The estrogen receptor alpha (ESR1) is a critical driver of breast tumorigenesis, and as such has been a target for therapy for many years. Early reports using Sanger sequencing and conformational assays reported that there were little if any mutations in ER-positive tumors, although a few somatic mutations have recently been described in tumors and cell lines. We set out to validate the authenticity of these reported somatic mutations by performing analysis of ER DNA sequence variants (DSVs) in 66 ER+ breast tumors, and 39 breast cancer cell lines. We utilized a combined approach of target capture sequencing of ESR1, and subsequent testing for novel and previously identified DSVs using an orthogonal mass spectrometry based sequencing approach. A DNA capture approach was designed to capture all exons, flanking splice sites, and the 3′ UTR of ESR1. DNA was captured and sequenced using SOLiD. Using stringency with a cut-off with at least 2 variant reads, variants in at least 20% of the reads, and requiring evidence for the variants in both strands, we identified 4 previously reported SNPs (rs2077647; rs46432; rs1801132; rs2228480), and two previously reported somatic mutations H6Y and N532Y. We developed mass-spectrometry assays, including controls, for these DSVs, and in addition, we included 10 DSVs which had previously been reported as somatic mutations in breast (and other) cancer. Applying mass-spec based analysis to breast tumors and cell lines, we were able to confirm previously reported SNPs, and one previously reported mutations (H6Y). This mutation was found in one breast tumor and one cell line. None of the other reported somatic mutations could be confirmed in tumors or cell lines. Functional assays on the ESR1H6Y DSV failed to identify differences to wildtype receptor. The lack of a phenotype, and the infrequent occurrence of this DSV do not support a major driver role for ESR1H6Y. This analysis suggests that ESR1 mutations are a rare event in ER+ primary breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-12.
WHAT IS CANCER? Cancer is not a single condition, but a set of many diseases that share common characteristics. Cancer is primarily a disorder caused by DNA mutations and epigenetic changes that make an abnormal cell multiply uncontrollably with the potential to invade other parts of the body, rather than the natural immune system response, which leads to cell death. [1], [2] The cancer researchers Douglas Hannahan and Robert Weinberg believe that cancer at a molecular level could be described in 10 basic steps. The first six were established in 2000 [3] another 4 in 2011 [4], which are two enabling hallmarks and two emerging characteristics. They proposed that the properties of a cancer cell are: 1. They can grow self-sufficiently 2. They do not listen to anti-growth signals 3. They evade death (apoptosis) 4. They continue to replicate and do not age 5. They can feed themselves (angiogenesis) 6. They can invade surrounding tissue and spread 7. They have abnormal metabolism 8. Immune system detection and destruction 9. Tumour-promoting inflammation 10. Genomic instability and mutation BREAST CANCER Breast cancer is one of the world's most common diseases, matching lung cancer as the world's most common cancer, both contributing 12.3 per cent of the total number of new cases diagnosed in 2018 according to the World Cancer Research Fund. [5] Among women in the United States, breast cancer mortality rates are higher than for any other disease, apart from lung cancer, with one-in-eight people having breast cancer at some point in their lifetime with 1-in-5 of those under the age of 50. Although breast cancer can occur in men, it is rare, less than one per cent of cases. [6],[7] Initially thought to be a hereditary disorder, only about 5% to 10% of cancers are based on inherited genes [7], and the figure for breast cancer is even smaller as it is currently inherited by only 3% of patients with the disease. [5] The 3% for breast cancers are caused by mutations of single inherited genes such as a defective BRCA gene. BRCA1 is a tumour suppressor gene; BRCA2 has a role in DNA repair. These mutations of BRCA allow damaged DNA to go unrepaired, and the accumulation of DNA mutations can lead to cancer. Having a positive
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