somal dominant or recessive syndromes: Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Bloom syndrome, Werner syndrome and Xeroderma Pigmentosum

Breast cancer is a common malignancy and the second most frequent cause of death among women. Our aim was to perform DNA copy number profiling of 22q in breast tumors using a methodology which is superior, as compared to the ones applied previously. We studied 83 biopsies from 63 tumors obtained from 60 female patients. A general conclusion is that multiple distinct patterns of genetic aberrations were observed, which included deletion(s) and/or gain(s), ranging in size from affecting the whole chromosome to only a few hundred kb. Overall, the analysis revealed genomic imbalances of 22q in 22% (14 out of 63) of tumors. The predominant profile (11%) was monosomy 22. The smallest identified candidate region, in the vicinity of telomere of 22q, encompasses ~220 kb and was involved in all but one of the tumors with aberrations on chromosome 22. This segment is dense in genes and contains 11 confirmed and one predicted gene. The availability of multiple biopsies from a single tumor provides an excellent opportunity for analysis of possible intra-tumor differences in genetic profiles. In 15 tumors we had access to two or three biopsies derived from the same lesion and these were studied independently. Four out of 15 (26.6%) tumors displayed indications of clonal intra-tumor genotypic differences, which should be viewed as a high number, considering that we studied in detail only a single human chromosome. Our results open up several avenues for continued genetic research of breast cancer. Introduction Breast cancer is the most common malignancy among women and the second most common cause of death after lung cancer (1). It is a complex genetic disorder and some aberrations have been correlated with heterogeneous histology and clinical behavior. Breast carcinoma arises from the epithelium of glandular tissue, which includes ducts and lobules. Histologically, this neoplasm can be classified into non-invasive (in situ) or invasive ductal and lobular carcinoma. The most common type of breast cancer, invasive ductal carcinoma, develops from ductal carcinoma in situ and accounts for 80% of all cases (2). The majority of breast cancer cases are sporadic, while a family history of the disease accounts for 15-20% (3). Less than 1% of all cases are associated with the autosomal dominant or recessive syndromes: Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Bloom syndrome, Werner syndrome and Xeroderma Pigmentosum (4). Individuals recognized with these syndromes or congenital malformations may have a high breast cancer risk. Approximately 5-10% of all cases are attributable to autosomal dominant susceptibility genes: breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2). Mutations in either of these genes account for the majority of families with multiple cases and confer a lifetime risk of breast cancer up to 85% for female BRCA1 or BRCA2 mutation carriers (5-8). Many other susceptibility candidate loci including known oncogenes and tumor suppressor genes have also been characterized [breast cancer (OMIM #114480)]. In recent years detailed cytogenetic and molecular investigations of breast cancer have led to the identification of a number of recurrent regions of DNA copy number alteration (9-13). Furthermore, it has been suggested that allelic loss of 22q is a common event in breast carcinoma, with a reported frequency between 11% and 66% (14-16). Previous studies have reported several regions along chromosome 22 showing allelic loss in sporadic breast carcinomas and a candidate tumor suppressor gene region, close to the teloINTERNATIONAL JOURNAL OF ONCOLOGY 29: 935-945, 2006 935 Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity MAGDALENA BENETKIEWICZ1,4, ARKADIUSZ PIOTROWSKI1, TERESITA DÍAZ DE STÅHL1, MICHAL JANKOWSKI2, DARIUSZ BALA2, JACEK HOFFMAN2, EWA SRUTEK2, RYSZARD LASKOWSKI2, WOJCIECH ZEGARSKI2 and JAN P. DUMANSKI1,3 1Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden; 2Department of Breast Cancer, Clinic of Oncological Surgery, Oncology Center, Collegium Medicum Nicolaus Copernicus University, 85 796 Bydgoszcz, Poland; 3Department of Genetics, University of Alabama at Birmingham, KAUL 420, 1530 3rd Ave. S, Birmingham, AL 35294, USA Received March 27, 2006; Accepted June 2, 2006 _________________________________________ Correspondence to: Dr M. Benetkiewicz, 4Present address: Unite 509 INSERM, Pathologie Moleculaires des Cancers, Institut Curie Section de Recherche, 26 rue d’Ulm, 75248 Paris cedex 05, France E-mail: [email protected]