The results of genetic mapping in breast cancer

Breast cancer is one of the most common cancers in women. Since the 70th, until the 90th twentieth century, a steady increase in the incidence of breast cancer could be observed. A breast cancer is now the cause of more than 450 000 deaths per year. Researchers from The Cancer Genome Atlas mapped genetically over 800 samples from different patients with breast cancer. The results were published in the Nature, 23 September 2012. The study takes into account the type and number of mutations, miRNA correlation with mutations, DNA methylation, and the number and type of amplified genes. Integrated molecular analysis of breast cancer broadens our knowledge of the disease and points to genetic factors affecting the formation and progression of cancer.

The results of the genetic mapping of breast cancer, of more than 500 sequenced samples, show the presence of more than 30 thousand different mutations. More than 28 thousand were point mutations and more than two thousand mutations resulted to be insertion / deletion type. Among the point mutations the most frequent were missense mutations (more than 19 thousand.), more than 6 thousand silent mutations, more than a thousand nonsense type and about 800 mutations in the RNA genes. In the test samples all the genes, which previously were known to contribute to the development of breast cancer, were detected (PIK3CA, PTCA, AKT1, p53, GATA3, CDH1, RB1, MLL3, MAPK3 and CDNK1). The new genes that may be responsible for the origin of this tumor, for example, TBX3, RUNX1, CBFB, AFF2, PIK3R1, PTPN22, PTPRD, NF1, SF3B1 I CCND3, were also identified. Some of these genes are also found in other pathological symptoms for example RUNX1 and CBFB in acute myeloid leukemia.

Despite the high diversity of mutated genes, a correlation between the type of cancer (luminal type A, luminal type B, basal and with HER2 receptors), and type of mutated genes, can be noted. The lowest number of mutations was observed in the cancer of luminal type A, and the highest in the basal type tumor or in the one with HER2 receptors. In type B luminal breast cancer, the most common mutated genes were TP53 and PIK3A (each in 29% of cases). In the type with HER2 receptors, usually there is HER2 gene duplication (80%) or mutation of p53 (72%) and PIK3CA (39%). In luminal breast cancer often comes to PIK3CA mutations (45%). In the basal breast cancer, the most common mutation is in the TP53 gene.

There was no significant correlation between mutations and miRNA.

Some of the DNA regions in case of breast cancer are characterized by hypermethylation. In these areas less likely comes to PICK3CA and MAP3K1 mutations and Wnt path genes are expressed less than in the normal tissue.

An important discovery was made in the basal breast cancer. Molecular analysis of the tumor revealed: a number of mutations in the ATM gene, inactivation of the BRCA1 and BRCA2 genes, loss of RB1 and cyclin E1 gene amplification. The mutation of these genes are similar to the genes mutated in ovarian serous carcinoma. In addition, in both of these tumors, in more than 10% of cases the mutated gene is TP53. Further analysis was performed on both tumors and in both cases duplications in 1q, 3q, 8q and 12q and losses of chromosome arms in 4q, 5q, and 8p were observed. Both tumors also exhibit similarities in the number of duplicate genes and the same changes in the genome. Molecular pathways most commonly used in both types of cancer were HIP1-alfa/ARNT, MYC and FOXM1. These findings suggest that in basal breast cancer tumor as well as in ovarian serous carcinoma the same therapy with platinum and taxanes can be used.

Treatment of basal-type breast cancer is very difficult because the tumor does not show the presence of any of the receptors. Some of the newly discovered mutations may imply new therapeutic solutions. For example, loss of PTEN and INPP4B genes may make the cells more sensitive to inhibitors of the path PI (3) K. Other genes that may be the target in new therapeutic options are: FGFR1, FGFR2, IGFR1, KIT, MET, and PDGFRA. The discovery of the pathway HIF1-alfa/ARNT in the breast cancer allows us to assume that inhibitors of angiogenesis and / or bioreductive drugs (which are activated under conditions of hypoxia) may be one of the treatment options.

In tumors with HER2 receptors several gene, that may be therapeutic targets, were also isolated (HER2, HER3, EGFR). Pertuzumab with trastuzumab can target HER2-HER3 heterodimers, but drugs targeting EGFR and HER2 may also be effective.

In the luminal breast cancer many genes, that in the future may be used as a help in the search for new therapies, were also discovered (ERBB2, PTEN, MAPK3K1, MAP2K4, PIK3CA, PIK3R1).

The results of the mapping of genes for breast cancer have expanded our current knowledge of the disease and have helped to identify new genes that may contribute to the development of cancer. In the future, the results of the mapping can lead to finding an effective treatment directed at specific signaling paths or genes. Despite the high diversity of mutation, the traditional division to luminal breast cancer type A and B, basal and with HER2 receptors, was confirmed. Another significant finding is a demonstration of the correlation between ovarian serous carcinoma and basal breast cancer. In the future, it may help to develop new therapies or improve already known treatments.

Written by: Magdalena Mroczek

Source:
1.The Cancer Genome Atlas Network Comprehensive molecular portraits of human breast Tumours,, Nature 490, 61-70, 04 October 2012
2.Chin, K. et al. Genomic Aberrations and transcriptional linked to breast cancer pathophysiologies. Cancer Cell 10, 529-541 (2006)
3.van ‘t Veer, L. J. et al. Gene expression profiling Predicts clinical outcome of breast cancer. Nature 415, 530-536 (2002)
4.http://www.medicalnewstoday.com/articles/250644.php
5. cancergenome.nih.gov


Would You like to know more? Watch on MEDtube.net: Metastatic breast carcinoma

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