International cancer seminars: a focus on kidney cancer.

Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.

Inflammation-related genetic variants predict toxicity following definitive radiotherapy for lung cancer.

Definitive radiotherapy improves locoregional control and survival in inoperable non-small cell lung cancer patients. However, radiation-induced toxicities (pneumonitis/esophagitis) are common dose-limiting inflammatory conditions. We therefore conducted a pathway-based analysis to identify inflammation-related single-nucleotide polymorphisms associated with radiation-induced pneumonitis or esophagitis. A total of 11,930 single-nucleotide polymorphisms were genotyped in 201 stage I-III non-small cell lung cancer patients treated with definitive radiotherapy. Validation was performed in an additional 220 non-small cell lung cancer cases. After validation, 19 single-nucleotide polymorphisms remained significant. A polygenic risk score was generated to summarize the effect from validated single-nucleotide polymorphisms. Significant improvements in discriminative ability were observed when the polygenic risk score was added into the clinical/epidemiological variable-based model. We then used 277 lymphoblastoid cell lines to assess radiation sensitivity and expression quantitative trait loci (eQTL) relationships of the identified single-nucleotide polymorphisms. Three genes (PRKCE, DDX58, and TNFSF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities.

Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma.

The long-term prognosis for clear cell renal cell carcinoma (ccRCC) is dramatically altered by the development of metastatic recurrence. However, there are very few indicators that can predict which patient will develop a recurrence. MicroRNAs regulate many cellular processes and have been shown to be associated with cancer development and recurrence. More recently it has been shown that microRNA genes can be epigenetically modified in cancer, resulting in aberrant silencing of microRNA genes with tumor suppressor functions. In this study, we show that two genes encoding for hsa-miR-9 are significantly hypermethylated in ccRCC tumors compared with adjacent normal tissues (P-value <0.001 for both miR-9-1 and miR-9-3) resulting in decreased expression, and that the methylation of these genes was more significant in DNA obtained from the primary tumor for patients who developed a recurrence (P-value: 0.012 and 0.009 for miR-9-1 and miR-9-3, respectively) than in tumors from nonrecurrent patients. Furthermore, methylation of miR-9-3 was significantly associated with an increased risk of recurrence (hazard ratio: 5.85, 95% confidence intervals: 1.30-26.35) and high methylation levels of either miR-9-1 or miR-9-3 resulted in a significant, nearly 30-month decrease in recurrence-free survival time (P-value: 0.034 and 0.007 for miR-9-1 and miR-9-3, respectively). Our results demonstrate that hsa-miR-9 is involved in the development of ccRCC while also having a role in the development of metastatic recurrence.