`Analysis of neo-antigens and immune profiles of Asian breast cancer patients, focusing on common germline deletion of APOBEC3B cytosine deaminase

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Breast cancer is the most common cancer among women, and in Asia, breast cancer incidence is increasing at 3% per annum because of increasing "westernization" and urbanization, along with changes in lifestyle factors. Much effort to catalogue the genomic alterations in common types of cancers including breast cancer, but this has mainly been done in women of European descent. Molecular profiling of breast cancer in multi-ethnic Asian populations has been limited in part because of cost and unavailability of large collections of good quality, clinically annotated tumour samples. The goal of understanding the genomic basis of Asian breast cancers can now be realized because newer DNA sequencing technologies provide high-throughput and accurate data at a significantly reduced cost. We have decided to focus on breast cancers arising in germline carriers of APOBEC3B (A3B) deletion, which is three times more common in Asians compared to Caucasians. The APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like") family of proteins are evolutionarily conserved cytosine deaminases associated with intrinsic mutations in response to viral and bacterial infection. Recently, germline A3B deletions were reported to be associated with increased risk to breast cancer, and breast cancers that have a hypermutator phenotype and activated immune signature. However, in part because germline mutations are less common in Caucasian populations and the majority of large sequencing projects have thus far been conducted in Caucasian sample collections, there remains limited information about A3B in breast cancers, particularly in Asian breast cancer samples. Tumour-infiltrating immune cells play a role in immunesurveillance and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies have been shown to elicit remarkable response in treatment of melanoma, non-small-cell lung cancer, renal-cell carcinoma, and other cancers. However, only a small fraction of patients benefit and it appears that cancers with higher mutation load are more likely benefit due to immune activation and consequently increased tumour-infiltrating immune cells. Indeed, colorectal patients with high mutation burden because of mismatch repair deficiency showed better immune-related objective response rate and progression-free survival, suggesting that high somatic mutation burden may be a predictive potential biomarker to immune checkpoint inhibitors. To date, there has been limited data of tumour response to immune checkpoint therapy in breast cancer. The majority of breast cancers in women of European descent are post menopausal breast cancer which is more likely to be positive for estrogen receptor and have a lower mutational load. However, for a subset of breast cancers, for example, those with triple negative breast cancers, with BRCA1 or BRCA2 germline alterations, and with A3B germline mutations, there is higher mutational load. Notably, the mutational load in Asian breast cancer samples, where A3B germline mutations are 3 times more common, has not yet been systematically tested in Asian women.Since 2012, we have established hospital-based cohort of breast cancer samples collected in fresh frozen format and all samples are associated with in depth risk factor information, sequencing for a comprehensive panel of 30 breast cancer predisposition genes, and A3B germline status analysis, thus providing a unique opportunity for this collaboration. In this project, we propose to conduct a systematic analysis of the mutational profile and immune response in a cohort of women with either wild-type, 1 copy deletion or 2 copy deletion of A3B and determine germline A3B status is associated with anti-tumour response. We believe that this work will lead to a better understanding of a common germline alteration in Asian women and may lay the grounds for future studies on immunotherapy in Asian breast cancer patients.