This study provided further evidence for the prognostic importance of KRAS status in terms of recurrence-free and overall survival. Neoadjuvant chemotherapy including bevacizumab elicited a response, irrespective of KRAS status, in this selected group of patients with CLM.
A hallmark of cancer cells is an activated telomere maintenance mechanism, which allows prolonged survival of the malignant cells. In more than 80% of tumours, telomeres are elongated by the enzyme telomerase, which adds de novo telomere repeats to the ends of chromosomes. Cancer cells are also characterized by expression of active LINE-1 elements (L1s, long interspersed nuclear elements-1). L1 elements are abundant retrotransposons in the eukaryotic genome that are primarily known for facilitating aberrant recombination. Using L1-knockdown (KD), we show for the first time that L1 is critical for telomere maintenance in telomerase-positive tumour cells. The reduced length of telomeres in the L1-KD-treated cells correlated with an increased rate of telomere dysfunction foci, a reduced expression of shelterin proteins and an increased rate of anaphase bridges. The decreased telomere length was associated with a decreased telomerase activity and decreased telomerase mRNA level; the latter was increased upon L1 overexpression. L1-KD also led to a decrease in mRNA and protein expression of cMyc and KLF-4, two main transcription factors of telomerase and altered mRNA levels of other stem-cell-associated proteins such as CD44 and hMyb, as well as a corresponding reduced growth of spheroids. The KD of KLF-4 or cMyc decreased the level of L1-ORF1 mRNA, suggesting a specific reciprocal regulation with L1. Thus, our findings contribute to the understanding of L1 as a pathogenicity factor in cancer cells. As L1 is only expressed in pathophysiological conditions, L1 now appears to be target in the rational treatment of telomerase-positive cancer.
The biomarker TP53 divides esophageal cancer patients into 2 categories with markedly different outcomes: patients with a normal TP53 marker status may experience notable benefits from neoadjuvant chemotherapy with cisplatin/fluorouracil, whereas those with a mutant TP53 marker status appear to be at risk for lack of response.
Previous cancer in one breast is a strong known risk factor for cancer in the contralateral breast. Differences in tumor histology and nuclear grading are applied to distinguish between a metastatic spread and a second primary cancer, although cancers of the breast often share the same histological features. Comparison of genetic alterations in paired tumors may provide the most reliable approach for discerning clonal relationships, hence uncovering the presence or absence of multiple primary cancers. We compared tumors from 33 patients with cancer in both breasts for mutations in the p53 gene. With this molecular approach, we were able to define the relationship within paired tumors in 13 patients. The paired tumors of two patients shared the same mutation, revealing the second lesion in one case as a contralateral metachronous lymph node metastasis appearing 29 months after first surgery, and in the other as a spread to the opposite breast. In 11 patients, mutations were either discordant or solely present in one of the lesions, confirming the diagnosis of bilateral breast cancer. Histopathological evaluation had failed to provide firm diagnosis in nine out of 11 instances on account of concordances in pathological parameters such as histological type and grading. In our study, we could show that bilateral breast malignancies most frequently represent two primary breast cancers. We could also demonstrate that contralateral breast cancer spread does occur. Standard pathological assessment allowed a firm diagnosis only in the presence of different histological types.
We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status.ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol.Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344–3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic.The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.
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