Ku70 predicts response and primary tumor recurrence after therapy in locally advanced head and neck cancer

Abstract

Abstract5‐Fluorouracil and cisplatin‐based induction chemotherapy (IC) is commonly used to treat locally advanced head and neck squamous cell carcinoma (HNSCC). The role of nonhomologous end joining (NHEJ) genes (Ku70, Ku80 and DNA‐PKcs) in double‐strand break (DSB) repair, genomic instability and apoptosis suggest a possible impact on tumor response to radiotherapy, 5‐fluorouracil or cisplatin, as these agents are direct or indirect inductors of DSBs. We evaluated the relationship between Ku80, Ku70 or DNA PKcs mRNA expression in pretreatment tumor biopsies, and tumor response to IC or local recurrence, in 50 patients with HNSCC. Additionally, in an independent cohort of 75 patients with HNSCC, we evaluated the relationship between tumor Ku70 protein expression and the same clinical outcomes or patient survival. Tumors in the responder group had significantly higher mRNA levels for Ku70, Ku80 and DNA‐PKcs than those in the nonresponder group. Ku70 mRNA was the marker most significantly associated with response to IC. Moreover, high tumor Ku70 mRNA expression was associated with significantly longer local recurrence‐free survival (LRFS). Ku70 protein expression was also significantly related to response, and patients with higher percentage of tumor cells expressing Ku70 had longer LRFS. In addition, the percentage of Ku70 positive cells, tumor localization and node involvement were significantly associated with overall survival of patient. Therefore, Ku70 expression is a candidate predictive marker that could distinguish patients who are likely to benefit from chemoradiotherapy or radiotherapy after the induction chemotherapy treatment, suggesting a contribution of the NHEJ system in HNSCC clinical outcome. © 2008 Wiley‐Liss, Inc.

DNA Ligase4 as a Prognostic Marker in Nasopharyngeal Cancer Patients Treated with Radiotherapy

“…No significant association was found between the level of RAD50 expression and clinical outcome. These results suggest that the response to DNA damage involving the NHEJ system could be dependent to the types of cancer cells (Pavon et al, 2008). Another possible explanation is that LIG4 may have other functions besides repairing DSB, like the DSB recognition of Nbs1.…”

Bobel-24 and Derivatives Induce Caspase-Independent Death in Pancreatic Cancer Regardless of Apoptotic Resistance

“…The lysates from two 96-well plates were collected into the same microcentrifuge tube and then processed according to the manufacturer's protocol. Reverse transcription was done with the High Capacity cDNA Archive kit (Applied Biosystems Incorp), and mRNA expression was determined using an ABIPrism 7000 Sequence Detection System (Applied Biosystems) as described (15). Predesigned Taqman Gene Expression Primer and Probe assays (Applied Biosystems) were available for human cathepsin B (HS00157194_m1) and the housekeeping gene hypoxanthine phosphoribosyltransferase 1 (HS99999909_m1; endogenous control).…”

“…Cancer Res 2008; 68: (15 finding in caspase-dependent and caspase-independent pancreatic carcinoma cell death induced by Bobel-24 or its derivatives, as we have previously described in caspase-independent cell death in leukemic cells (6). Consequently, we explored whether pancreatic carcinoma cell death by Bobel-24 or Bobel-16 was mediated by cytochrome c release (common in caspase-dependent death) and/ or mitochondrial release and nuclear translocation of AIF (common in caspase-independent death).…”

Individualising care of tongue cancer using markers of genomic stability

“…A pre and post-treatment trial demonstrated that nuclear PARP1 overexpression in oral cancer is inducible following radiotherapy, however overall intensity is not predictive of treatment effectiveness or prognosis [235]. A larger non-subsite specific HNSCC study also showed an exclusively nuclear staining pattern, and while this demonstrated a higher disease-free survival with high Ku70 expression this was a cross-site analysis with only 22% from the oral cavity [105]. A strong nuclear expression pattern for Ku70 was noted in colorectal carcinoma, with 20% of carcinoma and 55% of adenoma showing cytoplasmic staining [236].…”

“…While this study did not include tongue cancer specimens, the predictive value was greatest in HPV negative cancers (RR 9, P <0.01). In contrast, two similarly-sized mixed studies found Ku70 mRNA levels and protein overexpression improved recurrence-free survival in locally-advanced HNSCC [105] and tonsillar cancer [157], however these did not stratify for p16 status and had unusual treatment regimens. In support of these findings are in-vitro studies showing that Ku70 loss improved radioresistance in late G2/S, possibly by allowing the more error-free HR [145].…”