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.


OBJECTIVE
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.


CONCLUSIONS
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.
Price
Gareth R
GR
Cancer Genomics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne.
Armes
Jane E
JE
Ramus
Susan J
SJ
Provenzano
Elena
E
Kumar
Beena
B
Cowie
Tiffany F
TF
Ciciulla
John
J
Hutchins
Anne-Marie
AM
Thomas
Mervyn
M
Venter
Deon J
DJ
D000328:Adult; D017668:Age of Onset; D064173:Anaphase-Promoting Complex-Cyclosome; D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008938:Mitosis; D009693:Nucleic Acid Hybridization; D010641:Phenotype; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics
D019313:BRCA1 Protein; D004273:DNA, Neoplasm; C577447:CDC34 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome