Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition.

Hereditary breast cancers account for up to 5-10 % of breast cancers and a majority are related to the BRCA1 and BRCA2 genes. However, many families with breast cancer predisposition do not carry any known mutations for BRCA1 and BRCA2 genes. We explored the incidence of rare large rearrangements in the coding, noncoding and flanking regions of BRCA1/2 and in eight other candidate genes--CHEK2, BARD1, ATM, RAD50, RAD51, BRIP1, RAP80 and PALB2. A dedicated zoom-in CGH-array was applied to screen for rearrangements in 472 unrelated French individuals from breast-ovarian cancer families that were being followed in eight French oncogenetic laboratories. No new rearrangement was found neither in the genomic regions of BRCA1/2 nor in candidate genes, except for the CHEK2 and BARD1 genes. Three heterozygous deletions were detected in the 5' and 3' flanking regions of BRCA1. One large deletion introducing a frameshift was identified in the CHEK2 gene in two families and one heterozygous deletion was detected within an intron of BARD1. The study demonstrates the usefulness of CGH-array in routine genetic analysis and, aside from the CHEK2 rearrangements, indicates there is a very low incidence of large rearrangements in BRCA1/2 and in the other eight candidate genes in families already explored for BRCA1/2 mutations. Finally, next-generation sequencing should bring new information about point mutations in intronic and flanking regions and also medium size rearrangements.

Molecular study of CEBPA in familial hematological malignancies.

Familial aggregation in patients with several haematological malignancies has been described, but the genetic basis for this familial clustering is not known. Few genes predisposing to familial haematological malignancies have been identified, among which RUNX1 and CEBPA have been described as predisposing genes to acute myeloid leukemia (AML). Recent studies on RUNX1 suggest that germline mutations in this gene predispose to a larger panel of familial haematological malignancies than AML. In order to strengthen this hypothesis, we have screened CEBPA for germline mutations in several families presenting aggregation of hematological malignancies (including chronic or acute, lymphoid or myeloid leukemias, Hodgkin's or non Hodgkin's lymphomas, and myeloproliferative or myelodysplastic syndromes) with or without solid tumours. Although no deleterious mutations were found, we report two novel and rare variants of uncertain significance. In addition, we confirm that the in frame insertion c.1175_1180dup (p.P194_H195dup) is a germline polymorphism.

[Phenotype-genotype study in 154 French NF2 mutation carriers]. / Analyse phénotypique de 154 patients porteurs d'une mutation constitutionnelle du gène NF2.

INTRODUCTION: Germline mutations in the NF2 gene are responsible for 80 p.cent of neurofibromatosis type 2 typical cases. Mutations are mainly truncating mutations or deletions, missense mutations having been reported in few cases. An important phenotypic variability is observed among gene carriers. To assess whether the phenotypic variability of neurofibromatosis 2 could be linked to genotype, clinical data of 154 patients whose NF2 germline alteration had been identified in our laboratory have been collected. METHODS: A retrospective questionnaire was sent to the physicians in charge of these patients. Statistical analyses regarding genotypic and phenotypic data were performed by comparisons of average values and correlation tests. RESULTS: In French patients, type of mutation was correlated neither with patients' sex, nor with disease occurrence mode (de novo or inherited mutation). Disease associated with missense mutations occurred later, with a less severe symptomatology. Patients with nonsense or frameshift mutations were more frequently affected with meningiomas and spinal tumours, in addition to VIII nerve schwannomas, an observation that underlies the genetic determination of the number and type of NF2-related tumours. CONCLUSION: Results from the literature as well as from our study tend to show that only few correlations exist between genotype and phenotype in the NF2 disease. It also recognizes that missense mutations have a lower level of evolution, severity and mortality risk. Nonsense and frameshift mutations seem to be associated with a higher number of meningiomas and spinal tumours. Therefore, NF2 gene screening keeps its indications in both typical and moderate forms of the disease. Mutations are responsible of 80 p.cent of typical forms; in moderate forms, identification of a missense mutation seems linked to a lower disease evolution. In any case, assessment and supervision should be identical. Finally, in a small number of cases, the NF2 gene appears to be implicated in clinical forms different from those defined by NIH and it might be of interest to enlarge the clinical features suggestive of the disease.

Interaction of human cyclophilin hCyp-18 with short peptides suggests the existence of two functionally independent subsites.

The binding of peptides, derived from the model substrate Suc-Ala-Ala-Pro-Phe-pNA, to the human cyclophilin hCyp-18 was investigated. HCyp-18 is able to bind 2-4-mer peptides as well as shorter para-nitroaniline (pNA) derivatives and pNA surrogates. Although Suc-Ala-Phe-pNA binds hCyp-18, only proline-containing peptides are able to block efficiently the peptidyl-prolyl cis/trans isomerase activity. Competition experiments strongly suggest the existence of two independent subsites: a S1' 'proline' subsite and a S2'-S3' 'pNA' subsite. The interaction at S2'-S3' requires either a Phe-pNA C-terminus or a Phe-pNA surrogate bearing an H-bond acceptor able to bind Trp121 and Arg148 simultaneously.

[Do indications remain for total mastectomy for cancer?]. / Que reste-t-il des indications de mastectomie totale pour cancer?

Does radical mastectomy for cancer remain needed? Breast conserving treatment may be achieved by surgery, primary chemotherapy followed by radiotherapy and surgery. This article attempts at defining (according to clinical and pathological parameters of the tumor and patient's characteristics), when conservative treatment is not allowed and radical mastectomy must be performed. Mastectomy must be performed first when there are multiple tumors or a tumor too large with respect to the breast volume or diffuse microcalcifications on mammograms. Sometimes the stage of pregnancy, a personal history of collagen vascular disease or prior radiotherapy or the willing of the patient lead to perform radical mastectomy. Secondary mastectomy is necessary in case of failure of conservative treatment or recurrence after breast conserving treatment.

Measurement of cutaneous erythema by means of photodensitometry: application to cutaneous photosensitivity.

We have developed a photodensitometry method to evaluate the intensity of cutaneous erythema objectively. The method measures the optical density of photographic slides of cutaneous erythema. It combines techniques used commonly but separately by investigators: diffuse transmittance spectroscopy (which is a variant of diffuse reflectance spectroscopy) and photography. We have used this method to study photosensitivity in 22 volunteers who received increasing doses of ultraviolet radiation to the back. Our work confirms the usefulness of an important parameter in photobiology: the regression slope of the curve representing the erythema index, a function of the logarithm of the dose applied.

Remaining indications for total mastectomy in breast carcinoma

Does radical mastectomy for cancer remain needed? Breast conserving treatment may be achieved by surgery, primary chemotherapy followed by radiotherapy and surgery. This article attempts at defining (according to clinical and pathological parameters of the tumor and patient's characteristics), when conservative treatment is not allowed and radical mastectomy must be performed. Mastectomy must be performed first when there are multiple tumors or a tumor too large with respect to the breast volume or diffuse microcalcifications on mammograms.ometimes the stage of pregnancy, a personal history of collagen vascular disease or prior radiotherapy or the willing of the patient lead to perform radical mastectomy.econdary mastectomy is necessary in case of failure of conservative treatment or recurrence after breast conserving treatment.

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.

[Intraoperative radiotherapy of ORL cancers. Review of the literature]. / Radiothérapie peropératoire des cancers ORL. Revue de la littérature.

An optimal treatment of head and neck carcinoma is to be targeted at obtaining a good local control of the disease. Intraoperative radiotherapy is one of the means of increasing the irradiation dose in the tumoral volume. It appears particularly suitable for initial treatment of locally advanced head and neck lesions and treatment of recurrence of non irradiated tumors.

[Partial regression of Barret esophagus with high grade dysplasia and adenocarcinoma after photocoagulation and endocurietherapy under antisecretory treatment]. / Régression partielle d'un endobrachyoesophage en dysplasie de haut grade avec adénocarcinome après photocoagulation et endocuriethérapie sous traitement antisécrétoire.

Barrett's oesophagus is a premalignant condition. The possibility of eradicating at least partially the metaplastic epithelium has been reported recently. In this case report, a patient with Barrett's oesophagus complicated by high grade dysplasia and focal adenocarcinoma was treated by Nd:Yag laser then high dose rate intraluminal irradiation while on omeprazole 40 mg/day. A partial eradication of Barrett's oesophagus and a transient tumoural regression were obtained. Histologically, residual specialized-type glandular tissue was observed beneath regenerative squamous epithelium. Four months after intraluminal irradiation, a local tumoural recurrence was detected while the area of restored squamous epithelium was unchanged on omeprazole 40 mg/day. This indicates that physical destruction of Barrett's oesophagus associated with potent antisecretory treatment can induce a regression of the metaplastic epithelium, even in presence of high grade dysplasia. The persistence of specialized-type glands beneath the squamous epithelium raises important issues about its potential malignant degeneration.

Chronology of combined chemotherapy (5FU) and radiotherapy. I. In vitro study.

Since radiotherapy or chemotherapy alone may be ineffective, they are more and more often combined. In this in vitro studies the effects of the chronology of the treatments and of the time interval between them are evaluated. In murine leukaemia L1210 cells and in murine mammary adenocarcinoma Ca755 cells the highest efficacy, i.e. the lowest survival fraction, was observed when radiotherapy was administered 6 h before Fluorouracil (FU). To mimic treatment in man, a daily combined treatment was also tested. Under these circumstances, the chronology of the treatments and the time interval between them had different consequences, the highest efficacy being noticed when both treatments were given at the same time.

Chronology of combined chemotherapy (5FU) and radiotherapy. II. In vivo study.

In a previous study, we reported that repeated combined chemotherapy and radiotherapy, and a single combined treatment had different consequences. In this study the effect of the chronology of the repeated combined treatments was tested, i.e. it was determined whether the treatment is more efficient when the first treatment is Fluorouracil or irradiation, or when they are given simultaneously. It was first demonstrated that, under our conditions, neither radiotherapy nor chemotherapy were chronodependent. The combined treatments were more efficient that the single treatment although their chronology had no significant consequences. Nevertheless, the simultaneous treatment appeared slightly better than the administration of Fluorouracil 6 h before or 6 h after irradiation. These results confirm our in vitro experiments.

Superimposition of computed tomography and single photon emission tomography immunoscintigraphic images in the pelvis: validation in patients with colorectal or ovarian carcinoma recurrence.

A method of superimposing computed tomography (CT) and immunoscintigraphic (IS) single photon emission tomography (SPET) slices is presented and has been applied to 10 patients with suspected cancer recurrence. IS was performed with carcinoembryonic antigen (CEA)-specific indium-111 monoclonal antibodies (MoAbs) in 5 patients with colorectal cancer, and with OC125 111In-MoAbs in 5 patients with ovarian cancer. All patients had an abnormal CT image result in the pelvis, which was interpreted 5 times as recurrence, once as doubtful and four times as scar fibrosis. Recurrence was subsequently proven in all patients. Bone scintigraphy (BS) SPET was recorded at the same time as IS. No special technique was used during BS, IS or CT acquisition. CT images were fed into a computer using a CCD camera. Using the internal anatomical landmarks provided by the pelvic bone structures seen on CT and BS, an operator had to select corresponding fiducial points, which were used by the software to register the images. The final results were CT-BS and CT-IS superimposed images. CT-BS images were used for quality control. In all patients, the inspection of CT-BS and CT-IS showed that the registration process is accurate and assists in the co-interpretation of CT and IS images.

[Limited lumpectomy combined with peroperative curietherapy for conservative treatment of breast cancer]. / Tumorectomie limitée associée à la curiethérapie per-opératoire pour le traitement conservateur du cancer du sein.

Lumpectomy together with axillary clearance and radiotherapy is a good alternative to Patey's operation for treating early cancers of the breast. In any case it has not been definitely worked out how much should be removed. In certain patients not much needs to be removed, in other larger areas of tissue need to be excised. We present our technique for carrying out limited lumpectomy which is carried out at the same time as radiation therapy making it possible to perform a less radical clearance. The results in the first 17 patients we have followed up with a mean of 4.5 years are very encouraging. There was only one local recurrence; this was some distance away from the area of the lumpectomy. The limits for the method are determined by the examination that is carried out on the margins that have been removed and on the availability of a team comprising surgeon, histopathologist and radiotherapist.

[Cancer of the esophagus after mediastinal radiotherapy for Hodgkin's disease. Apropos of a case]. / Cancer de l'oesophage après radiothérapie médiastinale pour maladie de Hodgkin. A propos d'un cas.

Malignant solid tumors induced by radiotherapy for Hodgkin's disease are uncommon. We report one case of thoracic esophageal squamous carcinoma diagnosed 19 years after mediastinal irradiation. The criteria usually accepted for the diagnosis of radiation cancer were all present in this case. An oesophagectomy was performed and the patient made a good recovery from the operation.

Neoadjuvant chemotherapy and irradiation in multiple synchronous squamous cell carcinoma of the upper aero digestive tract.

Twenty-four patients with multiple, synchronous carcinoma of the head and neck, lung or esophagus, were treated with induction chemotherapy followed by irradiation to involved areas. Chemotherapy regimen consisted of cisplatinum either alone, or in combination with 5-FU or etoposide. Subsequently, external radiotherapy, 60-65 Gy and 70-75 Gy to the mediastinum and the head and neck areas, respectively, was carried out. Following chemotherapy, three patients (12.5%) had a complete clinical remission in both cervical and mediastinal sites. That rate was significantly increased by radiotherapy (66%). Tolerance was fair or mild even though half of the patients needed a rest break during irradiation. Follow-up ranges from 24 to 38 months. The median survival is 12 months and the actuarial survival rates are 45% and 5% at 12 and 24 months, respectively. It is suggested that induction chemotherapy will not drastically improve the overall prognosis of multiple squamous cell carcinoma of the upper aero digestive tract and that external irradiation remains a major part of treatment which should not be reduced in treated volumes, or in total dose delivered.