DNA amplifications at 20q13 and MDM2 define distinct subsets of evolved breast and ovarian tumours

Abstract

Summary DNA amplification seems to be particularly frequent in human breast tumours and has been associated with cancer evolution and aggressiveness. Recent data indicate that new events should be added to the list, such as the amplifications at chromosome 20q13 or the MDM2 gene. The present work aimed at determining the incidence and clinicopathological signification of these amplifications in a large series of breast and ovarian tumours. We tested 1371 breast and 179 ovarian tumours by Southern blotting and observed amplification of 20q13 in 5.4% breast and 2.8% ovarian carcinomas, whereas MDM2 was found amplified in 5.3% and 3.8% of breast and ovarian tumours respectively. MDM2 RNA expression levels were analysed in a subset of 57 breast tumours and overexpression was observed in 4/57 (7%) of the tumours. Elevated expression levels coincided with amplification of the gene. In breast cancer, 20q13 and MDM2 amplifications seem to define subsets of aggressive tumours. Indeed, 20q13 was correlated to axillary nodal involvement and occurred preferentially in younger patients (<50 years). Furthermore, 20q 13 correlated, as did MDM2 amplification, to aneuploidy. In parallel, we had also tested our tumour DNAs for amplification of CCNDJ, ERBB-2 and MYC, which made it possible to test for correlations with 20q13 or MDM2 amplifications. Whereas 20q13 showed a very strong correlation to CCNDI amplification, that of MDM2 was prevalent in MYC-amplified tumours. Interestingly, 20q13 and MDM2 amplifications showed some degree of correlation to each other, which may possibly be owing to the fact that both events occurred preferentially in aneuploid tumours. In ovarian cancer, no statistically significant correlation was observed. However, 20q13 amplification occurred preferentially in stage 3 tumours and MDM2 was correlated to ERBB-2 amplification. This may suggest that in ovarian tumours also, 20q13 and MDM2 amplifications occur in late or aggressive cancers.

Chromosome alterations in breast carcinomas: frequent involvement of DNA losses including chromosomes 4q and 21q

“…The first regulates the G S transition whereas the second acts as a transcriptional modulator. Both genes have been implicated in breast carcinogenesis (Bland et al, 1995;Courjal et al, 1996). Additionally, we observed amplifications on chromosome 20q.…”

Identification of three distinct regions of allelic deletions on the short arm of chromosome 8 in hepatocellular carcinoma

“…In addition, isochromosome 8q (i8q) is common in carcinomas of the lung, colon and stomach (Johansson et al, 1996) and speci®c multiplications of the distal part of 8q(q22 ± 24) are detected in HCC and other tumors (Fujiwara et al, 1993b). Ampli®cation as well as translocation implicating 8p12 appear as major genetic events in breast tumors (Courjal et al, 1997). These data have cast some doubt on the existence of a bona ®de tumor suppressor gene on 8p, leading some authors to consider ampli®cation of 8q as the main aberration for tumorigenesis (Johansson et al, 1996).…”

Cloning of TACC1, an embryonically expressed, potentially transforming coiled coil containing gene, from the 8p11 breast cancer amplicon

“…This suggests that deregulation of TACC1 gene expression directly through ampli®cation of the entire gene, or through disruption of transcriptional regulatory elements could contribute to the aggressive phenotype noted for breast tumors harbouring ampli®cation of 8p11. Interestingly, the second TACC family member, TACC2 is located close to FGFR2, in a region of chromosome 10q26 which is also ampli®ed in a small percentage of breast tumors (Adnane et al, 1991, Courjal et al, 1997. TACC1 and additional TACC family members are, therefore, attractive candidates as potential progression factors in breast cancer.…”

“…In a search for other regions of the genome which are ampli®ed in breast cancer, an additional amplicon in 8p11 has been identi®ed in 10 ± 15% of tumors (Adnane et al, 1991, Theillet et al, 1993. The presence of ampli®cation in 8p11 has been associated with estrogen receptor-positive, lobular carcinomas, which metastasize to axillary lymph nodes (Adnane et al, 1991, Courjal et al, 1997. Although this region includes the gene, which encodes the ®broblast growth factor receptor, FGFR1, the exact involvement of this receptor in the progression of the cancer is unclear because, in some tumors, it is not included in the ampli®ed region (Dib et al, 1995).…”