Tag Archives: Hererogeneity

Breast Cancer: New Driver Genes identified

Breast Cancer is the most common cancer type amongst women (but not to be mistaken, it can also affect men). Sadly, the cause of this disease has still to be pinned-down. The reason is the multiple-sided nature of the cancer i.e, each patient has a different cancer genetic profile. The genetic heterogeneity is not only among patients, but it is also, present at the very level of the tumor itself, i.e, researchers face the fact the the tumor is composed by cells of different genetic consistency, quality and mutational dictionary, thus forming a heterogeneous intra-tumor profile. Therefore this fact makes things even more complicated when it comes to understanding the genetic driving force behind tumor initiation, evolution and metastasis.

A recent publication by Stephens et al., (2012), undertook the advent of sequencing 21,416 protein coding genes, 1,664 microRNAs and copy numbers from breast cancer samples in order to understand the genetic roots and branches of  the cancer . From, the analysis, the authors concluded with 9 new candidate-cancer-driver genes: MAP3K1, MAP3K13, AKT2, NCOR1, SMARCD1, ARID1B, CDKN1B, CASP8 and TBX3.  In 6% of the cancers, a (somatic) mutation in  MAP3K1 (mitogen-activated protein kinase) was observed. Moreover, the authors state that this was observed predominantly in ER+ breast cancers. Moreover mutations were observed in MAP2K4 and MAP3KI3 and along with MAP3K1, these genes/proteins are implicated in the JUN kinase pathway and also in activation of the known tumor suppressor gene TP53. Along with MAP3K1, MAP3K13, AKT2 is another identified breast cancer-driver gene, which participates in the JUN kinase pathway.

A -complicated- illustration of JNK cascades and some of their effects on cellular physiology.

Genes NCORI, ARID1B and SMARCD1 , also included in the list of the newly recognized driver genes of this study, all participate in chromatin regulation.  CDKN1B is another identified target gene, which regulates cell cycle progression at phase G1 whereas, CASP8 is implicated in apoptosis. The last member on the 9 breast cancer driver-genes list is TBX3, which it self is a transcriptional factor that regulates morphogenesis of the forelimb in the anterior/posterior axis. Actually this gene participates in the normal development of the mammary tissue (Howard, B. & Ashworth), thus it could be considered a breast tissue specific-gene (?).

From the 40 driver mutations recognized, the authors state that a 58% was attributed to 7 known breast cancer genes: TP53, PIK3CA, ERBB2, MYC, FGFR1/ZNF703, GATA3 and CCND1.  This left a 42% (!) of driver mutations to be attributed in the relatively less frequently breast cancer associated/linked genes which includes the 9 new breast cancer driver-genes.

The importance of this study and others of its kind ( look for the specific edition of Nature Letters for similar studies) highlight the importance of deciphering the basic genetic dictionary and how it is read in cancer cells vs.in normal cells. Moreover, using whole-genome information, we can advance a step in understanding and predicting response to cancer treatment as Ellis et al., (2012) showed in the same edition of Nat.Letters.

References

Stephens et al., Nature Letters (2012) The landscape of cancer genes and mutational processes in breast cancer

Howard, B. & Ashworth, A. PLoS Genet. (2006) Signalling pathways implicated in early mammary gland morphogenesis and breast cancer. 

Ellis et al., Nature Letters (2012) Whole-genome analysis informs breast cancer response to aromatase inhibition.

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