Exploring the Neoantigen burden in Breast Carcinoma Patients

Abstract

In this study we performed a multi-omics analysis comprising whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) on seven breast cancer patients, consisting of three Estrogen receptor (ER) positive and four Triple negative breast cancer (TNBC) subtypes to understand the neoantigen burden in breast cancer tumor samples. We predicted both class-I and class-II human leukocyte antigen (HLA) bound neoantigens by analyzing matched tumor-normal pair of exomes. Across all the patients, we predicted 434 unique neoantigens (NeoFil) in total, affecting 237 different genes and 87% of them (n = 378) are expressed at RNA level (Neoexp). The missense mutations (87%) are the major contributor in neoantigen (Neoexp) generation, followed by frameshift (11%) and indels (2%). The neoantigens (NeoFil) were found to be positively correlated with the somatic mutations (R2 = 0.89). We also noted that the vast majority (99.98%) of the predicted neoantigens are patient specific. Overall, the current study offers significant insight into the neoantigen profile in tumor types with intermediate/low mutation burdens like breast cancer.

Whole exome-seq and RNA-seq data reveal unique neoantigen profiles in Kenyan breast cancer patients

“…Similar to most studies on neoantigen prediction in breast cancer, we have found that neoantigens burden is positively correlated with tumor mutational burden and that neoantigens were patient-specific (Narang et al, 2019; Animesh et al, 2022). Although most of the top 10 mutated genes (80%) were also the top 10 in the number of neoantigens generated, genes like TP53 and PIK3CA that are reported to be highly mutated in most patient cohorts were not among the top 10 mutated genes in this study, but generated among the highest number of neoantigens (Figure 6; Figure 7).…”

Identification of HLA class I-restricted immunogenic neoantigens in triple negative breast cancer

“…Analyses of expression of mutated sequences revealed that about 65% of mutations were located at expressed genes. A high variability regarding expression of mutated genes with potential neoAg-coding capacity has been reported in TNBC, ranging from 35-50% in some cases ( 4 , 34 ), to more than 80% in others ( 35 ). The sample size and the filtering criteria used to define expression in the different studies may account for these discrepancies, as well as for the differences with our results.…”

“…Recent studies have analyzed the presence of neoAgs in TNBC tumors ( 4 , 35 ) and in some cases, their immunogenicity has been demonstrated by using T cells from patients ( 34 , 38 , 39 ). In all cases, and in agreement with our results, the number of neoAgs and the proportion of them with confirmed immunogenicity indicates that the mutational load found in TNBC patients would be sufficient to generate a neoAg-based vaccine.…”

Targeting Neoantigens in Cancer: Possibilities and Opportunities in Breast Cancer

“…A broad diversity of non-canonical HLA-binding peptides was detected with this approach; however, the authors noted that the majority of neoantigens detected originated from variants identified from the RNA-seq data, also pointing to the transcriptome as a source for novel neoantigen detection. Animesh et al [ 85 ] also explored a multi-omics approach combining WES and RNA-seq data to assess the neoantigen burden of breast carcinoma on seven breast cancer patients. A report from their preprint demonstrated their pipeline was able to predict 434 unique neoantigens from 237 different genes with 87% of the neoantigens expressed at the RNA level.…”

“…Additionally, 99.98% of the novel neoantigens were patient-specific and infrequently shared between patients. Furthermore, most of the neoantigens were MHC class I specific and are rarely shared between MHC class I and MHC class II [ 85 ].…”