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22-04-2012 | Genetics | Article

Genetic data reclassifies breast cancer subtypes


Free abstract

MedWire News: Researchers have reclassified breast cancer tumors into 10 new categories based on common genetic features that correlate with survival.

The study's lead author, Carlos Caldas (University of Cambridge, UK) told reporters that the findings "will pave the way for doctors in the future to diagnose the type of breast cancer a woman has, the types of drugs that will work, and those that won't, in a much more precise way than is currently possible.

"This means that women who are diagnosed and treated fairly uniformly today will in the future receive treatment targeted to the genetic fingerprint of their tumour."

Caldas and team explain that inherited genetic variation and acquired genomic aberrations contribute to breast cancer initiation and progression.

In the largest global study of breast cancer tissue performed to date, the researchers performed a complex, integrated analysis of gene copy number and expression in a discovery and validation set of 997 and 995 primary breast tumors, respectively, with long-term clinical follow up. They hoped to identify breast cancer subgroups and their molecular drivers.

The findings, reported in Nature, show that inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) are associated with expression in approximately 40% of genes, with roughly equal numbers of genes associated in cis (meaning the variant impacts its own expression) and trans (where the variant is associated with genes at other sites in the genome).

Further analysis revealed several known and putative cancer genes, including deletions in PPP2R2A (protein phosphatase 2, regulatory subunit B, alpha), MTAP (methylthioadenosine phosphorylase), and MAP2K4 (mitogen-activated protein kinase kinase 4).

The researchers observed that the mutations cluster within 10 novel subgroups with distinct clinical outcomes, which were reproduced in the validation cohort. The subgroups split many of the currently used intrinsic breast cancer subtypes.

The new clusters include a high-risk, estrogen receptor (ER)-positive 11q13/14 cis-acting subgroup of luminal tumors that exhibit a steep mortality curve (15-year survival ~40%), and two favorable prognosis subgroups characterized by lack of CNAs (15-year survival ~78%).

One of the groups lacking CNAs contains predominantly luminal A type tumors while the other includes both ER-positive and ER-negative tumors with varied intrinsic subtypes. A common feature of this mixed group is significant infiltration of inflammatory cells and lymphocytes.

"This subset of breast cancer is a very important one for us to have recognised," said Caldas, "because it looks like in this subset the immune system is playing a very active role in improving the prognosis of these women."

The remaining seven subgroups are made up of predominantly ER-positive tumors with intermediate prognosis; 15-year survival ranged from less than 40% to more around 70% in these groups.

"We've drilled down into the fundamental detail of the biological causes of breast cancer in a comprehensive genetic study. Our results have reclassified breast cancer into 10 types - making breast cancer an umbrella term for an even greater number of diseases," Caldas remarked.

"Essentially we've moved from knowing what a breast tumor looks like under a microscope to pinpointing its molecular anatomy - and eventually we'll know which drugs it will respond to.

"The next stage is to find how tumours classified under each sub group behave - for example do they grow or spread quickly? And we need to carry out more research in the laboratory and in patients to confirm the most effective treatment plan for each of the 10 types of breast cancer," he concluded.

By Laura Cowen

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