title: Identification of alternative splicing markers for breast cancer.
abstract: 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.
authors.affiliation: Laboratoire de génomique fonctionnelle de l'Université de Sherbrooke, Québec, Canada.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Venables
authors.forename: Roscoe
authors.initials: R
authors.lastname: Klinck
authors.forename: Anne
authors.initials: A
authors.lastname: Bramard
authors.forename: Lyna
authors.initials: L
authors.lastname: Inkel
authors.forename: Geneviève
authors.initials: G
authors.lastname: Dufresne-Martin
authors.forename: ChuShin
authors.initials: C
authors.lastname: Koh
authors.forename: Julien
authors.initials: J
authors.lastname: Gervais-Bird
authors.forename: Elvy
authors.initials: E
authors.lastname: Lapointe
authors.forename: Ulrike
authors.initials: U
authors.lastname: Froehlich
authors.forename: Mathieu
authors.initials: M
authors.lastname: Durand
authors.forename: Daniel
authors.initials: D
authors.lastname: Gendron
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brosseau
authors.forename: Philippe
authors.initials: P
authors.lastname: Thibault
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Lucier
authors.forename: Karine
authors.initials: K
authors.lastname: Tremblay
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Prinos
authors.forename: Raymund J
authors.initials: RJ
authors.lastname: Wellinger
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
authors.forename: Claudine
authors.initials: C
authors.lastname: Rancourt
authors.forename: Sherif Abou
authors.initials: SA
authors.lastname: Elela
mesh_terms: 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
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen