Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case–control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10−9) and Hispanic children (OR, 2.77; P = 3.78 × 10−4). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS “hits” and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors. Cancer Res; 75(22); 1–11. ©2015 AACR.

For the first time the incidence of breast cancer among black women is equal to that of white women, the American Cancer Society reports.

Human melanomas show considerable variations in genetic changes, cell morphology and in microenvironmental composition. Genetically engineered mice have successfully been used to model the impact of genomic aberrations involved in melanoma pathogenesis. However, it is unclear whether they recapitulate the phenotypic heterogeneity of human melanoma cells and the complex interactions with the immune system. Here we report the unexpected finding that immune-cell poor pigmented and immune-cell rich amelanotic melanomas develop simultaneously in Cdk4R24C mutant mice upon melanocyte-specific conditional activation of oncogenic BrafV600E and a single application of the carcinogen DMBA. Interestingly, amelanotic melanomas showed morphological and molecular features of malignant peripheral nerve sheath tumors (MPNST). A bioinformatic cross-species comparison using a gene expression signature of MPNST-like mouse melanomas identified a subset of human melanomas with a similar histomorphology in the TCGA database. Exploring their transcriptional immune cell subtype compositions we found a highly significant association with mast cells. Importantly, mouse MPNST-like melanomas were also extensively infiltrated by mast cells and expressed mast cell chemoattractants similar to their human counterparts. A transplantable mouse MPNST-like melanoma cell line recapitulated mast cell recruitment in syngeneic mice demonstrating that this cell state can directly orchestrate histomorphology and microenvironmental composition. Our study emphasizes the importance of reciprocal, phenotype-dependent melanoma-immune cell interactions and argues for a critical role of mast cells in a subset of melanomas. We further conclude that our BrafV600E-Cdk4R24C model will facilitate the development of cell state-selective and microenvironment-directed therapies as it recapitulates at least two distinct human melanoma phenotypes at once.

Rapid improvements in the detection and tracking of early-stage tumor progression aim to guide decisions regarding cancer treatments as well as predict metastatic recurrence in patients following surgery. Mathematical models may have the potential to further assist in estimating metastatic risk, particularly when paired with in vivo tumor data that faithfully represent all stages of disease progression. Herein we describe mathematical analysis that uses data from mouse models of spontaneous metastasis developing after surgical removal of orthotopically implanted primary tumors. Both presurgical (primary tumor) and postsurgical (metastatic) growth was quantified using bioluminescence and was then used to generate a mathematical formalism based on general laws of the disease (i.e. dissemination and growth). The model was able to fit and predict pre-/post-surgical data at the level of the individual as well as the population. Our approach also enabled retrospective analysis of clinical data describing the probability of metastatic relapse as a function of primary tumor size. In these data-based models, inter-individual variability was quantified by a key parameter of intrinsic metastatic potential. Critically, our analysis identified a highly nonlinear relationship between primary tumor size and postsurgical survival, suggesting possible threshold limits for the utility of tumor size as a predictor of metastatic recurrence. These findings represent a novel use of clinically relevant models to assess the impact of surgery on metastatic potential and may guide optimal timing of treatments in neoadjuvant (presurgical) and adjuvant (postsurgical) settings to maximize patient benefit.

A randomized trial has found that neither calcium nor vitamin D was effective in reducing the risk of tumors of the colon or rectum.