Search

Background We aimed to compare the predictive performance of three distinct clinical models purported to predict the resolution of aldosteronoma-associated hypertension after adrenalectomy. Methods A tri-institutional database of aldosteronoma patients who underwent adrenalectomy between 2004 and 2019 was retrospectively reviewed. The three models of interest incorporate various preoperative clinical factors, such as age and sex. The predictive accuracy, as measured by area under the curve of receiver operator characteristic, was estimated. Receiver operator characteristic was evaluated across the whole cohort, then stratified by treatment location. Results A total of 200 patients were included (91 American, 109 French). The clinicodemographic variables between groups were similar; the French cohort had a lower mean body mass index (P = .02). The overall complete clinical resolution of hypertension after adrenalectomy for the entire data set was 45.5% (n = 91). The regression coefficients in the Utsumi et al (2014) Japanese model produced a superior overall area under the curve (0.78, 95% confidence interval [CI] [0.71–0.84]). This model also performed best when the cohort was stratified by treatment location (French area under the curve = 0.74, 95% CI [0.64–0.83], US area under the curve = 0.82, 95% CI [0.72–0.91]). Conclusion When comparing three predictive models of aldosteronoma-associated hypertension resolution after adrenalectomy, the Utsumi et al model demonstrated the highest predictive validity across all cohorts. Counseling based on this model regarding probability of cure is recommended.

Background Although the COVID-19 pandemic has increased the incidence of distress in youth, some children show increased resilience, emphasizing the need to better understand the predictors of distress in youth. Objective This longitudinal study aimed to assess the combined impact of known socio-emotional predictors of stress-related psychopathology, namely anxiety sensitivity, anxiety trait, intolerance to uncertainty, and rumination, on COVID-related distress in healthy youth. Method A total of 92 parent-child dyads that previously participated in a laboratory-based experiment assessing observational fear learning in families between 2017 and 2019 (T0) were recontacted. Of them, 84 children aged between 9 and 14 agreed to participate. They completed online questionnaires in June 2020 (T1), September 2020 (T2), December 2020 (T3), and March 2021 (T4). Participants were free of mental illness at T0 and T1. To create a socio-emotional composite score (SECS), we measured anxiety sensitivity (Childhood Anxiety Sensitivity Index) at T0, trait anxiety (Trait subscale of the State-Trait Anxiety Inventory for Children (STAI-C)), intolerance to uncertainty (Intolerance of Uncertainty Scale for Children), and trait rumination (Children’s Response Style Scale) at T1 and created a weighted z-score. To assess symptoms of anxiety, post-traumatic stress (PTS), and depression in reaction to COVID-19, participants completed the State subscale of the STAI-C, the Children’s Revised Impact of Event Scale, and the Children’s Depression Inventory at T1–T4. Three general linear models were run with sex, age group (9–11 and 12+ years old), and SECS as predictors. Results Analyses revealed a SECS*Time interaction, with higher SECS predicting elevated anxiety symptoms at T1 and T4, and elevated PTS symptoms at T1 and T2. Conclusion These results suggest that healthy youth endorsing high levels of socio-emotional vulnerability to psychopathology have a higher risk of suffering from anxiety and PTS, but not depressive symptoms, in the year following a major stressor., HIGHLIGHTS This longitudinal study conducted in Quebec, Canada shows that healthy youth endorsing elevated socio-emotional vulnerability, as assessed by a composite score, report greater post-traumatic stress and anxiety symptoms, but not depressive symptoms in response to the COVID-19 pandemic.The study also reveals that girls and adolescents present greater symptomatology as opposed to boys and younger children.

Interpretation of missense variants remains a major challenge for genetic diagnosis, even in well-known genes such as the DNA-mismatch repair (MMR) genes involved in Lynch syndrome. We report the characterization of a variant in MSH2: c.1022T>C, which was identified in 20 apparently unrelated families living in the North of France. A total of 150 patients from 20 families were included in this study. Family segregation studies, tumor analyses and functional analyses at both the RNA and protein levels were performed. Founder effect was evaluated by haplotype analysis.We show that MSH2 c.1022T>C is a missense variant (p.Leu341Pro) that affects protein stability. This variant is frequent in the North of France (7.7% of pathogenic variations identified in MMR genes), and is located on an ancestral haplotype. It is associated with a high risk of a broad tumor spectrum including brain and cutaneous cancers. The MSH2 c.1022T>C variant is a pathogenic founder variation associated with a high risk of cancer. These findings have important implications for genetic counseling and management of variant carriers.

Background Actionable fibroblast growth factor receptor 3 (FGFR3)–transforming acidic coiled-coil protein 3 fusions (F3T3) are found in approximately 3% of gliomas, but their characteristics and prognostic significance are still poorly defined. Our goal was to characterize the clinical, radiological, and molecular profile of F3T3 positive diffuse gliomas. Methods We screened F3T3 fusion by real-time (RT)-PCR and FGFR3 immunohistochemistry in a large series of gliomas, characterized for main genetic alterations, histology, and clinical evolution. We performed a radiological and radiomic case control study, using an exploratory and a validation cohort. Results We screened 1162 diffuse gliomas (951 unselected cases and 211 preselected for FGFR3 protein immunopositivity), identifying 80 F3T3 positive gliomas. F3T3 was mutually exclusive with IDH mutation (P < 0.001) and EGFR amplification (P = 0.01), defining a distinct molecular cluster associated with CDK4 (P = 0.04) and MDM2 amplification (P = 0.03). F3T3 fusion was associated with longer survival for the whole series and for glioblastomas (median overall survival was 31.1 vs 19.9 mo, P = 0.02) and was an independent predictor of better outcome on multivariate analysis. F3T3 positive gliomas had specific MRI features, affecting preferentially insula and temporal lobe, and with poorly defined tumor margins. F3T3 fusion was correctly predicted by radiomics analysis on both the exploratory (area under the curve [AUC] = 0.87) and the validation MRI (AUC = 0.75) cohort. Using Cox proportional hazards models, radiomics predicted survival with a high C-index (0.75, SD 0.04), while the model combining clinical, genetic, and radiomic data showed the highest C-index (0.81, SD 0.04). Conclusion F3T3 positive gliomas have distinct molecular and radiological features, and better outcome.

Heterozygous germlineWe report 200Genomic rearrangements account for 18% of alterations. The c.137GT variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours fromOur results provide further insight into the role of the

Importance Adrenal venous sampling is recommended prior to adrenalectomy for all patients with hyperaldosteronism; however, cross-sectional imaging resolution continues to improve, while the procedure remains invasive and technically difficult. Therefore, certain patients may benefit from advancing straight to surgery. Objective To determine whether clinical and biochemical resolution varied for patients with primary aldosteronism with unilateral adenomas who underwent adrenal venous sampling vs those who proceeded to surgery based on imaging alone. Design, setting, and participants Retrospective, international cohort study of patients treated at 3 tertiary medical centers from 2004 to 2019, with a median follow-up of approximately 6 months. A total of 217 patients were consecutively enrolled. Exclusion criteria consisted of unknown postoperative serum aldosterone level and imaging inconsistent with unilateral adenoma with a normal contralateral gland. A total of 125 patients were included in the analysis. Data were analyzed between October 2019 and July 2020. Exposures Adrenal venous sampling performed preoperatively. Main outcomes and measures The primary outcome measurements were the clinical and biochemical success rates of surgery for the cure of hyperaldosteronism secondary to aldosterone-producing adenoma. Results A total of 125 patients were included (45 cross-sectional imaging with adrenal venous sampling and 80 imaging only). The mean (SD) age of the study participants was 50.2 (10.6) years and the cohort was 42.4% female (n = 53). Of those patients for whom race or ethnicity were reported (n = 80), most were White (72.5%). Adrenal venous sampling failure rate was 16.7%, and the imaging concordance rate was 100%. Relevant preoperative variables were similar between groups, except ambulatory systolic blood pressure, which was higher in the imaging-only group (150 mm Hg; interquartile range [IQR], 140-172 mm Hg vs 143 mm Hg, IQR, 130-158 mm Hg; P = .03). Resolution of autonomous aldosterone secretion was attained in 98.8% of imaging-only patients and 95.6% of adrenal venous sampling patients (P = .26). There was no difference in complete clinical success (43.6% [n = 34] vs 42.2% [n = 19]) or partial clinical success (47.4% [n = 37] vs 51.1% [n = 23]; P = .87) between groups. Complete biochemical resolution was similar as well (75.9% [n = 41] vs 84.4% [n = 27]; P = .35). There was no difference in clinical or biochemical cure rates when stratified by age, although complete clinical success rates downtrended in the older cohorts, and sample sizes were small. Conclusions and relevance Given the improved sensitivity of cross-sectional imaging in detection of adrenal tumors, adrenal venous sampling may be selectively performed in appropriate patients with clearly visualized unilateral adenomas without affecting outcomes. This may facilitate increased access to surgical cure for aldosterone-producing adenomas and will decrease the incidence of morbidities associated with the procedure.

Beta-catenin, encoded by the CTNNB1 gene, plays an important role in cell proliferation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Our study was conducted on 26 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Twenty three cases were from a series of 925 tumors (2.48%). The hospital files and pathological data, from surgical samples (n = 16), small biopsies (n = 5) and trans-bronchial fine needle aspirations (n = 5), were reviewed. Immunohistochemistry was performed with an anti-beta-catenin antibody. There were 10 female and 16 male patients aged 52 to 83. Eleven of 25 patients were no-smoking or light smokers. Three cases were diagnosed while under treatment with EGFR tyrosine kinase inhibitor. There were 25 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas had a papillary component and were TTF1-positive. One case was a well-differentiated fetal adenocarcinoma. Eleven cases (42%) with CTNNB1 mutations showed associated EGFR mutations. The frequency of CTNNB1 mutations was higher among EGFR mutated carcinomas. Immunohistochemistry showed heterogeneous nuclear or cytoplasmic abnormal expression. Our study shows that CTNNB1 mutations mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are often associated with EGFR mutations and possibly interfer in the mechanism of resistance to tyrosine kinase inhibitors. Our experience suggests that immuno-histochemistry cannot be used for screening.

International audience; Lynch syndrome (LS) is the most frequent cause of hereditary colorectal cancer. A subset of patients with a history of LS shows no causal germline pathogenic alteration and are identified as having Lynch‐like syndrome (LLS). Alu retrotransposons are the most abundant mobile DNA sequences in the human genome and have been associated with numerous human cancers by either disrupting coding regions or altering epigenetic modifications or splicing signals. We report a family first classified as having LLS by Sanger sequencing analysis. Next‐generation sequencing (NGS) analysis identified an AluY5a insertion in MLH1 exon 6 that led to exon skipping. This splicing alteration inducing a pathogenic frameshift was found in patients who developed colorectal adenocarcinomas. Retroelement insertion might thus be an important but underestimated mechanism of cancer genetics that could be systematically tested in patients with a phenotype suggesting LS to accurately assess family risk and surveillance approaches.

Constitutional epimutations are an alternative to genetic mutations in the etiology of genetic diseases. Some of these epimutations, termed secondary, correspond to the epigenetic effects of cis-acting genetic defects transmitted to the offspring following a Mendelian inheritance pattern. In Lynch syndrome, a few families with such apparently heritable MLH1 epimutations have been reported so far. We designed a long-range polymerase chain reaction next-generation sequencing strategy to screen MLH1 entire gene and applied it to 4 French families with heritable epimutations and 10 additional patients with no proven transmission of their epimutations. This strategy successfully detected the insertion of an Alu element in MLH1 coding sequence in one family. Two previously unreported MLH1 variants were also identified in other epimutation carriers: a nucleotide substitution within intron 1 and a single-nucleotide deletion in the 5′-UTR. Detection of a partial MLH1 duplication in another family required multiplex ligation-dependent probe amplification technology. We demonstrated the segregation of these variants with MLH1 methylation and studied the functional consequences of these defects on transcription. This is the largest cohort of patients with MLH1 secondary epimutations associated with a broad spectrum of genetic defects. This study provides further insight into the complexity of molecular mechanisms leading to secondary epimutations.

Background: Microsatellite instability (MSI) is a molecular phenotype due to defective DNA mismatch repair (MMR) system. It is used to predict outcome of colorectal tumours and to screen tumours for Lynch syndrome (LS). A pentaplex panel composed of five mononucleotide markers has been largely recommended for determination of the MSI status. However, its sensitivity may be taken in default in occasional situations. The aim of the study was to optimise this panel for the detection of MSI. Methods: We developed an assay allowing co-amplification of six mononucleotide repeat markers (BAT25, BAT26, BAT40, NR21, NR22, NR27) and one polymorphic dinucleotide marker (D3S1260) in a single reaction. Performances of the new panel were evaluated on a cohort of patients suspected of LS. Results: We demonstrate that our assay is technically as easy to use as the pentaplex assay. The hexaplex panel shows similar performances for the identification of colorectal and non-MSH6-deficient tumours. On the other hand, the hexaplex panel has higher sensitivity for the identification of MSH6-deficient tumours (94.7% vs 84.2%) and MMR-deficient tumours other than colorectal cancer (92.9% vs 85.7%). Conclusion: The hexaplex panel could thus be an attractive alternative to the pentaplex panel for the identification of patients with LS.

Purpose: Characterizing the earliest chromosomal alterations of pancreatic precursor neoplasms from individuals with a familial aggregation of pancreatic cancer may provide clues as to the loci of pancreatic cancer susceptibility genes. Experimental Design: We used Illumina 370/660K SNP arrays to conduct genome-wide copy number analysis in 60 benign neoplasms [58 mostly low-grade pancreatic intraepithelial neoplasias (PanIN) and intraductal papillary mucinous neoplasms (IPMN) and two pancreatic neuroendocrine tumors (PNET)] and matched normal tissues from 16 individuals with a family history of pancreatic cancer. PanINs and IPMNs were analyzed for KRAS codon 12/13 mutations. Results: Of 40 benign neoplasms with adequate SNP calls and allele ratios, somatic chromosomal copy number changes were identifiable in only nine lesions, including eight of the 38 PanIN/IPMNs (two of which had identical alterations) and one of the two PNETs. Only two precursor lesions had more than one somatic copy number alteration. In contrast, the overwhelming majority (∼95%) of PanINs harbored KRAS mutations. The chromosomal alterations identified included nine chromosomal arms affected by chromosomal loss and two by chromosomal gain. Copy number loss spanning 9p21.3 was identified in three precursor lesions; two precursors had chromosomal losses affecting 6q and 17p. Conclusions: Low- and intermediate-grade PanINs and IPMNs from patients with a family history of pancreatic cancer harbor few if any somatic chromosomal alterations. The absence of a locus of recurrent chromosomal loss in most low-grade pancreatic cancer precursor lesions supports the hypothesis that there is no one tumor suppressor gene locus consistently involved in initiating familial pancreatic neoplasia. Clin Cancer Res; 18(16); 4303–12. ©2012 AACR.

The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disease due to mutations in the tumor suppressor gene STK11. PJS is characterized by periorificial hyperpigmented macules (lentiginosis) and hamartomatous polyposis. Polyps can be located anywhere in the gastrointestinal tract, but are preferably observed in the small bowel (70-90%), the colon (50%) and the stomach (25%). They tend to be cancerous in a particular sequence hamartoma-dysplasia-cancer. The diagnosis is often made in the first or second decade following the appearance of lentigines or upon the occurrence of complications due to polyps (obstruction, intussusception, occult bleeding responsible for anemia). Furthermore PJS is associated with a significant increase in cancer risk (relative risk of 89% over the life according to the most recent series). Digestive cancers are the more frequent with cumulative incidences of 55% for gastro-intestinal cancer (39% for colorectal cancer, 13% for small bowel cancer and between 11 and 36% for pancreatic cancer, respectively). There is also an increased risk of non digestive cancers. In particular the risk of breast cancer is similar to that of patients carrying deleterious BRCA1 or BRCA2 mutations (cumulative incidence of 45%). Gynecological and gonadal tumors are frequent as well and can be more (adenoma malignum) or less aggressive (ovarian sex cord tumors with annular tubules and testicular tumors with calcified Sertoli cells). Finally the frequency of lung cancer is moderately increased. Recommendations for screening and management based on retrospective series in the literature have led to various strategies. The aim of this paper is to summarize the clinical and molecular diagnostic criteria of PJS as well as recommendations on screening strategies, management and monitoring.

Objective: To explore if self-reported presence of thinking about tics or body-focused repetitive behaviours (BFRBs; gests) are direct triggers of tic or gest onset in 3 groups: Tourette syndrome (TS; n =18), persistent chronic tic disorders (TDs; n = 42), and a comparison group with BFRB ( n = 36). Method: The 3 groups completed a thinking about tics inventory, listing 22 items derived from clinician consensus that asked whether thoughts always, sometimes, or never exclusively triggered tic onset. Other questionnaires measured mood, perfectionism, impulsivity, premonitory urge, and self-rated tension. Sixty-three participants completed the inventory twice, and the inventory was completed pre- and post-behavioural intervention by a further 54. Results: The ranking of the thoughts reported as likely to trigger tics or gests was positively correlated across TD and BFRB groups. Exploratory principal components analysis of a reduced 12-item set (the thinking about tics inventory) in TS and TD groups revealed that such thoughts could be grouped into 3 separate subscales: thoughts about the interference of tics or gests, thoughts anticipating tics or gests, and thoughts about whether the person has permission to perform the tic or the gest. The 3 sets of subscales showed good and acceptable internal consistency and overall score showed good test–retest reliability, suggesting thoughts about tics or gests are robust and measurable. The subscales correlated with impulsivity, tic or behaviour severity, and ratings of frequency decreased post-behavioural treatment. Conclusions: Thinking about tics or gests is reported as triggering tics or gests in both TD and BFRB, and meta-cognition seems independent of premonitory sensations and relates to distinct clinical characteristics in each clinical group.

International audience; BACKGROUND:The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma.METHODS:Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics.RESULTS:97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation.CONCLUSIONS:Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD

International audience; Among the 1700 mutations reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a missense mutation, p.Ser1235Arg, initially reported in a CF patient with a second mutation (p.Gly628Arg) on the same allele, is a relatively frequent finding. To clarify its clinical significance, we collected data from 104 subjects heterozygous for the mutation p.Ser1235Arg from the French CF network, addressed for various indications including classical CF, atypical phenotypes or carrier screening in subjects with or without a family history. Among them, twenty-six patients (five having CF, ten CBAVD -Congenital Absence of the Vas Deferens- and eleven with CF-like symptoms) and fourteen healthy subjects were compound heterozygous for a second CFTR mutation. An exhaustive CFTR gene analysis identified a second mutation in cis of p.Ser1235Arg in all CF patients and in 81.8% CBAVD patients. Moreover, epidemiological data from more than 2100 individuals found a higher frequency of p.Ser1235Arg in the general population than in CF or CBAVD patients. These data, added to the fact that in silico analysis and functional assays suggest a benign nature of this substitution gives several lines of evidence against an association of p.Ser1235Arg with CF or CBAVD.

The lung is directly exposed to a wide variety of inhaled toxicants and carcinogens. In order to improve our knowledge of the cellular processing of these compounds in the respiratory tract, we investigated the mRNA expression level of 380 genes encoding xenobiotic-metabolizing enzymes (XME), transporters, nuclear receptors and transcription factors, in pulmonary parenchyma (PP), bronchial mucosa (BM) and tumoral lung tissues from 12 patients with non-small cell lung cancer (NSCLC). Using a high throughput quantitative real-time RT-PCR method, we found that ADH1B, CYP4B1, CES1 and GSTP1 are the major XME genes expressed both in BM and PP. Our results also documented the predominant role played by the xenosensor AhR in human lung. The gene expression profiles were different for BM and PP, with a tendency toward increased mRNA levels of phase I and phase II XME genes in BM, suggesting major differences in the initial stages of xenobiotic metabolism. Some of the significantly overexpressed genes in BM (i.e. CYP2F1, CYP2A13, CYP2W1, NQO1…) encode proteins involved in the bioactivation of procarcinogens, pointing out distinct susceptibility to xenobiotics and their toxic effects between these two tissue types. Additionally, interindividual differences in transcript levels observed for some genes may be of genetic origin and may contribute to the variability in response to environmental exposure and, consequently, in the risk of developing lung diseases. A global decrease in gene expression was observed in tumoral specimens. Some of the proteins are involved in the metabolism or transport of anti-cancer drugs and their influence in the response of tumors to chemotherapy should be considered. In conclusion, the present study provides an overview of the cellular response to toxicants and drugs in healthy and cancerous human lung tissues, and thus improves our understanding of the mechanisms of chemical carcinogenesis as well as cellular resistance to chemotherapy.

Susceptibility to lung diseases, such as lung cancer and chronic obstructive pulmonary disease, is largely influenced by the metabolic capacity of lung tissues. This capacity is partly determined by the expression profile of the cytochromes P450 (CYPs), a superfamily of enzymes that have relevant catalytic properties toward exogenous and endogenous compounds. Using quantitative real-time RT-PCR, we conducted a comprehensive analysis of the expression profile of the 57 human CYP genes in non-tumoral (bronchial mucosa and pulmonary parenchyma) and tumoral lung tissues of 18 patients with non-small cell lung cancer. This study highlights (i) inter-individual variations in lung expression for some CYPs, (ii) different CYP expression patterns between bronchial mucosa and pulmonary parenchyma, that indicate distinctive susceptibility of these tissues toward the deleterious effects of inhaled chemical toxicants and carcinogens, (iii) high intertumoral variability, that could have major implications on lung tumor response to anti-cancer drugs.

Since human cytochrome P450 2F1 (CYP2F1) is predominantly expressed in lung tissue and is involved in the metabolism of various pneumotoxicants with potential carcinogenic effects, variations in the nucleotidic sequence of its gene may contribute to interindividual and interethnic differences in the susceptibility to lung tumorigenesis. The aim of the current study was to compare the frequency of a previously reported frameshift mutation, namely c.14_15insC, responsible for the synthesis of a severely truncated protein, between several populations of different ethnic origins. The frequencies of this polymorphism were 26.1, 51.6, 42.7 and 22.9% in French, Gabonese, Senegalese, and Tunisian population samples, respectively, thereby representing a substantial inter ethnic variation in the CYP2F1 gene. These findings provide data for further studies that investigate the potential association of CYP2F1 haplotypes with an incidence of lung cancer genesis in respect of ethnicity.