PIK3CA Mutations Are Common in Many Tumor Types and Are Often Associated with Other Concurrent Mutations
Matthew D Stachler, Neal Lindeman. Brigham and Women's Hospital, Boston, MA
Background: PIK3CA mutations have been commonly reported in a variety of cancers. The widespread nature of PIK3CA mutations has generated significant interest in developing targeted therapy. Unfortunately, to date there has been limited success with these therapeutics. Many of the patients enrolled in these trials have had limited, if any, molecular testing. Tumor genotyping clinical cancer specimens provides an opportunity to determine a fuller spectrum of mutations an individual tumor harbors and thus provide better insight into its molecular pathogenesis. Using this data may improve the design, rationale, and outcome of PI3K targeted therapy.
Design: Invasive cancer samples of all types containing >250 ng of DNA were genotyped for 471 mutations in 41 cancer-associated genes (including 15 mutations in PIK3CA) using a PCR-mass spectrometry assay (Sequenom). The number of PIK3CA mutations found from each primary tumor site was quantified. The total number and types of mutations each sample harbored was compared between PIK3CA mutated and non-PIK3CA mutated samples.
Results: A total of 1973 cancers were genotyped. 172(9%) contained a mutation in PIK3CA, involving 22 different primary sites. Most PIK3CA mutation frequencies were similar to what has been reported by the Sanger Center (COSMIC), however a significantly higher prevalence was observed in cancers of the endometrium, biliary tract, and liver and a lower prevalence was seen in cutaneous cancers. Interestingly, in 79(45%) cases the PIK3CA mutation was found with at least one other mutation while only 6% of the non PIK3CA mutated cases had more than one mutation (p<0.0001). The additional mutations found with PIK3CA tended to be in the Ras/Raf pathway, WNT pathway, or in growth factor receptors, but were varied.
Conclusions: PIK3CA mutations are found in a wide variety of tumors and tend to occur with other mutations. This suggests that either PIK3CA mutations are a late event (possibly evan a “passenger” mutation) or lead to additional mutations. Previous studies have shown PIK3CA mutations to be associated with advanced disease in several cancers. These findings also have implications for targeted therapy. If other pro-oncogenic pathways are commonly mutated along with PIK3CA, then PIK3CA inhibition alone may not be effective and combination therapy may be warranted.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 223, Tuesday Morning