This study describes two innovations. First, we show a 20.6% mutation rate of the
PIK3CA gene in breast cancer, indicating that
PIK3CA mutation is a frequent genetic alteration in breast cancer. The 8% mutation rate of
PIK3CA in breast cancer, reported in a previous study, was underestimated [
10], probably because of the smaller number of cases examined. Another possibility might be the grade status of the tumors used, as all of the tumors in our study were of high grade. It will be useful and interesting in the future to explore whether
PIK3CA mutation is correlated with tumor grade status.
Second, CGH (comparative genomic hybridization) studies have shown that 3q26 is an amplified chromosome region in various cancers, including breast cancer [
4,
5]. Unfortunately, it was not previously possible to identify the
PIK3CA gene amplification pattern, because of the low resolution of the methods used. In our study, we used quantitative real-time PCR, a very sensitive and far more accurate technique [
14,
15], to specifically quantitate the genomic copy number of
PIK3CA not only in primary breast tumors but also in paired tissues. Our data showed that gene amplification or gain of
PIK3CA copy number is not a frequent genetic alteration event. This suggests that gene amplification is not the main molecular mechanism in activating the PIK3/AKT-driven tumorigenesis pathway in breast cancer.
Even though a complex and heterogeneous set of genetic alterations, including gene amplification/gain of copy number, deletion, and mutation, were reported to be involved in the etiology of breast cancer [
16,
17], our paper confirmed that gain of gene copy number and somatic mutation of one oncogene exist in parallel in breast cancer. Both amplification/gain of gene copy number and somatic mutation of
PIK3CA have been shown to be associated with increased PI3K activity and might contribute to cancer through inhibition of apoptosis [
6,
9]. Gene amplification/gain of gene copy is well accepted as a later event in tumor progression [
18,
19], as is somatic mutation [
10]. To determine the relation between somatic mutation and gain of gene copy number of
PIK3CA gene in breast cancer, we integrated our mutation and gene copy number data. As shown in Table
2, 19 (20.6%) of 92 cases had a
PIK3CA gene mutation and 4 cases did not harbor a mutation but showed a gain of gene copy number. Overall, a quarter (23 of 92) of all breast tumors examined had either a mutation or gain of copy number of the
PIK3CA. In addition, 15 of 19 mutations were identified in tumors without gain of copy number of
PIK3CA, suggesting that somatic mutations are a major contributory factor in the
PIK3CA signaling pathway. Only four cases in the whole study had both a mutation and gain of copy number of
PIK3CA. We did not observe a significant association between somatic mutation and gain of
PIK3CA gene copy number in 92 cases of breast tumors (Table
2). We suggest that further studies using larger number of cases be undertaken in order to determine whether somatic mutation and gene amplification are independent genetic alterations in breast cancer.
Table 2
The relation of somatic mutation and gain of copy number of PIK3CA in breast cancer
Gain+ | 4 | 4 | 8 |
Gain- | 69 | 15 | 84 |
Total | 73 | 19 | 92 |