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Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ∼75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.

Ornithine transcarbamylase (OTC) deficiency is the most common inherited disorder of the urea cycle and is transmitted as an X‐linked trait. Defects in the OTC gene cause a block in ureagenesis resulting in hyperammonemia, which can lead to brain damage and death. Three previous mutation updates for the OTC gene have been published, in 1993, 1995, and 2002. The most recent comprehensive update, in 2002, contained 244 mutations including 13 nondisease‐causing mutations and polymorphisms. This current update reports 341 mutations, of which 93 have not been previously reported, and an additional 29 nondisease‐causing mutations and polymorphisms. Out of the 341 mutations, 149 were associated with neonatal onset of hyperammonemia (within the first week of life), 70 were seen in male patients with later onset of hyperammonemia, and 121 were found in heterozygous females (one unknown). Along with the reported mutations, residual enzyme activities and other pertinent clinical information are included whenever available. Most mutations in the OTC gene are specific to a particular family (“private” mutations). They are distributed throughout the gene, with a significant paucity of mutations in the 32 first codons encoding the “leader” peptide (exon 1 and the beginning of exon 2). Almost all mutations in consensus splice sites confer a neonatal onset phenotype. Using the current molecular screening methods, mutations are found in about 80% of the patients. The remaining patients may have mutations in regulatory domains or mutations deep in the introns, which constitute 98.5% of the genomic sequence. In addition, a phenocopy of OTC deficiency caused by mutations in another unknown gene cannot be excluded. Hum Mutat 27(7):626–632, 2006. Published 2006 Wiley‐Liss, Inc.

Management of early-stage breast cancer in young women with mutations in BRCA1 or BRCA2 remains controversial. This study assessed the long-term risks of ipsilateral and contralateral breast cancer in a cohort of young women who underwent breast-conserving surgery followed by radiotherapy. Between 1975 and 1998, 290 women with breast cancer diagnosed at age 42 years or younger underwent lumpectomy followed by radiotherapy at our hospital. We recruited 127 of these women for complete sequencing of BRCA1 and BRCA2. Demographic, clinical, pathological, and outcome data were recorded. The primary endpoints were rates of ipsilateral and contralateral breast cancer, in relation to germline BRCA1/2 status. 105 women were classified as having sporadic disease (94 with wild-type or known polymorphisms and 11 with variants of unclear significance) and 22 as having genetic predisposition (deleterious mutations in BRCA1 [15] or BRCA2 [seven]). At 12 years of follow-up, the genetic group had significantly higher rates of ipsilateral (49% vs 21%, p=0·007) and contralateral events (42% vs 9%, p=0·001) than the sporadic group. The majority of events were classified as second primary tumours. No patient in the genetic group had undergone oophorectomy or was taking prophylactic agents such as tamoxifen. Patients with germline mutations in BRCA1 or BRCA2 have a high risk of developing late ipsilateral and contralateral second primary tumours. With breast-conserving therapy, chemoprophylaxis or other interventions to reduce the rate of second cancers may be valuable. Alternatively, bilateral mastectomy may be considered, to minimise the risk of second tumours in the breasts.

Basal cell carcinoma (BCC) incidence is increasing, particularly among adults under the age of 40 years. Pigment-related characteristics are associated with BCC in older populations, but epidemiologic studies among younger individuals and analyses of phenotype–genotype interactions are limited. We examined self-reported phenotypes and melanocortin 1 receptor gene (MC1R) variants in relation to early-onset BCC. BCC cases (n=377) and controls with benign skin conditions (n=390) under the age of 40 years were identified through Yale's Dermatopathology database. Factors most strongly associated with early-onset BCC were skin reaction to first summer sun for 1 hour (severe sunburn vs. tan odds ratio (OR)=12.27, 95% confidence interval (CI)=4.08–36.94) and skin color (very fair vs. olive OR=11.06, 95% CI=5.90–20.74). Individuals with two or more MC1R non-synonymous variants were 3.59 times (95% CI=2.37–5.43) more likely to have BCC than those without non-synonymous variants. All host characteristics and MC1R were more strongly associated with multiple BCC case status (37% of cases) than a single BCC case status. MC1R, number of moles, skin reaction to first summer sun for 1 hour, and hair and skin color were independently associated with BCC. BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, traditionally considered to be at low risk of skin cancer.

Background Despite educational and public health campaigns to convey the risks of indoor tanning, many individuals around the world continue to engage in this behavior. Few descriptive studies of indoor tanning have collected information pertaining to the lifetime history of indoor tanning, thereby limiting our ability to understand indoor tanning patterns and potentially target interventions for individuals who not only initiate, but continue to persistently engage in indoor tanning. Methods In-person interviews elicited detailed retrospective information on lifetime history of indoor tanning among white individuals (n = 401) under age 40 seen by a dermatologist for a minor benign skin condition. These individuals were controls in a case-control study of early-onset basal cell carcinoma. Outcomes of interest included ever indoor tanning in both males and females, as well as persistent indoor tanning in females - defined as females over age 31 who tanned indoors at least once in the last three or all four of four specified age periods (ages 11-15, 16-20, 21-30 and 31 or older). Multivariate logistic regression was used to identify sociodemographic and lifestyle correlates of ever and persistent indoor tanning in females. Results Approximately three-quarters (73.3%) of females and 38.3% of males ever tanned indoors, with a median age of initiation of 17.0 and 21.5, respectively. Among indoor tanners, 39.3% of females and 21.7% of males reported being burned while indoor tanning. Female ever indoor tanners were younger, had darker color eyes, and sunbathed more frequently than females who never tanned indoors. Using unique lifetime exposure data, 24.7% of female indoor tanners 31 and older persistently tanned indoors starting as teenagers. Female persistent indoor tanners drank significantly more alcohol, were less educated, had skin that tanned with prolonged sun exposure, and sunbathed outdoors more frequently than non-persistent tanners. Conclusions Indoor tanning was strikingly common in this population, especially among females. Persistent indoor tanners had other high-risk behaviors (alcohol, sunbathing), suggesting that multi-faceted behavioral interventions aimed at health promotion/disease prevention may be needed in this population.

Objectives:Non alcoholic fatty liver disease (NAFLD) is a leading cause of liver damage in childhood, its occurrence is influenced by genetic and environmental factors. Recently, the rs626283 polymorphism in the MBOAT7 gene has been found to be associated with alcoholic liver disease and NAFLD in adults.Methods:In a multiethnic cohort of obese children and adolescents we genotyped the rs626283 polymorphism in the MBOAT7 gene, evaluated insulin sensitivity by an oral glucose tolerance test, and measured the intra-hepatic fat content (HFF%) by magnetic resonance imaging.Results:In Caucasian youth, the minor allele (C) was associated with HFF% in (P=0.003), fasting insulin (P=0.03), area under the curve of glucose (P=0.03), and lower degree of whole-body insulin sensitivity (P=0.01) independent of age, gender, and body mass index z-score. A partial correlation showed that the association between the rs626283 variant and insulin resistance was driven by the presence of hepatic steatosis (P=0.009). However, there was no association between the rs626283 and hepatic steatosis among Hispanic and African American children and youth. The association between the rs626283 in the MBOAT7 gene among Caucasians was independent of the PNPLA3 rs738409, GCKR 1260326, and TM6SF2 rs58542926 (P=0.01). The four polymorphisms combined explained~19% of the HFF% in Caucasian obese children and adolescents.Conclusions:The rs626283 variant in the MBOAT7 gene is associated with NAFLD and may affect glucose metabolism by modulating intra-hepatic fat content in Caucasian obese children and adolescents.

Purpose Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss. Methods A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were selected for ES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated. Results ES detected 6 pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multisystem abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders, and renal diseases. Conclusion These results supported the clinical utility of ES for detecting monogenic etiology of pregnancy loss. The identification of disease-associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

This study determines which clinical features predict positive test results among samples submitted for DNA-based diagnostic nevoid basal cell carcinoma syndrome (NBCCS) testing, and further defines the mutational spectrum of the PTCH gene. DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction products from exons 1 to 23 of the PTCH gene were directly sequenced. Pedigree phenotypic information was obtained by written questionnaire. Among 106 presumably unrelated pedigrees, 44 independent mutations were found in 47 families. There were 11 nonsense mutations; 1 in-frame deletion; 17 deletions, 6 insertions, and 1 deletion-insertion that generated frameshifts; 5 splice-site mutations; 1 in-frame duplication; and 2 presumptive missense mutations. Twenty-seven of 46 pedigrees (58.7%) with two or more typical radiographic or pathologic features of NBCCS tested positive for PTCH mutations. Of these, 26 had jaw cysts in combination with other characteristics or neoplasms including basal cell carcinomas, palmar pits, skeletal abnormalities, ocular abnormalities, medulloblastomas, cardiac or ovarian fibromas, calcification of the falx cerebri, polydactyly, cleft lip and/or palate, and agenesis of the corpus callosum or other central nervous system malformations. None of the 13 pedigrees solely affected by multiple or early-onset basal cell carcinomas and none of the four pedigrees with jaw cysts alone had PTCH mutations. Pedigrees with multiple features of NBCCS were most likely to test positive for PTCH mutations. Pedigrees with multiple or early-onset basal cell carcinomas without other features of the disease did not test positive for PTCH mutations.

Based on results of diagnostic MEN1 testing, we have attempted to further define the mutational spectrum of the MEN1 gene and the clinical features most frequently associated with MEN1 mutations. Mutation testing was performed on blood samples by PCR amplification and sequencing of exons 2 to 10 of the MEN1 gene and the corresponding intron-exon junctions. Pedigree phenotypic information was obtained by written questionnaire. Among 288 presumably unrelated pedigrees, 73 independent mutations were found in 89 families. Five mutations were found in 2 pedigrees, and 4 mutations were seen in more than 2 pedigrees. There were 17 nonsense mutations (23.3%), 2 in-frame deletions (2.7%), 18 frameshift-deletion mutations (24.7%), 10 frameshift-insertion or -duplication mutations (13.7%), 13 splice-site mutations (17.8%), and 13 presumptive missense mutations (17.8%). Thirty-nine of 56 pedigrees with parathyroid and pancreatic islet neoplasia tested positive, compared with 4/24 and 8/32 pedigrees affected with hyperparathyroidism or hyperparathyroidism and pituitary tumors. MEN1 mutations were found in 6/20 sporadic patients, all of whom had both parathyroid and pancreatic neoplasms. Of 14 mutation-negative sporadic patients, 10 exhibited hyperparathyroidism and pituitary tumors without islet cell neoplasia. Somatic mosaicism was detected in 1 sporadic patient. Patients from pedigrees with hyperparathyroidism and pancreatic islet tumors are most likely to test positive for MEN1 mutations. Mutations are less often detected in patients from pedigrees with hyperparathyroidism alone or in combination with pituitary tumors without pancreatic islet neoplasia. Sporadic cases are less likely to test positive than familial cases, in part due to somatic mosaicism.