Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients.

PURPOSE: Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. MATERIALS AND METHODS: The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. RESULTS: For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. CONCLUSION: This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.

Arabidopsis UNHINGED encodes a VPS51 homolog and reveals a role for the GARP complex in leaf shape and vein patterning.

Asymmetric localization of PIN proteins controls directionality of auxin transport and many aspects of plant development. Directionality of PIN1 within the marginal epidermis and the presumptive veins of developing leaf primordia is crucial for establishing leaf vein pattern. One mechanism that controls PIN protein distribution within the cell membranes is endocytosis and subsequent transport to the vacuole for degradation. The Arabidopsis mutant unhinged-1 (unh-1) has simpler leaf venation with distal non-meeting of the secondary veins and fewer higher order veins, a narrower leaf with prominent serrations, and reduced root and shoot growth. We identify UNH as the Arabidopsis vacuolar protein sorting 51 (VPS51) homolog, a member of the Arabidopsis Golgi-associated retrograde protein (GARP) complex, and show that UNH interacts with VPS52, another member of the complex and colocalizes with trans Golgi network and pre-vacuolar complex markers. The GARP complex in yeast and metazoans retrieves vacuolar sorting receptors to the trans-Golgi network and is important in sorting proteins for lysosomal degradation. We show that vacuolar targeting is reduced in unh-1. In the epidermal cells of unh-1 leaf margins, PIN1 expression is expanded. The unh-1 leaf phenotype is partially suppressed by pin1 and cuc2-3 mutations, supporting the idea that the phenotype results from expanded PIN1 expression in the marginal epidermis. Our results suggest that UNH is important for reducing expression of PIN1 within margin cells, possibly by targeting PIN1 to the lytic vacuole.

Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer.

BACKGROUND AND PURPOSE: Rectal bleeding can occur following radiotherapy for prostate cancer and negatively impacts quality of life for cancer survivors. Treatment and clinical factors do not fully predict rectal bleeding, and genetic factors may be important. MATERIALS AND METHODS: A genome-wide association study (GWAS) was performed to identify SNPs associated with the development of late rectal bleeding following radiotherapy for prostate cancer. Logistic regression was used to test the association between 614,453 SNPs and rectal bleeding in a discovery cohort (79 cases, 289 controls), and top-ranking SNPs were tested in a replication cohort (108 cases, 673 controls) from four independent sites. RESULTS: rs7120482 and rs17630638, which tag a single locus on chromosome 11q14.3, reached genome-wide significance for association with rectal bleeding (combined p-values 5.4×10(-8) and 6.9×10(-7) respectively). Several other SNPs had p-values trending toward genome-wide significance, and a polygenic risk score including these SNPs shows a strong rank-correlation with rectal bleeding (Sommers' d=5.0×10(-12) in the replication cohort). CONCLUSIONS: This GWAS identified novel genetic markers of rectal bleeding following prostate radiotherapy. These findings could lead to the development of a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified.

A novel, semi-dominant allele of MONOPTEROS provides insight into leaf initiation and vein pattern formation.

Leaf vein pattern is proposed to be specified by directional auxin transport through presumptive vein cells. Activation of auxin response, which induces downstream genes that entrain auxin transport and lead to vascular differentiation, occurs through a set of transcription factors, the auxin response factors. In the absence of auxin, auxin response factors are inactive because they interact with repressor proteins, the Aux/IAA proteins. One member of the auxin response factor protein family, Auxin Response Factor 5/MONOPTEROS (MP), is critical to vein formation as indicated by reduced vein formation in loss-of-function MP alleles. We have identified a semi-dominant, gain-of-function allele of MP, autobahn or mp ( abn ), which results in vein proliferation in leaves and cotyledons. mp ( abn ) is predicted to encode a truncated product that lacks domain IV required for interaction with its Aux/IAA repressor BODENLOS (BDL). We show that the truncated product fails to interact with BDL in yeast two-hybrid assays. Ectopic expression of MP targets including the auxin efflux protein PINFORMED1 (PIN1) further supports the irrepressible nature of mp ( abn ). Asymmetric PIN1:GFP cellular localization does not occur within the enlarged PIN1:GFP expression domains, suggesting the asymmetry requires differential auxin response in neighbouring cells. Organ initiation from mp ( abn ) meristems is altered, consistent with disruption to source/sink relationships within the meristem and possible changes in gene expression. Finally, mp ( abn ) anthers fail to dehisce and their indehiscence can be relieved by jasmonic acid treatment, suggesting a specific role for MP in late anther development.