Biological significance of allele specific loss of the p53 gene in breast carcinomas.
The p53 tumor suppressor gene has a central role in the defense against cancer, including breast cancer, and contains a polymorphic variant (Arg/Pro) at codon 72 that has been shown to have different biological properties regarding apoptosis and cell cycle arrest. Earlier studies have shown allele specific loss of heterozygosity (LOH) at this particular site and we aimed to investigate its biological relevance in codon 72 heterozygous breast cancer patients (i.e., survival and age of disease onset). 199 postmenopausal cases were analyzed for LOH using MegaBACE(1000) and statistics was performed using Statistical Package for Social Sciences. LOH was found in totally 124 (62.3%) patients and the Pro allele (n = 103) was significantly more often deleted compared to the Arg allele (n = 21) (P = 0.001). Patients with LOH of the Arg allele were diagnosed at an earlier age (mean age 62.5 years) than those with loss of the Pro allele (mean age 69.2 years) (P = 0.011). LOH of the Arg allele was also associated with worse survival (P = 0.05). LOH in comparison to ROH correlated significantly with increased S-phase fraction. Tumor size, stage or number of positive lymph nodes was not related to LOH. Our results and earlier findings suggest a selective loss of the Pro allele during carcinogenesis that might confer a growth advantage for cancer cells. On the other hand, it appears to be more harmful for patients to loose the Arg allele since we found that loss of this allele was associated with earlier onset and worse prognosis.
Department of Health and Medical Sciences, Orebro University, 701 82, Orebro, Sweden.
Pia P
PP
Wegman
Nashwan J
NJ
Marcus
Breezy Paul
BP
Malakkaran
Sten
S
Wingren
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D003062:Codon / Q000235:genetics; D004967:Estrogens; D005260:Female; D016158:Genes, p53; D006801:Humans; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D009376:Neoplasms, Hormone-Dependent / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis; D016196:S Phase; D013548:Sweden / Q000453:epidemiology
D003062:Codon; D004967:Estrogens; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen