Phenotype-directed analysis of genotype in early-onset, familial breast cancers

Pathology. 2006 Dec;38(6):520-7. doi: 10.1080/00313020601024052.


Considerable heterogeneity of morphology and disease outcome exists within breast cancers (BC), which likely reflects variable molecular pathogeneses within this broad clinical group.

Aim: To evaluate the underlying genomic alterations associated with familial, early-onset BC (EOBC) phenotypes, in order to improve the management of this disease.

Methods: Using hierarchical clustering of morphological and immunophenotypical parameters, 116 EOBC were stratified into six groups. Conventional and array-based comparative genomic hybridisation was used to analyse the genomic alterations.

Results: Specific areas of genomic imbalance were associated with individual phenotypes. The largest phenotypical group was high grade, oestrogen receptor and HER-2 negative. This group contained the majority of BRCA1 germline mutation-associated tumours and commonly showed loss of chromosomal regions 5cent-5q13, 5q14-22 and 4q28-32. High mitotic rate, an important indicator of tumour cell proliferation and poor prognosis, was associated with gain of 19p, mapped within 7 Mb of the telomere. This region contains the candidate oncogene CDC34, the protein product of which is involved in ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor, p27Kip1.

Conclusion: Phenotype-based analysis can be used to determine the genetic changes important in subtypes of BC. Further, the different morphological phenotypes could act as a cost-effective surrogate for genotypical stratification to facilitate optimal management of this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Anaphase-Promoting Complex-Cyclosome
  • BRCA1 Protein / genetics
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cluster Analysis
  • DNA, Neoplasm / genetics
  • Female
  • Genotype*
  • Humans
  • Mitosis
  • Nucleic Acid Hybridization
  • Phenotype*
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligase Complexes / genetics


  • BRCA1 Protein
  • DNA, Neoplasm
  • CDC34 protein, human
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome