Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) — the most common chromosomal translocation observed in childhood ALL — which leads to an ETV6–RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, PCMH=8.94 × 10−9, OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10−11, OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10−9, OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10−7, OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6–RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis

Prolactinomas and nonfunctioning adenomas: preoperative diagnosis of tumor type using serum prolactin and tumor size.

OBJECTIVE: Prolactinoma and nonfunctioning adenoma (NFA) are the most common sellar pathologies, and both can present with hyperprolactinemia. There are no definitive studies analyzing the relationship between the sizes of prolactinomas and NFAs and the serum prolactin level. Current guidelines for serum prolactin level cutoffs to distinguish between pathologies are suboptimal because they fail to consider the adenoma volume. In this study, the authors attempted to describe the relationship between serum prolactin level and prolactinoma volume. They also examined the predictive value that can be gained by considering tumor volume in differentiating prolactinoma from NFA and provide cutoff values based on a large sample of patients. METHODS: A retrospective analysis of consecutive patients with prolactinomas (n = 76) and NFAs (n = 217) was performed. Patients were divided into groups based on adenoma volume, and the two pathologies were compared. RESULTS: A strong correlation was found between prolactinoma volume and serum prolactin level (r = 0.831, p \u3c 0.001). However, there was no significant correlation between NFA volume and serum prolactin level (r = -0.020, p = 0.773). Receiver operating characteristic curve analysis of three different adenoma volume groups was performed and resulted in different serum prolactin level cutoffs for each group. For group 1 (≤ 0.5 cm3), the most accurate cutoff was 43.65 μg/L (area under the curve [AUC] = 0.951); for group 2 (\u3e 0.5 to 4 cm3), 60.05 μg/L (AUC = 0.949); and for group 3 (\u3e 4 cm3), 248.15 μg/L (AUC = 1.0). CONCLUSIONS: Prolactinoma volume has a significant impact on serum prolactin level, whereas NFA volume does not. This finding indicates that the amount of prolactin-producing tissue is a more important factor regarding serum prolactin level than absolute adenoma volume. Hence, volume should be a determining factor to distinguish between prolactinoma and NFA prior to surgery. Current serum prolactin threshold level guidelines are suboptimal and cannot be generalized across all adenoma volumes