(ChemotherapyAdvisor) – The most comprehensive genomic study to date of breast tumors has identified four genetically-distinct types of breast cancer – and revealed that the mutational milieu found in triple-negative breast cancer more closely resembles ovarian cancer than other breast cancers, according to analyses published in Nature on Sunday, by the federally-funded Cancer Genome Atlas Network.

Primary breast cancer genomes, DNA methylation epigenomes, exomes, messenger RNA, and microRNA were sequenced. The team sequenced the entire genomes of 510 breast tumors from 507 patients and identified more than 30,600 somatic mutations, the authors reported.

The analysis suggests there exist four distinct genetic types of breast cancer: basal-like (triple-negative), luminal A and B, and HER2-enriched.

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“Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities,” reported the team of more than 150 authors. “The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.”

The team identified 40 mutations that can be targeted by drugs in development for the same mutations in other cancer types, they reported.

The findings might help shed light on why poly(ADP-Ribose) polymerase (PARP) inhibitors appear to be promising in the treatment of both ovarian cancers and HER2+ breast cancers, in addition to BRCA-associated breast and ovarian cancers.

Comparing their results to the COSMIC and OMIM gene databases, the authors found 619 of the breast cancer mutations occurred in 177 previously-reported cancer genes, they reported.

“Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype,” they wrote. “We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype.”

“Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity,” the authors noted. “In addition to identifying nearly all genes previously implicated in breast cancer (PIK3CA, PTEN, AKT1, TP53, GATA3, CDH1, RB1, MLL3, MAP3K1 and CDKN1B), a number of novel significantly mutated genes were identified including TBX3, RUNX1, CBFB, AFF2, PIK3R1, PTPN22, PTPRD, NF1, SF3B1 and CCND3. TBX3, which is mutated in ulnar-mammary syndrome and involved in mammary gland development, harbored 13 mutations (8 frame-shift indels, 1 in-frame deletion, 1 nonsense, and 3 missense), suggesting a loss of function.”

Two more identified mutations were located in TBX4, and one mutation was identified in TBX5 – genes involved in Holt-Oram syndrome, they reported.

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