PIK3CA Mutations Correlate with Hormone Receptors, Node Metastasis, and ERBB2, and Are Mutually Exclusive with PTEN Loss in Human Breast Carcinoma

Abstract

Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit A of PI3K (PIK3CA) occurs frequently in human cancer. We identified PIK3CA mutations in 26% of 342 human breast tumor samples and cell lines at about equal frequency in tumor stages I to IV. To investigate the relationship between PTEN and PIK3CA, we generated a cohort of tumors that had lost PTEN expression and compared it with a matched control set that had retained PTEN. A highly significant association between PIK3CA mutations and retention of PTEN protein expression was observed. In addition, PIK3CA mutations were associated with expression of estrogen and progesterone receptors (ER/PR), lymph node metastasis, and ERBB2 overexpression. The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate (PIP 3 ) is critical for tumorigenesis in a significant fraction of breast cancers and that loss of PIP 3 homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene. The correlation of PIK3CA mutation to ER/PR-positive tumors and PTEN loss to ER/PR-negative tumors argues for disparate branches of tumor evolution. Furthermore, the association between ERBB2 overexpression and PIK3CA mutation implies that more than one input activating the PI3K/AKT pathway may be required to overcome intact PTEN. Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications. (Cancer Res 2005; 65(7): 2554-9)

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

“…This suggests that PTEN alterations are more commonly involved in a distinct pathway of CRC tumorigenesis that is separate from the pathway of mismatch repair deficiency. Because both PIK3CA mutations and loss of PTEN function are thought to activate PI3K/AKT pathway, it is speculated that PIK3CA mutations and loss of PTEN expression are mutually exclusive (Broderick et al, 2004;Frattini et al, 2005;Saal et al, 2005). However, we have found no association between PTEN alteration and PIK3CA mutations.…”

“…Sequencing of PIK3CA exons 9, 20 was done by PCR amplification and direct sequencing of both strands for all CRC cases and their matched normal samples as previously described (Saal et al, 2005;Abubaker et al, 2007). In brief, step-down PCR was performed as follows: after a 10-min denaturing at 95 1C, the PCR was run with each temperature for 1 min at five step-down steps, for two cycles each.…”

“…The samples were finally analysed on an ABI PRISM 3100 Â l Genetic Analyzer (Applied Biosystems). Primer pairs flanking PIK3CA exons-9 and -20 were selected to avoid the frequent cross-amplification of chromosome 22q (known PIK3CA pseudogene) observed with those previously reported (Campbell et al, 2004;Saal et al, 2005).…”

PIK3CA and PTEN mutations in adenoid cystic carcinoma of the breast metastatic to kidney

“…Several studies have pointed out that PIK3CA mutations were mutually exclusive with the mutations of PTEN, suggesting that oncogenic signaling occur either through activation of PIK3CA or inactivation of PTEN. 9 However, recently published studies in endometrial carcinoma demonstrated that coexistent mutations of PIK3CA and PTEN genes are indeed possible. 10 Our case also showed that such combination can also occur in mammary ACC.…”

“…11 PIK3CA mutations have been detected in 8-40% of breast carcinomas and are associated with poor outcome. 12 Saal et al 9 identified PIK3CA mutations in 26% of 342 breast carcinoma specimens at about equal frequency irrespective of the tumor stage.…”