Accurate subtyping or classification of breast cancer is important for
ensuring proper treatment of patients and also for understanding the molecular
mechanisms driving this disease. While there have been several gene signatures
proposed in the literature to classify breast tumours, these signatures show
very low overlaps, different classification performance, and not much relevance
to the underlying biology of these tumours. Here we evaluate DNA-damage
response (DDR) and cell cycle pathways, which are critical pathways implicated
in a considerable proportion of breast tumours, for their usefulness and
ability in breast tumour subtyping. We think that subtyping breast tumours
based on these two pathways could lead to vital insights into molecular
mechanisms driving these tumours. Here, we performed a systematic evaluation of
DDR and cell-cycle pathways for subtyping of breast tumours into the five known
intrinsic subtypes. Homologous Recombination (HR) pathway showed the best
performance in subtyping breast tumours, indicating that HR genes are strongly
involved in all breast tumours. Comparisons of pathway based signatures and two
standard gene signatures supported the use of known pathways for breast tumour
subtyping. Further, the evaluation of these standard gene signatures showed
that breast tumour subtyping, prognosis and survival estimation are all closely
related. Finally, we constructed an all-inclusive super-signature by combining
(union of) all genes and performing a stringent feature selection, and found it
to be reasonably accurate and robust in classification as well as prognostic
value. Adopting DDR and cell cycle pathways for breast tumour subtyping
achieved robust and accurate breast tumour subtyping, and constructing a
super-signature which contains feature selected mix of genes from these
molecular pathways as well as clinical aspects is valuable in clinical
practice.Comment: 28 pages, 7 figures, 6 table