Identification of alternative splicing markers for breast cancer.
Breast cancer is the most common cause of cancer death among women under age 50 years, so it is imperative to identify molecular markers to improve diagnosis and prognosis of this disease. Here, we present a new approach for the identification of breast cancer markers that does not measure gene expression but instead uses the ratio of alternatively spliced mRNAs as its indicator. Using a high-throughput reverse transcription-PCR-based system for splicing annotation, we monitored the alternative splicing profiles of 600 cancer-associated genes in a panel of 21 normal and 26 cancerous breast tissues. We validated 41 alternative splicing events that significantly differed in breast tumors relative to normal breast tissues. Most cancer-specific changes in splicing that disrupt known protein domains support an increase in cell proliferation or survival consistent with a functional role for alternative splicing in cancer. In a blind screen, a classifier based on the 12 best cancer-associated splicing events correctly identified cancer tissues with 96% accuracy. Moreover, a subset of these alternative splicing events could order tissues according to histopathologic grade, and 5 markers were validated in a further blind set of 19 grade 1 and 19 grade 3 tumor samples. These results provide a simple alternative for the classification of normal and cancerous breast tumor tissues and underscore the putative role of alternative splicing in the biology of cancer.
Venables
Julian P
JP
Laboratoire de génomique fonctionnelle de l'Université de Sherbrooke, Québec, Canada.
Klinck
Roscoe
R
Bramard
Anne
A
Inkel
Lyna
L
Dufresne-Martin
Geneviève
G
Koh
ChuShin
C
Gervais-Bird
Julien
J
Lapointe
Elvy
E
Froehlich
Ulrike
U
Durand
Mathieu
M
Gendron
Daniel
D
Brosseau
Jean-Philippe
JP
Thibault
Philippe
P
Lucier
Jean-Francois
JF
Tremblay
Karine
K
Prinos
Panagiotis
P
Wellinger
Raymund J
RJ
Chabot
Benoit
B
Rancourt
Claudine
C
Elela
Sherif Abou
SA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen