However, in our screening of three Tetrahydroberberine different populations, the p.R415Q allele tended to associate with breast 20(S)-NotoginsenosideR2 cancer in only one study, HaBCS, where the association was restricted to ductal breast cancer and was in the opposite direction as the risk effect reported by Ding and co-workers. Since our study has a total size that is similar to the previously published meta-analysis, we conclude that the p.R415Q is unlikely to exert a strong effect on breast cancer risk. Similar conclusions have been drawn for another SNP in intron 1 of ERCC4 that is weakly correlated with p.R415Q and failed to be reproduced in larger studies. Additional ERCC4 mutations are unlikely to account for study heterogeneity, since our resequencing of 12 p.R415Q homozygotes and 26 p.R415Q heterozygotes led to the detection of two further potential mutations in three patients, thereby representing at most some 6% of the sequenced p.R415Q chromosomes. The substitution p.E17V is a non-conservative missense substitution that is predicted to be deleterious. The substitution p.E875G is a non-conservative missense substitution in a conserved domain but is predicted to be neutral. It is presently undetermined whether these variants, alone or in combination with p.R415Q, would indeed be pathogenic, as the heterozygous patients identified had no strong family history of cancer. For p.E875G, that is listed with an allele frequency of 0.009, much larger case-control studies would be required to clarify any risk association. For p.E17V, that is neither listed in the 1000genomes project nor in the NCBI SNP database and appears to be a very rare variant, the potential role of the p.E17Vp.R415Q double substitution for breast cancer risk, if any, is expected to be limited. While this manuscript was under review, an independent study was published that assessed the frequency of ERCC4 mutations in Spanish breast cancer patients. Osorio et al. scanned 1,573 breast cancer patients using DHPLC and identified one truncating mutation and two functionally relevant missense variants. Their mutation frequency in cases was not different from controls, suggesting that ERCC4 is not a breast cancer susceptibility gene. Missense substitution p.R415Q was not addressed specifically, but as this allele is not uncommon in Spain, mutations associated with it would have been picked up. Thus, our observations are in full concordance with results from the Spanish population. Altogether, this study did not support a major role for ERCC4 coding variants in familial breast cancer risk, although rare mutations such as p.E17V could make minor contributions. We also did not confirm previously suggested associations of the p.R415Q substitution with an increased breast cancer risk. Currently, the detection of genetic aberrations in tumor tissues is the clinically most powerful biomarker for stratification of “targeted” pharmacotherapies in metastatic lung cancer. Treatment with gefitinib and crizotinib, as well as first-line erlotinib, is conditional on the demonstration of EGFR mutations and ALK rearrangements. Mutation detection is frequently performed in small and/or archival tumor specimens, which may not reflect the current genomic profile at treatment initiation. Moreover, the mutational spectrum of a cancer 
changes under the selective pressure of a given therapy, which can only be revealed by sequential biopsies. Against this background, the detection of cancer-specific mutations in other formats than tumor biopsies has gained interest. In NSCLC, successful detection of mutated DNA sequences was reported in serum, plasma or bronchioalveolar lavage fluid. Nevertheless, most of these reports displayed a level of sensitivity below clinical requirements.