Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.

BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. OBJECTIVE: To characterise genetic and clinical findings in individuals with SHH mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. RESULTS: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. CONCLUSIONS: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.

Piecing together the HIF-1 puzzle: the role of the CTGF as a molecular mechanism of HIF-1 regulation.

Understanding the role that molecular compounds have in cancer is of significant interest, as the identification of molecular markers will aid in the prevention and elimination of cancer. Completing this expansive puzzle proves to be challenging because there is great diversity among tumors, specifically within the microenvironment. In a recent article by Chang et al. published in The Journal of the National Cancer Institute (Vol., 2006) new insight is provided of three specific molecular compounds: hypoxia-inducible factor-1alpha (HIF-1alpha), the connective tissue growth factor (CTGF) and the vascular endothelial growth factor-A (VEGF-A). As shown by Chang et al., these molecular compounds have significant implications in the role of human lung adenocarcinoma, and are shown to be integral within this microenvironment. This journal club article reviews the study of Chang et al. and briefly discusses the broader implications of their findings.

Disclosing a diagnosis of cancer: where and how does it occur?

PURPOSE: While disclosing a cancer diagnosis to a patient is common practice, how it is disclosed and the impact it has on the patient are poorly understood. We examined how cancer diagnoses were first given to patients and the impact of different aspects of disclosure on patient satisfaction. PATIENTS AND METHODS: We provided a self-administered questionnaire to a total of 460 oncology patients of the National Cancer Institute (NCI) being treated at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD. RESULTS: Of the 437 patients who completed the survey, 54% were told their diagnosis in-person in the physician's office, 18% by phone, and 28% in the hospital. Forty-four percent of patients reported discussions of 10 minutes or fewer, 53% reported discussions lasting longer than 10 minutes, and 5% could not remember. Treatment options were not discussed for 31% of those who could clearly remember. Higher mean satisfaction scores were associated with diagnoses revealed in person rather than over the phone (68.2 +/- 1.6 v 47.2 +/- 3.7), diagnoses revealed in a personal setting rather than an impersonal setting (68.9 +/- 1.6 v 55.7 +/- 2.8), discussions lasting longer than 10 minutes rather than fewer than 10 minutes (73.5 +/- 1.9 v 54.1 +/- 2.4), and inclusion of treatment options rather than exclusion (72.0 +/- 1.9 v 50.7 +/- 3.2; P < .001 for each aspect). CONCLUSION: Physicians should disclose a cancer diagnosis in a personal setting, discussing the diagnosis and treatment options for a substantial period of time whenever possible.