APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma

Abstract

Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities—PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.

Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers

“…This pattern is remarkable because it stands in some contrast to the idea that APOBEC mutagenesis is particularly prone to be the source of driver mutations in cancer. However, remarkable or not, it may not be unusual: it has been shown in head and neck squamous cell carcinoma that while APOBEC mutagenesis increases the total number of mutations occurring, on average, mutations with an APOBEC signature exhibit a lower cancer effect size [11]. Furthermore, it is not unique to non-coding mutations: it has also been demonstrated in UBC that S249C, the FGFR3 coding mutation with the highest mutation rate and highest prevalence (due to APOBEC), does not possess the highest effect size of FGFR3 mutations [12].…”

“…TBC1D12 provides an example of the importance of such an analysis to the interpretation of noncoding variant site data-an example in which the inferred cancer effect size is corroborated by experimental data, and for which the relationship between APOBEC-induced mutagenesis and cancer effect size has previously been explored [11]. While the purposes of variant detection panels can be diverse, quantification of the relative roles of sites as passenger or driver mutations assists in their precise and thoughtful design.…”

LOXL2 Expression Status Is Correlated With Molecular Characterizations of Cervical Carcinoma and Associated With Poor Cancer Survival via Epithelial-Mesenchymal Transition (EMT) Phenotype

“…Previous studies have indicated that APOBEC3 family genes play a key role in innate immunity (28,29), HPV associated carcinogenesis (30), and development of chemoresistance in cancer (31,32). By clustering the 176 core-set samples into two groups, we found that the mean expression of APOBEC3 family genes was higher in the low-LOXL2 cluster (Figure 4A), including APOBEC3A (8.384 ± 0.2478 in low cluster vs. 6.80 ± 0.2578 in high cluster), APOBEC3B (9.904 ± 0.1226 in low cluster vs. 8.588 ± 0.2501 in high cluster), APOBEC3D (7.273 ± 0.1367 in low cluster vs. 6.547 ± 0.1360 in high cluster), APOBEC3F (7.988 ± 0.09133 in low cluster vs. 7.597 ± 0.08861 in high cluster), APOBEC3G (8.929 ± 0.1288 in low cluster vs. 8.333 ± 0.1326 in high cluster), and APOBEC3H (4.163 ± 0.1426 in low cluster vs. 3.617 ± 0.1237 in high cluster).…”

Exploration of Feasible Immune Biomarkers for Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma Treatment in Real World Clinical Practice

“…Apolipoprotein-B mRNA editing enzyme catalytic polypeptide-like (APOBEC) enzymes, a family that catalyzes the deamination of cytosine bases, have been linked to mutagenesis in HPV-positive HNSCC [ 75 ]. HPV-positive HNSCC tumors exhibited a higher APOBEC signature than HPV-negative tumors [ 76 ]. In addition, high APOBEC activity was correlated with upregulated immune signaling pathways, which might be linked to better ICI sensitivity [ 77 ].…”