Breast+Cancer+Gene+of+Interest

A gene of interest is __ PIK3CA __.


From the HapMap database, PIK3CA and its known associated SNPs can be viewed:



__ Study 1 __
One study used a dataset of information from patients that had invasive breast carcinomas. The dataset was from a large scale whole genome project called The Cancer Genome Atlas (TCGA). TCGA was established to research and explore disease mechanisms at a genomic scale, using multidimensional tools (Ping, Z., 2014). The study focused on the analysis of gene sequence data including Mutation Counts (MC) and Copy Number Variants (CNV). MCs are any change in a DNA sequence compared to the control. CNVs are when the number of copies of a particular gene differs from one individual to the next.

In this study, the control was a group of genes that had a known pattern of malignant neoplasms. The idea behind this kind of control design, compared to a set of genes without genetic abnormalities, was to easily identify the gene sequence data for a specific cancer (Ping, Z., 2014). The majority (76.9%) of patients had invasive ductal carcinoma and 15.9% of patients had lobular carcinoma. This percentage of carcinoma histopathologic types are comparable to the frequencies we see in the United States (Ping, Z., 2014). Figure 6 shows ER+ or PR+ with HER2- breast carcinomas have lower MCs and CNVs than HER2+ and triple negative tumors (ER-/PR-/HER2-) (Ping, Z., 2014). Similar results were found when molecular subtypes were looked at. Figure 7 shows lower MCs and CNVs versus luminal B, HER2 enriched, and basal-like tumors (Ping, Z., 2014).



Another interesting correlation the authors found were with breast cancer grading and the genetic abnormalities associated with them. The grading score ranges from I to III based on the tubule formation, the nuclear pleomorphism (the size, shape, and staining of cancer cells), and the mitotic count (how much the cancer cells are dividing). Relating to the tumor grade, some genes were found to have sequence changes between different levels. For example, gene TP53 was found to be in 4% of grade I lesions but jumped to 58% within grade II carcinomas. The PIK3CA gene was found more frequently than TP53, but with inverse grading. In grade I invasive carcinomas, PIK3CA was at 61% but only found in 27% of grade III tumors (Ping, Z., 2014). Figure 8 shows all the mutated genes found within different grades of invasive ductal carcinoma.



__ Study 2 __
Another study that looks at gene PIK3CA looked at circulating tumor cells within the blood and disseminated (traveling) tumor cells from bone marrow. The idea of this study was to determine if there were mutated PIK3CA genes, using a quicker and less expensive method for detection.

Due to the multiple and internal locations of organs with metastases, researchers have been looking at other methods to collect disease genetic biomarkers and genotype determinants (Deng et al., 2014). Circulating tumor cells (CTCs) are easy to obtain, through a standard blood draw and can be done throughout different treatment times (Deng et al., 2014).

Another method of investigating biomarkers for genetic characteristics is hoped to be through the collecting and analyzing of disseminated tumor cells (DTCs) from inside bone marrow. This is a new treatment method and is in its early testing period. The idea is that tumor cells, both active and dormant, live in the reservoirs in the marrow, waiting to be released. By finding them, clinicians may be able to determine future cancer types.

In this study researchers looked at exon 9 and exon 20 of the PIK3CA gene, since it has been found to be one of the most commonly mutated genes in breast cancer (Deng et al., 2014). The goal of the study was to investigate the mutual heterogeneity (the diversity or differences) among CTCs, DTCs, the primary tumor site and metastases (Deng et al., 2014).

185 CTCs, 24 DTCs, and 33 tumor cells were analyzed for PIK3CA mutations, comparing them to the control sample of the known mutated gene PIK3CA on exon 9 (G1633A) (Deng et al., 2014). Three out of seventeen patients showed the PIK3CA gene exon 9 mutation in tissue (Deng et al., 2014). From that 18%, individual tumor cells were sequenced 100% showing the exon 9 sequence.

This study also found that there was genotypic discordance between CTCs, DTCs, and metastases between isolated samples taken at different times even though within the overall sample there was mutational heterogeneity (Deng et al., 2014). For example, one patient tested positive for ER and PR at her primary cancer site but once a sample from bone marrow was taken from a metastatic tumor location, it tested ER- and PR-, demonstrating that the tumors can change biological markers (Deng et al., 2014). Figure 9 shows the one patient which had the differing markers.



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