title: Molecular subtyping for clinically defined breast cancer subgroups.
abstract: BACKGROUND
  Breast cancer is commonly classified into intrinsic molecular subtypes. Standard gene centering is routinely done prior to molecular subtyping, but it can produce inaccurate classifications when the distribution of clinicopathological characteristics in the study cohort differs from that of the training cohort used to derive the classifier.
  
  
  METHODS
  We propose a subgroup-specific gene-centering method to perform molecular subtyping on a study cohort that has a skewed distribution of clinicopathological characteristics relative to the training cohort. On such a study cohort, we center each gene on a specified percentile, where the percentile is determined from a subgroup of the training cohort with clinicopathological characteristics similar to the study cohort. We demonstrate our method using the PAM50 classifier and its associated University of North Carolina (UNC) training cohort. We considered study cohorts with skewed clinicopathological characteristics, including subgroups composed of a single prototypic subtype of the UNC-PAM50 training cohort (n = 139), an external estrogen receptor (ER)-positive cohort (n = 48) and an external triple-negative cohort (n = 77).
  
  
  RESULTS
  Subgroup-specific gene centering improved prediction performance with the accuracies between 77% and 100%, compared to accuracies between 17% and 33% from standard gene centering, when applied to the prototypic tumor subsets of the PAM50 training cohort. It reduced classification error rates on the ER-positive (11% versus 28%; P = 0.0389), the ER-negative (5% versus 41%; P < 0.0001) and the triple-negative (11% versus 56%; P = 0.1336) subgroups of the PAM50 training cohort. In addition, it produced higher accuracy for subtyping study cohorts composed of varying proportions of ER-positive versus ER-negative cases. Finally, it increased the percentage of assigned luminal subtypes on the external ER-positive cohort and basal-like subtype on the external triple-negative cohort.
  
  
  CONCLUSIONS
  Gene centering is often necessary to accurately apply a molecular subtype classifier. Compared with standard gene centering, our proposed subgroup-specific gene centering produced more accurate molecular subtype assignments in a study cohort with skewed clinicopathological characteristics relative to the training cohort.
authors: Xi
authors: X
authors: Zhao
authors: Einar Andreas
authors: EA
authors: Rødland
authors: Robert
authors: R
authors: Tibshirani
authors: Sylvia
authors: S
authors: Plevritis
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D015331:Cohort Studies; D066264:Datasets as Topic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058889:Molecular Typing / Q000379:methods; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen