of patients with breast cancer revealed far less mutation burden compared to melanoma, lung cancer, bladder cancer, or colon cancer in TCGA cohort in agreement with previous reports that analyzed different cohorts (Fig. 1)[40,41]
Summary
Accumulation of somatic mutations, or somatic genome instability, has been the principle of carcinogenesis; cancer cells stem from a clone that has gained the somatically acquired genetic abnormalities, leading to malignant transformation and further progression[1]. APOBEC family is known for its ability to deaminate genomic DNA cytosines[9], which normally function in the innate immune system to protect against viral pathogens. They can generate C-to-T (Cytosine to Thymine) mutations in the host genome[10,11]. Recent studies demonstrated that APOBEC3B, a member of APOBEC family, is a mutagenic enzyme and is significantly associated with its mutational load in breast cancer[10,12]. It is well known that patients with colorectal cancer with MSI correlated with improved survival, which has been suggested to be a result of increased TILs in TME caused by hypermutation[16]. Breast cancer (BC) is known to have low mutation rates[5], we hypothesized that BCs with high mutation rates would demonstrate biologically worse phenotypes, while simultaneously attracting anti-cancer immune cells in TME
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