The NeiI polymorphism in the cyclin D1 gene and sporadic primary hyperparathyroidism

OBJECTIVES: The cell cycle regulator cyclin D1 plays an important role in parathyroid tumourigenesis. The NciI polymorphism in exon 4 has recently been associated with early onset of hereditary nonpolyposis colorectal cancer and is a prognostic indicator of nonsmall cell lung cancer and squamous cell carcinomas. Furthermore, a limited study of 28 primary hyperparathyroidism (pHPT) patients displayed a tendency of NciI influence on HPT development. We hypothesized that the NciI polymorphism may relate to a risk of developing pHPT. DESIGN, SETTING AND SUBJECTS: We genotyped 182 patients with sporadic pHPT and matched controls for the cyclin D1 polymorphism. A total of 88 pHPT patients and controls were recruited via a health-screening. RESULTS: The frequency distribution of the NciI genotypes NN, Ni, and ii were in pHPT patients and controls 22, 44 and 34%, and 26, 49 and 25%, respectively. The calculated allele frequencies were A = 0.56; G = 0.44 in cases and A = 0.49; G = 0.51 in controls. The frequency distributions did not differ comparing cases and controls when subgrouped after age and menopausal status. The NciI genotypes were not significantly associated with age of the individuals, serum (s)-calcium, s-parathyroid hormone (PTH), bone mineral density (BMD) or parathyroid tumour weight in any of the groups of pHPT patients or controls. CONCLUSIONS: No significant differences in distribution of the genotypes could be detected between the groups, suggesting that the polymorphism has minor or no pathogenic importance in the development of pHPT. Our results suggest that determination of the NciI polymorphism in the cyclin D1 gene is not a clinically useful tool for prediction of pHPT.     

Identification of somatic mutations in parathyroid tumors using whole-exome sequencing

Context: The underlying molecular alterations causing sporadic parathyroid adenomas that drive primary hyperparathyroidism have not been thoroughly defined. Objective: The aim of the study was to investigate the occurrence of somatic mutations driving tumor formation and progression in sporadic parathyroid adenoma using whole-exome sequencing. Design: Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Selected genes were analyzed for mutations in an additional 185 parathyroid adenomas. Results: Four of eight tumors displayed a frame shift deletion or nonsense mutation in MEN1, which was accompanied by loss of heterozygosity of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing. Conclusion: This study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.     

Whole‐exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene

As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole‐exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis‐related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well‐established cancer gene lysine (K)‐specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome‐sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D‐mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.     

Work-rate of substitutes in elite soccer: A preliminary study

The aim of this study was to investigate the work-rate of substitutes in professional soccer. A computerised player tracking system was used to assess the work-rates of second-half substitutes (11 midfielders and 14 forwards) in a French Ligue 1 club. Total distance, distance covered in five categories of movement intensity and recovery time between high-intensity efforts were evaluated. First- and second-half work-rates of the replaced players were compared. The performance of substitutes was compared to that of the players they replaced, to team-mates in the same position who remained on the pitch after the substitution and in relation to their habitual performances when starting games. No differences in work-rate between first- and second-halves were observed in all players who were substituted. In the second-half, a non-significant trend was observed in midfield substitutes who covered greater distances than the player they replaced whereas no differences were observed in forwards. Midfield substitutes covered a greater overall distance and distance at high-intensities (p < 0.01) and had a lower recovery time between high-intensity efforts (p < 0.01) compared to other midfield team-mates who remained on the pitch. Forwards covered less distance (p < 0.01) in their first 10-min as a substitute compared to their habitual work-rate profile in the opening 10-min when starting matches while this finding was not observed in midfielders. These findings suggest that compared to midfield substitutes, forward substitutes did not utilise their full physical potential. Further investigation is warranted into the reasons behind this finding in order to optimise the work-rate contributions of forward substitutes.     

Do heart rate and velocity variability derived from umbilical artery velocity waveforms change prior to clinical pregnancy-induced hypertension?

OBJECTIVE: To investigate the hypothesis that alterations in heart rate variability, peak systolic velocity variability and time-averaged velocity variability in the human umbilical artery may predict early signs of dysfunctional fetal-placental coupling in pregnancies that later develop pregnancy-induced hypertension. METHODS: Doppler flow velocity recordings from the umbilical artery were performed at 10-20 weeks of gestation in 12 nulliparous women who subsequently developed pregnancy-induced hypertension. From umbilical artery velocity waveforms of at least 12 s in duration we determined absolute values and beat-to-beat variability in fetal heart rate, peak systolic and time-averaged velocity and compared these findings with those in normal nulliparous pregnant women matched for gestational age. RESULTS: Absolute values for fetal heart rate, peak systolic and time-averaged velocity as well as beat-to-beat variability in fetal heart rate did not differ significantly between women later developing pregnancy-induced hypertension and normal controls. However, variability in peak systolic velocity and time-averaged velocity were decreased in women who subsequently developed pregnancy-induced hypertension. CONCLUSIONS: Whereas fetal heart rate variability was similar, umbilical artery flow velocity variability was reduced in women developing pregnancy-induced hypertension compared with controls. It is proposed from this study that variability of the umbilical artery flow velocity is associated with mechanical changes in the vascular bed of women who later develop pregnancy-induced hypertension.     

Do anthropometric and fitness characteristics vary according to birth date distribution in elite youth academy soccer players?

We examined whether maturity, anthropometric profiles and fitness measures vary according to birth date distribution in elite, under-14 youth academy soccer players. The selection year was divided into four quarters, with 160 male players grouped according to individual birth date. Players had their skeletal age determined and were assessed using a battery of standard anthropometric and physical performance tests. Players born across all quarters of the year were investigated for differences in the various performance characteristics using multi- and univariate analyses. An uneven birth distribution was observed, with players born early in the selection year highly represented ( P <0.01). A significant difference in height was observed across quarters ( P <0.01) with higher values reported in the earlier-born players. No significant differences were observed across any of the fitness measures, although the trend was for players born in the first quarter to out-perform peers born in the later quarters. These findings suggest that the relative age of the performer may not always be linked to a significant advantage in physical components. The selection criteria for entry into the academy may explain the present results.