Breast Cancer Genomics: Primary and Most Common Metastases

Abstract

Specific genomic alterations have been found in primary breast cancer involving driver mutations that result in tumorigenesis. Metastatic breast cancer, which is uncommon at the time of disease onset, variably impacts patients throughout the course of their disease. Both the molecular profiles and diverse genomic pathways vary in the development and progression of metastatic breast cancer. From the most common metastatic site (bone), to the rare sites such as orbital, gynecologic, or pancreatic metastases, different levels of gene expression indicate the potential involvement of numerous genes in the development and spread of breast cancer. Knowledge of these alterations can, not only help predict future disease, but also lead to advancement in breast cancer treatments. This review discusses the somatic landscape of breast primary and metastatic tumors.

Multiomics insights on the onset, progression, and metastatic evolution of breast cancer

“…Copy number alterations have been observed in PIK3CA , ERBB2 , TP53 , MAP2K4 , MLL3 , CDKN2A , PTEN , and RB1 ( 44 ). Approximately 35-40% of primary breast cancers harbor mutations in TP53 and PIK3CA , as well as amplification of ERBB2 , FGFR1 , and CCND (~15%), and mutations in MUC16 , AHNAK2 , SYNE1 , KMT2C , AKT1 , and GATA3 genes (10%) ( 25 , 45 ). In 2012, the Cancer Genome Atlas Network (CGAN) identified novel significantly mutated genes (SMGs), including TBX3 , RUNX1 , CBFB , AFF2 , PIK3R1 , PTPN22 , PTPRD , NF1 , SF3B1 , and CCND3 ( 26 ).…”

“…PTEN and INPP4B have also been identified as genes of interest. Deletions in PPP2R2A , MTAP , and MAP2K4 genes have been reported ( 45 ). Among the HSP genes, CRYAB , SACS , DNAJB4 , DNAJC18 , HSPA12A , HSPA12B , HSPB2 , HSPB6 , HSPB7 , HSPB8 , DNAJC5G and BBS12 are downregulated, while the upregulated genes are DNAJC5B , DNAJB13 , DNAJC1 , DNAJC22 , HSPB1 , CCT5 , CCT3 , HSPE1 , DNAJC9 , HSPD1 , DNAJA4 , HSPH1 , HYOU1 , DNAJB11 , CCT6A and DNAJB3 ( 18 ).…”

“…Finally, mutations in TP53 are observed in 80% of TNBC cases, followed by alterations in PIK3R1 and NF1 ( 26 ). INPP4B is another gene of interest in TNBC, and deletions in PPP2R2A , MTAP and MAP2K4 genes have also been reported ( 45 ). Among the downregulated HSP genes in TNBC, we found DNAJB4 , DNAJC18 , HSPA12A , HSPA12B , HSPB2 , HSPB6 , HSPB7 , HSPB8 , DNAJC12 and DNAJC27 .…”

“…Common alterations in TP53 (51%) and PIK3CA (49%), as well as mutations/deletions in NF1 (15%), mutations in PTEN (10%), and mutations/deletions in ARID1A (15%) have been identified in metastatic breast cancer tumors ( 108 ). Bone metastases of breast cancer are characterized by increased expression of the TFF1 , TFF3 , AGR2 , NAT1 and CR1P1 genes, as well as the chemokine receptors CXCR4 and C-C chemokine receptor type 7 (CCR7), and upregulation of the zinc finger protein SNAI1 (SNAI1) ( 45 , 109 ), which is involved in the induction of EMT ( 110 ). In breast to lung cancer metastasis, a number of genes such as MMP1 , MMP2 , CXCL1 , PTGS2 , ID1 , VCAM1 , EREG , SPARC , and IL13RA2 have been identified in breast to lung cancer metastasis that promote and are clinically correlated; as well as the mitogen-activated protein kinases (MAPK), NFκB and vascular endothelial growth factor (VEGF) signaling pathways ( 111 ) ( 45 ).…”

“…Bone metastases of breast cancer are characterized by increased expression of the TFF1 , TFF3 , AGR2 , NAT1 and CR1P1 genes, as well as the chemokine receptors CXCR4 and C-C chemokine receptor type 7 (CCR7), and upregulation of the zinc finger protein SNAI1 (SNAI1) ( 45 , 109 ), which is involved in the induction of EMT ( 110 ). In breast to lung cancer metastasis, a number of genes such as MMP1 , MMP2 , CXCL1 , PTGS2 , ID1 , VCAM1 , EREG , SPARC , and IL13RA2 have been identified in breast to lung cancer metastasis that promote and are clinically correlated; as well as the mitogen-activated protein kinases (MAPK), NFκB and vascular endothelial growth factor (VEGF) signaling pathways ( 111 ) ( 45 ). Mutations in the ESR1 , AKT1 , ERBB2 , and FGFR4 genes have been observed in metastatic breast tumors in the liver ( 45 , 112 , 113 ).…”