Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

Abstract

The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways in invasive breast carcinoma, with phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) mutations in 25% of invasive carcinomas. Ductal carcinoma in situ (DCIS), benign papillomas, and small numbers of columnar cell lesions harbor an analogous spectrum of PIK3CA and AKT1 mutations, yet there is little data on usual ductal hyperplasia and atypical ductal and lobular neoplasias. We screened 192 formalin-fixed paraffin-embedded breast lesions from 75 patients for point mutations using a multiplexed panel encompassing 643 point mutations across 53 genes, including 58 PIK3CA substitutions. PIK3CA point mutations were identified in 31/62 (50%) proliferative lesions (usual ductal hyperplasia and columnar cell change), 10/14 (71%) atypical hyperplasias (atypical ductal hyperplasia and flat epithelial atypia), 7/16 (44%) lobular neoplasias (atypical lobular hyperplasia and lobular carcinoma in situ), 10/21 (48%) DCIS, and 13/37 (35%) invasive carcinomas. In genotyping multiple lesions of different stage from the same patient/specimen, we found considerable heterogeneity; most notably, in 12 specimens the proliferative lesion was PIK3CA mutant but the concurrent carcinoma was wild type. In 11 additional specimens, proliferative epithelium and cancer contained different point mutations. The frequently discordant genotypes of usual ductal hyperplasia/columnar cell change and concurrent carcinoma support a role for PIK3CA-activating point mutations in breast epithelial proliferation, perhaps more so than transformation. Further, these data suggest that proliferative breast lesions are heterogeneous and may represent non-obligate precursors of invasive carcinoma. Keywords: atypical ductal hyperplasia; breast carcinoma; columnar cell change; PIK3CA; usual ductal hyperplasia The phosphatidylinositol-3-kinase pathway is one of the most commonly mutated pathways in invasive breast carcinoma. Activating mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are present in B25% of invasive carcinomas and are present in an even higher percentage (on the order of 40%) of low-grade estrogen receptorpositive carcinomas (luminal A intrinsic subtype). 1-10 PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development. [8][9][10][11] In recent large studies of estrogen receptor-positive tumors, the presence of activating PIK3CA hotspot point mutations has been paradoxically associated with more favorable outcome as compared with breast carcinomas with wild-type PIK3CA. 3,12,13 We and other groups have previously s...

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

“…The prevalence of PIK3CA mutations in this cohort (55%) is somewhat higher than that previously reported for DCIS (17-48%) 7,8,14,15,38,39 and invasive breast cancers (25-36%). 4,5,40,41 The relatively small number of cases included in this and other DCIS each studies (involving between six and 202 cases), 7,8,14,15,38,39 may account for the variation in prevalence.…”

“…4,5,40,41 The relatively small number of cases included in this and other DCIS each studies (involving between six and 202 cases), 7,8,14,15,38,39 may account for the variation in prevalence. Alternatively, the high read-depth of our targeted sequencing may have led to increased detection rates compared with exome or Sanger studies: four DCIS cases had a PIK3CA variant frequency of o20%, which could have been missed by less sensitive methods.…”

Multiplexed imaging reveals heterogeneity of PI3K/MAPK network signaling in breast lesions of known PIK3CA genotype

“…Accumulating data from a number of different studies shows that concurrent invasive and in-situ breast carcinoma (ductal carcinoma in-situ, DCIS) in the same patient frequently harbor identical PIK3CA mutations [7–11]. This observation fits the prevailing notion of DCIS as direct precursor of invasive breast cancer, and furthers the concept of activating PIK3CA mutations as a potential ‘driver’ of breast carcinogenesis.…”

“…This observation fits the prevailing notion of DCIS as direct precursor of invasive breast cancer, and furthers the concept of activating PIK3CA mutations as a potential ‘driver’ of breast carcinogenesis. Further, we and others have recently shown that PIK3CA mutations are present in both ‘benign’ and ‘atypical’ proliferative breast lesions [11–13]. However, the PIK3CA mutation status of these proliferative breast lesions was frequently different than that of concurrent invasive carcinoma sampled from the same tissue specimen.…”

“…However, the PIK3CA mutation status of these proliferative breast lesions was frequently different than that of concurrent invasive carcinoma sampled from the same tissue specimen. For example, ten patients with PIK3CA -wild type (WT) carcinoma each had PIK3CA exon-20 mutated proliferative lesions present in the same breast tissue specimen [11]. Activating PIK3CA mutations have been shown to evoke downstream PI3K network signaling that fuels cellular transformation and cancer growth in vitro , but their in vivo activity within lesional tissue is more difficult to establish[14, 15], in light of intra-network inhibitory feedback loops or inter-network cross-talk[2–4, 16, 17].…”