Detection of PIK3CA Mutations in Anal Dysplasia

The incidence of anal cancer is increasing despite screening and treatment options for anal dysplasia, the precursor to anal cancer. Once anal dysplasia is identified, predicting which patients are at the highest risk of progressing to anal cancer remains challenging, as there are no molecular biomarkers for risk stratification. The most common mutation in anal cancer affects the catalytic subunit of Phosphatidylinositol (3, 4, 5)-trisphosphate Kinase (PI3K). We sought to determine if PIK3CA mutations are detectable in precancerous anal lesions.

DNA was extracted from formalin-fixed, paraffin-embedded anal tissue slides. Digital polymerase chain reaction was performed to test each sample for the presence or absence of three of the most common PIK3CA mutations: E545 K (c.1633 G > A), H1047 R (c.3140 A > G), and H1047 L (c.3140 A > T). Mutation data, histology, and demographic data were compared.

We analyzed 124 tissue samples from 68 unique patients across the spectrum of anal disease. Forty of these samples were E545 K positive, three were H1047 R positive, and two were H1047 L positive. PIK3CA mutations were detected in 8/42 (19%) low-grade dysplasia samples, 14/45 (31%) high-grade dysplasia samples, and 20/37 (54%) cancer samples. The presence of a mutation was associated with higher grade of disease on per-sample analysis (P = 0.004).

PIK3CA mutations can be detected in anal tissue samples across the spectrum of carcinogenesis with increasing incidence with higher grade of disease. Our results warrant further evaluation of PIK3CA mutations as a biomarker for identifying patients with anal dysplasia at highest risk of progression to anal cancer.