ABSTRACT
Human mouse double minute 2 (Mdm2) plays an essential role in the regulation of the tumor suppressor p53. The G/G variant of SNP309 was shown to increase Mdm2 mRNA/protein expression and to be associated with an increased risk and earlier onset of different cancers in Asian populations. However, the frequency and impact of these G/G variants have not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). When separating all females into two groups at their median age (68 years), 7 and 1 patients with the G/G variant and 9 and 13 patients with the T/T variant were noted in these age groups (P=0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was investigated, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P=0.039 and 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP309 G/G genotype showed significantly earlier tumor onset than patients with the wild-type T/T genotype.
ABSTRACT
Local treatment of breast cancer with tumor-free surgical margins is the standard procedure in the treatment of T1 and small T2 breast cancers. Surgery is followed by radiation therapy, and adjuvant systemic therapy is offered depending on primary tumor characteristics, such as tumor size, grade of differentiation, number of involved axillary lymph nodes, the status of estrogen (ER) and progesterone (PR) receptors, and the expression of the human epidermal growth factor 2 (HER2) receptor. Although this approach implies a higher risk of ipsilateral breast tumor recurrence, the total risk of recurrence is low (1% per year), with rates of overall survival similar to that after radical procedures. The most peripheral part of epithelial tumors, the tumor margin, is the part which is most likely to remain in loco after surgical resection. Thus, understanding the biology of the invasion front is important as these tumor cells have been reported to lose epithelial properties, such as cohesiveness and keratin expression, and to acquire features of mesenchymal cells. The parallel appearance of tumor cells in different states of cell dedifferentiation implicates a dynamic equilibrium that is determined by the induction of epithelial-mesenchymal transition (EMT). EMT has been suggested to be of prime importance for tissue and vessel invasion. Furthermore, features of EMT are associated with the activity of tumor stem cells (TSC). TSC exist in breast cancer and their appearance varies depending on the used marker profile. Consequently, intratumoral heterogeneity is reflected by the grade of EMT activation. A specific function at the invasion front is hypothesized but has not yet been proven. Nevertheless, the molecular differentiation between the tumor center and the invasion front enhances the importance of tumor-free surgical margins.
