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Oncogenes and human breast cancer
J M Hall1, P J Zuppan, L A Anderson
1School of Public Health, University of California, Berkeley 94720.
Abstract:
The role of oncogenes in breast tumorigenesis is unclear. Alterations and/or amplification of several oncogene sequences have been observed in primary human breast tumors, in breast tumor cell lines, and in mammary tumors in model systems. In principle, such alterations could be sites of primary lesions for human breast cancer, causes of tumor progression or metastasis, or simply secondary lesions of highly aberrant tumor genomes. The present study tested genetic linkage of breast cancer susceptibility to nine oncogenes in 12 extended families including 87 affected individuals. Lod scores for close linkage of each candidate sequence to breast cancer were -19.6 for HRAS, -12.3 for KRAS2, -1.0 for NRAS, -6.0 for MYC, -6.1 for MYB, -8.2 for ERBA2, -7.9 for INT2, and -5.1 for RAF1. Regions of chromosome 11p associated with tumor homozygosity and the region of 3p carrying the gene for Von Hippel-Lindau disease could also be excluded from linkage to human breast cancer. The 5-kb allele of the MOS oncogene, previously proposed to be associated with breast cancer, was absent in these families, suggesting that polymorphism at this locus is not associated with inherited susceptibility. These results strongly suggest that oncogenes are not the sites of primary alterations leading to breast cancer. On the other hand, alterations in one or more of these sequences may be associated with tumor progression.
Insights
Oncogenes are unlikely to be the primary cause of inherited breast cancer. This study found no genetic linkage between breast cancer susceptibility and nine common oncogenes in affected families.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The role of oncogenes in breast cancer development remains uncertain.
- Observed alterations in oncogene sequences in breast tumors suggest potential involvement.
- These alterations could represent primary lesions, drivers of progression, or secondary genomic changes.
Purpose of the Study:
- To investigate the genetic linkage between breast cancer susceptibility and nine specific oncogenes.
- To determine if alterations in these oncogenes are associated with inherited predisposition to breast cancer.
Main Methods:
- Analyzed genetic linkage in 12 extended families with 87 affected individuals.
- Calculated Lod scores to assess the probability of close linkage between breast cancer and candidate oncogene sequences.
- Excluded specific chromosomal regions and oncogene alleles from linkage.
Main Results:
- Strong evidence against close linkage between breast cancer susceptibility and HRAS, KRAS2, MYC, MYB, ERBA2, INT2, and RAF1 oncogenes.
- Ruled out linkage to NRAS and excluded specific regions on chromosomes 11p and 3p.
- The MOS oncogene's 5-kb allele, previously implicated, was absent, indicating no association with inherited susceptibility.
Conclusions:
- The study strongly suggests that oncogenes are not the primary sites of alterations leading to inherited breast cancer.
- Alterations in these oncogenes may, however, play a role in tumor progression or metastasis.