PIK3R1 underexpression is an independent prognostic marker in breast cancer.
BACKGROUND
The present study focused on the prognostic roles of PIK3CA and PIK3R1 genes and additional PI3K pathway-associated genes in breast cancer.


METHODS
The mutational and mRNA expression status of PIK3CA, PIK3R1 and AKT1, and expression status of other genes involved in the PI3K pathway (EGFR, PDK1, PTEN, AKT2, AKT3, GOLPH3, WEE1, P70S6K) were assessed in a series of 458 breast cancer samples.


RESULTS
PIK3CA mutations were identified in 151 samples (33.0%) in exons 1, 2, 9 and 20. PIK3R1 mutations were found in 10 samples (2.2%) and underexpression in 283 samples (61.8%). AKT1 mutations were found in 15 samples (3.3%) and overexpression in 116 samples (25.3%). PIK3R1 underexpression tended to mutual exclusivity with PIK3CA mutations (p = 0.00097). PIK3CA mutations were associated with better metastasis-free survival and PIK3R1 underexpression was associated with poorer metastasis-free survival (p = 0.014 and p = 0.00028, respectively). By combining PIK3CA mutation and PIK3R1 expression status, four prognostic groups were identified with significantly different metastasis-free survival (p = 0.00046). On Cox multivariate regression analysis, the prognostic significance of PIK3R1 underexpression was confirmed in the total population (p = 0.0013) and in breast cancer subgroups.


CONCLUSIONS
PIK3CA mutations and PIK3R1 underexpression show opposite effects on patient outcome and could become useful prognostic and predictive factors in breast cancer.
Magdalena
M
Cizkova
Sophie
S
Vacher
Didier
D
Meseure
Martine
M
Trassard
Aurélie
A
Susini
Dana
D
Mlcuchova
Celine
C
Callens
Etienne
E
Rouleau
Frederique
F
Spyratos
Rosette
R
Lidereau
Oncogenetic Laboratory, Institut Curie, Hospital René Huguenin, Saint-Cloud, France. ivan.bieche@curie.net.
Ivan
I
Bièche
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C588001:PIK3R1 protein, human; C484760:PIK3CA protein, human; C494918:AKT1 protein, human