B69
Columnar cell lesions are the early precursors of some forms of invasive breast carcinoma: a new genetic map for the evolutionary pathway of low nuclear grade breast neoplasia (LNGBN) family
Tarek M. A. Abdel-Fatah1, Des G. Powe1, Maryou Lambros3, Dareo De Biase3, Kay Savage3, Alan Mackay3, Jorge S. Reis-Filho3, Ian O. Ellis1
1University of Nottingham, UK, 2National Liver Institute, Menoufyia University, Egypt, 3Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
Background
There is evidence to suggest that a number of low nuclear grade invasive breast
cancers (LNGBC) and putative precursor lesions may consist in a family of
interrelated lesions.
Method
To identify molecular genetic profile and to indentify potential evolutionary
pathogenetic pathways of lesions belonging to the LNGBN family, 15 LNGBCs and
matched coexisting columnar cell lesions (CLLs), ductal carcinoma in situ
(DCIS) and lobular neoplasia (LN) were microdissected from formalin fixed
paraffin embed tissues. The isolated non-amplified-DNA subjected to
high-resolution array-Comparative Genomic Hybridization (aCGH; 16K BAC-array
platform), single nucleotide polymorphisms (SNPs; affimetrix platform 6) and
loss of heterozygosity analysis. Results were validated using, fluorescent
(FISH) and chromogenic (CISH) in situ hybridization and immunohistochemistry.
Comparative analysis was performed with aCGH dataset derived from high grade
breast cancer cases.
Results
We observed that at the genetic level, lesions from the same patient displayed
remarkably similar patterns of genetic aberrations (Spearman's correlations
0.55-0.89; p<0.00001). All CLLs, low grade DCIS, LN and their matching
invasive carcinoma harboured gain/amplification of 1q31-32 and loss of 16q12,
16q21 and 16q23. In addition to the aberrations found in CCLs, in situ and
matching invasive components displayed additional genetic aberrations at one or
more of 16p13.3, 13q34, 20q13.33, 11q13.1-q14.1, 17q25.3, 19p13.3, 7p22.2,
8q24.3, 9q34.3, 14q32.33, 5p15.33 and 10q25.3 and losses on 10q22, 8p,
11q24-25, 15q11.2, 17p11.2, 9p11.2 and Xq. Amplification of cyclin D1 was
detected by CISH in invasive lobular carcinoma and their matching LN and flat
epithelial atypia.
Conclusion
Our results confirm that 1) CLLs are early non obligate precursor components of
the LNGBN family, 2) loss of 16q and gain 1q are the earliest genetic changes
that lead to the activation of the luminal pathway and 3) once committed to
this low grade molecular pathway, progression to other genotypes / phenotypes
appears to be unlikely.
