Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.

Aberrant microRNA (miRNA) expression in cancer affects the transcription of target genes, and profoundly influences cancer‑associated signaling pathways. Radiation resistance is a major problem encountered in the treatment of cancer. The present study aimed to investigate the role of miRNA (miR)‑21 in the development of radiation resistance in non‑small cell lung cancer cells. A radiation‑resistant cell line was generated from A549 cells. Significant upregulation of miR‑21 was detected in the radioresistant cancer cells, as compared with the radiosensitive cells, and overexpression of miR‑21 rendered A549 parental cells resistant to radiation. In addition, glycolysis was increased in the radioresistant cells, as compared with the sensitive cells. Furthermore, hypoxia‑inducible factor‑1α (HIF1α) was upregulated by miR‑21 in radioresistant cells, resulting in promotion of the key enzymes of glycolysis. Inhibition of HIF1α by small interfering RNA suppressed glycolysis and resensitized the cancer cells to radiation, whereas the recovery of HIF1α in miR‑21‑inhibited radioresistant cells resulted in recovery of radioresistance. In conclusion, the present study suggested that miR‑21 may modulate radioresistance through the upregulation of HIF1α. These results may provide a novel perspective on miRNA for the development of anti-radioresistance drugs.

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PurposeThe analysis was designed to compare dosimetric parameters among 3-D conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) and RapidArc (RA) to identify which can achieve the lowest risk of radiation-induced liver disease (RILD) for hepatocellular carcinoma (HCC).MethodsTwenty patients with HCC were enrolled in this study. Dosimetric values for 3DCRT, IMRT, and RA were calculated for total dose of 50 Gy/25f. The percentage of the normal liver volume receiving >40, >30, >20, >10, and >5 Gy (V40, V30, V20, V10 and V5) were evaluated to determine liver toxicity. V5, V10, V20, V30 and Dmean of liver were compared as predicting parameters for RILD. Other parameters included the conformal index (CI), homogeneity index (HI), and hot spot (V110%) for the planned target volume (PTV) as well as the monitor units (MUs) for plan efficiency, the mean dose (Dmean) for the organs at risk (OARs) and the maximal dose at 1% volume (D1%) for the spinal cord.ResultsThe Dmean of IMRT was higher than 3DCRT (p = 0.045). For V5, there was a significant difference: RA > IMRT >3DCRT (p <0.05). 3DCRT had a lower V10 and higher V20, V30 values for liver than RA (p <0.05). RA and IMRT achieved significantly better CI and lower V110% values than 3DCRT (p <0.05). RA had better HI, lower MUs and shorter delivery time than 3DCRT or IMRT (p <0.05).ConclusionFor right lobe tumors, RapidArc may have the lowest risk of RILD with the lowest V20 and V30 compared with 3DCRT or IMRT. For diameters of tumors >8 cm in our study, the value of Dmean for 3DCRT was lower than IMRT or RapidArc. This may indicate that 3DCRT is more suitable for larger tumors.

The objective was to evaluate DNA mutations of KRAS, BRAF, and PIK3CA and their clinicopathological correlations with colorectal cancer (CRC) and to identify their contribution to distant metastases in CRC. A total of 148 tumor samples were obtained from patients with CRC in the Shandong Tumor Hospital and Institute between January 2008 and December 2009. DNA was extracted for polymerase chain reaction amplification and pyrosequencing to evaluate mutations of KRAS, BRAF, and PIK3CA, and clinicopathological correlations of these mutations with CRC [including age, gender, tumor location, pathological type, tumor-node-metastasis (TNM) classification, and distant metastatic status] were analyzed. KRAS, BRAF, and PIK3CA mutation rates were identified in 46 (31.1 %), 11 (7.4 %), and 14 (9.5 %) of the total 148 CRC tumor samples, respectively. Neither mutation had significant correlation with age, gender, size and location of the tumor, and pathological type. KRAS, BRAF, and PIK3CA mutations were found in 14 (66.7 %), 3 (14.3 %), and 8 (38.1 %) of the 21 distant metastatic colorectal tumor samples, respectively. The relative risks of distant metastasis for KRAS, BRAF, and PIK3CA mutations were 30.4 versus 6.8 % (P = 0.001), 27.3 versus 13.1 % (P = 0.191), and 57.1 versus 9.7 % (P < 0.001) (5-year risks), respectively. Patients with either KRAS or PIK3CA mutations are more susceptible to distant metastasis. Thus, these two mutations might be used as independent predictors of distant metastatic CRC.

The aim of this study was to determine whether pretreatment status of human epidermal growth factor receptor-2 (HER-2) could predict pathologic response to neoadjuvant chemoradiotherapy (nCRT) and outcomes for patients with locally advanced rectal cancer (LARC). A total of 119 patients diagnosed with LARC received standardized multimodal treatment. Their HER-2 status was determined in pretreatment biopsies by immunohistochemistry (IHC) and FISH. Tumor response was assessed in resected regimens using the tumor regression grade system and TNM staging system. Twenty-two cases in 119 patients assessed as IHC3+ or IHC2+ plus gene-amplified were determined as HER-2 positive. Positive HER-2 status was not associated with any pretreatment clinicopathologic parameters (P > 0.05). HER-2 status could not predict pathologic response to nCRT based on downstaging (P = 0.210) and tumor regression grade (P = 0.085) but it provides us with a trend that HER-2-positive tumors may be resistant to nCRT. Positive HER-2 status was significantly associated with poor 5-year disease-free survival (P = 0.015) and 5-year overall survival (P = 0.026). It can act as a worse prognostic factor for LARC patients.

Askin tumors are rare malignant neoplasms that are localized in the thoracopulmonary region and mainly occur in children and adolescents. Further investigation with regard to the effective treatment of this disease is required, since the disease has a low incidence and limited knowledge is available on the biological activity and prognostic factors of this type of tumor. The present study describes the case of a 30-year-old male patient with a histologically and morphologically proven Askin tumor who was treated in Shandong Cancer Hospital and Institute (Jinan, China). A chest computed tomography (CT) scan demonstrated a large mass filling the entire left lung, associated with mediastinum and right lung compression and accompanied by destruction of the 2nd rib. The patient accepted chemotherapy and radiotherapy instead of a radical mass resection since the mass was irresectable. A good clinical response was achieved to the chemotherapy and radiotherapy. The diagnosis and treatment of Askin tumors remains a challenge for clinicians and surgeons due to the absence of standard therapeutic guidelines for the treatment of this disease. According to the experience obtained from the cases encountered to date, treatment strategies should aim to reduce local recurrence and distant metastasis. Moreover, surgery, chemotherapy and radiotherapy or a combination of these methods appears to constitute an effective treatment strategy for Askin tumors.

Objective: The purpose of this study was to examine the role of programmed cell death 4 (PDCD4) expression in predicting tumor response to neoadjuvant chemoradiotherapy and outcomes for patients with locally advanced rectal cancer. Methods: Clinicopathological factors and expression of PDCD4 were evaluated in 92 patients with LARC treated with nCRT. After the completion of therapy, 4 cases achieved clinical complete response (cCR), and thus the remaining 88 patients underwent a standardized total mesorectal excision procedure. There were 38 patients (41.3%) with a good response (TRG 3-4) and 54 (58.7%) with a poor one (TRG 0-2). Results: Immunohistochemical staining analyses showed that patients with high expression of PDCD4 were more sensitive to nCRT than those with low PDCD4 expression (P=0.02). High PDCD4 expression before nCRT and good response (TRG3-4) were significantly associated with improved 5-year disease-free survival and 5-year overall survival (P<0.05). Multivariate analysis demonstrated that the pretreatment PDCD4 expression was an independent prognostic factor. Conclusion: Our study demonstrated that high expression of PDCD4 protein is a useful predictive factor for good tumor response to nCRT and good outcomes in patients with LARC.