Purpose: NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci.Experimental Design: Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and American Joint Committee on Cancer (AJCC) staging.Results: Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild-type tumors the least depth. Ulceration also differed significantly among the genotypes, with BRAF mutants demonstrating the highest rate. In addition, tumors with mutated NRAS were more likely to be located on the extremities. Patients whose tumors carried either mutation presented with more advanced AJCC stages compared with patients with wild-type tumors, and specifically, were more likely to have stage III disease at diagnosis. Overall survival did not differ among the 3 groups.Conclusions: Distinct clinical phenotypes exist for melanomas bearing NRAS and BRAF mutations, whether considered together or separately, and are associated with features known to predict aggressive tumor behavior. The impact of these mutations is most evident at earlier stages of disease progression.

Gastric cancer (GC) imposes a significant health burden around the globe despite its declining incidence. GC is often diagnosed in advanced stages and carries a poor prognosis. In depth understanding of molecular underpinnings of GC has lagged behind many other cancers of its magnitude, as a result our knowledge base for identifying germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets) is limited. A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1, and c-MET) alterations are emerging and some are being pursued in the clinic. Novel somatic gene targets, Arid1a, FAT4, and MLL/MLL3 are of interest. Clinically, variations in the therapeutic approaches for localized GC are evident by geographic regions. These are driven by preferences for the adjunctive strategies and the extent of surgery coupled with philosophical divides. However, there is a greater uniformity in approaches to metastatic cancer, an incurable condition. Having realized only modest successes, the momentum is building for carrying out more phase 3 comparative trials and some are using biomarker-based patient selection. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here we review representative molecular and clinical dimensions of GC.

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.

We report a genome-wide association study of melanoma, conducted by GenoMEL, of 2,981 cases, of European ancestry, and 1,982 study-specific controls, plus a further 6,426 French and UK population controls, all genotyped for 317,000 or 610,000 SNPs. The analysis confirmed previously known melanoma susceptibility loci. The 7 novel regions with at least one SNP with p<10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Houston, Texas). Additional replication came from UK and Dutch case-control series. Three of the 7 regions replicated at p<10−3: an ATM missense polymorphism (rs1801516, overall p=3.4×10−9); a polymorphism within MX2 (rs45430, p=2.9×10−9) and a SNP adjacent to CASP8 (rs13016963, p=8.6×10−10). A fourth region near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication. Unlike the previously known regions, the novel loci showed no association with nevus or pigmentation phenotypes in a large UK case-control series.

Background-Genetic variation plays an important role in the development of non-small cell lung cancer (NSCLC). However, major genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which deters us from using a polygenic risk score (PRS) to identify sub-populations at high-risk of lung cancer for prevention.Methods-To systematically identify genetic variants for NSCLC risk, we newly genotyped 19,546 samples and conducted a meta-analysis of genome-wide association studies (GWASs) of Dai et al.