A germline mutation in PBRM1 predisposes to renal cell carcinoma.

BACKGROUND: Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC. METHODS: We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene. RESULTS: A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours. CONCLUSIONS: We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice.

Familial melanoma: clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family.

BACKGROUND: Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. OBJECTIVE: We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family). METHODS: We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. RESULTS: The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. LIMITATIONS: The study was not population based. CONCLUSIONS: This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.

Reconstruction of coronary arteries from a single rotational X-ray projection sequence.

Cardiovascular diseases remain the primary cause of death in developed countries. In most cases, exploration of possibly underlying coronary artery pathologies is performed using X-ray coronary angiography. Current clinical routine in coronary angiography is directly conducted in two-dimensional projection images from several static viewing angles. However, for diagnosis and treatment purposes, coronary artery reconstruction is highly suitable. The purpose of this study is to provide physicians with a three-dimensional (3-D) model of coronary arteries, e.g., for absolute 3-D measures for lesion assessment, instead of direct projective measures deduced from the images, which are highly dependent on the viewing angle. In this paper, we propose a novel method to reconstruct coronary arteries from one single rotational X-ray projection sequence. As a side result, we also obtain an estimation of the coronary artery motion. Our method consists of three main consecutive steps: 1) 3-D reconstruction of coronary artery centerlines, including respiratory motion compensation; 2) coronary artery four-dimensional motion computation; 3) 3-D tomographic reconstruction of coronary arteries, involving compensation for respiratory and cardiac motions. We present some experiments on clinical datasets, and the feasibility of a true 3-D Quantitative Coronary Analysis is demonstrated.

Multiple skin hamartomata: a possible novel clinical presentation of SUFU neoplasia syndrome.

Medulloblastoma tumours may arise sporadically or as part of an inherited syndrome. A subset of children with medulloblastoma carry germline and somatic mutations in the SUFU tumour suppressor gene located at 10q24. We report a 55 year old woman referred for investigation on the basis of skin lesions and a family history of two children from different unions with medulloblastoma. Examination of our patient revealed facial papules (classified as benign folliculosebaceous hamartomatous lesions) and dysmorphology (macrocephaly, hypertelorism and prognathism). She reported her father and her son share the same dermatological features; photographs of the son display hypertelorism. Sequencing in our patient revealed a splice-site mutation in intron 6 of SUFU (c. 756+1G>A), predicted to lead to skipping of exon 6. We suggest that the emerging phenotype in SUFU associated with familial medulloblastoma may include hamartomatous skin lesions. Consideration of these features, along with macrocephaly will alert clinicians to the likely genetic basis of the syndrome, affording the opportunity for genetic counselling, prenatal or pre-implantation genetic diagnosis in at-risk families.

3D tomographic reconstruction of coronary arteries using a precomputed 4D motion field.

In this paper, we present a new method to perform 3D tomographic reconstruction of coronary arteries from cone-beam rotational x-ray angiography acquisitions. We take advantage of the precomputation of the coronary artery motion, modelled as a parametric 4D motion field. Contrary to data gating or data triggering approaches, we homogeneously use all available frames, independently of the cardiac phase. In addition, we artificially subtract angiograms from their background structures. Our method significantly improves the reconstruction, by removing both motion and background artefacts. We have successfully tested it on the datasets from a synthetic phantom and 10 patients.

Photodetachment microscopy of the P, Q, and R branches of the OH(-)(v=0) to OH(v=0) detachment threshold.

A photodetachment experiment is performed on the v=0-->v=0 OH(-) detachment threshold. The weak O and S branches provide a signal strong enough to make amplitude measurements on all five O, P, Q, R, and S branches possible, which are used to fix the formulas for their relative intensities. Photodetachment microscopy is applied to 15 different thresholds of the P, Q, and R branches. The quantitative analysis of the interference patterns obtained does not show any effect of the dipole moment of OH, but yields a new measurement of the rotational parameters of OH(-)(v=0) and of the electron affinity of the molecule. The new recommended value for the electron affinity of (16)O(1)H is 14 740.982(7) cm(-1) or 1.827 648 7(11) eV.

Molecular photodetachment microscopy.

The photodetachment microscopy technique, which was originally used with atomic negative ions, is now applied to a molecular anion. The interferograms of several rotational thresholds corresponding to transitions from OH- X (1)Sigma(+) v=0 states to OH X (2)Pi(3/2,1/2) v=0 states have been recorded. No effect due to the 1/r(2) dipolar potential of the neutral molecule appears. Using a double-pass scheme of the laser on the negative ion beam, we measure the energy of the first few detachment thresholds with improved accuracy. The new recommended value of the electron affinity of 16OH is 14,740.996(13) cm(-1), or 1.827 650 3(17) eV.