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

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

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

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.

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.

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.