Abstract
Human breast cancers comprise a complex and highly heterogeneous population of tumor cells. Intratumor heterogeneity is an underlying cause of resistance to effective therapies and disease recurrence. To explore prognostic factors based on intratumor heterogeneity, we analyzed genomic mutations in breast cancer patients registered in The Cancer Genome Atlas. We calculated the variant allele frequency (VAF) at each mutation site and evaluated the associations of VAFs with the prognosis of breast cancer. VAFs of HMCN1 correlated with the prognosis and lymph node status. Although the detailed function of HMCN1 remains unknown, it is located in extracellular matrix and the mutation in the gene might be associated with cancer cell invasion and metastasis. This finding suggests that HMCN1 is a potential metastatic factor and can be a candidate gene for targeted breast cancer therapy.
Highlights
Breast cancer is the most common type of cancer affecting women worldwide
Assuming that average purity is 85% the cutoff should be 0.3 (0.25/0.85 = 0.294). We conducted this analysis without adjusting for other covariates just for a screening of genes that are possibly associated with breast cancer prognosis
variant allele frequency (VAF) of HMCN1 was found to be possibly associated with breast cancer prognosis (FDR < 0.1) (Table 1), and we focused on HMCN1, for which no association with breast cancer has previously been reported
Summary
Breast cancer is the most common type of cancer affecting women worldwide. In 2012, approximately 1.7 million cases of breast cancer were newly diagnosed [1]. Breast cancer is a clinically heterogeneous disease for which four basic therapeutic or molecular subtypes have been classified based on the expression status of three receptors: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [2, 3]. Tumor recurrence and drug resistance remain major challenges in the field of breast cancer. These challenges are mainly attributed to intratumor heterogeneity [4], which is characterized by subclonal diversity within a tumor that originates from the accumulation of various somatic mutations during cell division and proliferation [5,6,7]. Drug-resistant subclones may develop via clonal evolution and reside at low frequencies within a tumor; after drug therapy, these subclones become the main population, leading to recurrence [9,10,11]
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