ABSTRACT
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Exome Sequencing , Oligonucleotide Array Sequence Analysis , Polymorphism, Genetic/genetics , Adult , Brain/metabolism , Female , Genetic Loci/genetics , Genetic Variation , Genotype , Humans , Male , Open Reading Frames/geneticsABSTRACT
APOA2 is a protein implicated in triglyceride, fatty acid and glucose metabolism. In pigs, the APOA2 gene is located on pig chromosome 4 (SSC4) in a QTL region affecting fatty acid composition, fatness and growth traits. In this study, we evaluated APOA2 as a candidate gene for meat quality traits in an Iberian × Landrace backcross population. The APOA2:c.131T>A polymorphism, located in exon 3 of APOA2 and determining a missense mutation, was associated with the percentage of hexadecenoic acid [C16:1(n-9)], linoleic acid [C18:2(n-6)], α-linolenic acid [C18:3(n-3)], dihomo-gamma-linolenic acid [C20:3(n-6)] and polyunsaturated fatty acids (PUFAs) in backfat. Furthermore, this SNP was associated with the global mRNA expression levels of APOA2 in liver and was used as a marker to determine allelic expression imbalance by pyrosequencing. We determined an overexpression of the T allele in heterozygous samples with a mean ratio of 2.8 (T/A), observing a high variability in the allelic expression among individuals. This result suggests that complex regulatory mechanisms, beyond a single polymorphism (e.g. epigenetic effects or multiple cis-acting polymorphisms), may be regulating APOA2 gene expression.
Subject(s)
Apolipoprotein A-II/genetics , Fatty Acids/chemistry , Meat , Sus scrofa/genetics , Adipose Tissue/chemistry , Alleles , Animals , Crosses, Genetic , Gene Expression , Genetic Association Studies , Genotype , Liver/metabolism , Mutation, Missense , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Quantitative Trait Loci , Sequence Analysis, DNAABSTRACT
Recent technological advances have made it possible to detect circulating tumor cells (CTCs) as a prognostic marker in operable breast cancer patients. Whether the presence of CTCs in cancer patients correlates with molecular alterations in the primary tumor has not been widely explored. We identified 14 primary breast cancer specimens with known CTC status, in order to evaluate the presence of differential genetic aberrations by using SNP array assay. There was a global increase of altered genome, CNA, and copy-neutral loss of heterozygosity (cn-LOH) observed in the CTC-positive (CTC(+)) versus CTC-negative (CTC(-)) cases. As the preliminary results showed a higher proportion of copy number alteration (CNA) at 8q24 (MYC loci) and the available evidence supporting the role of MYC in the processes cancer metastases is conflicting, MYC status was determined in tissue microarray sections in a larger series of patients (n = 49) with known CTC status using FISH. MYC was altered in 62% (16/26) CTC(+) patients and in 43% (6/14) CTC(-) patients (p = 0.25). Based on the observation in our study, future studies involving a larger number of patients should be performed in order to definitively define if this correlation exists.
Subject(s)
Breast Neoplasms/genetics , DNA Copy Number Variations/genetics , Genes, myc/genetics , Loss of Heterozygosity/genetics , Adult , Aged , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Metastasis , Neoplastic Cells, Circulating , Polymorphism, Single Nucleotide/geneticsABSTRACT
Long-chain acyl-CoA synthetase (ACSL) family members catalyse the formation of long-chain acyl-CoA from fatty acid, ATP and CoA, thus playing an important role in both de novo lipid synthesis and fatty acid catabolism. Previous studies in our group evaluated ACSL4 as a positional candidate gene for quantitative trait loci located on chromosome X in an Iberian × Landrace cross. A DQ144454:c.2645G>A SNP located in the 3' untranslated region of the ACSL4 gene was associated with the percentages of oleic and monounsaturated fatty acids. The aim of the present work was to evaluate the functional implication of this genetic variant. An expression analysis was performed for 120 individuals with different genotypes for the DQ144454:c.2645G>A polymorphism using real-time quantitative PCR. Differences between genotypes were identified in liver, with the ACSL4 mRNA expression levels higher in animals with the G allele than in animals with the A allele. A SNP genome-wide association study with ACSL4 relative expression levels showed significant positions on chromosomes 6 and 12. Description of positional candidate genes for ACSL4 regulation on chromosomes 6 and 12 is provided.
Subject(s)
Coenzyme A Ligases/genetics , Meat , Sus scrofa/genetics , Animals , Chromosome Mapping/veterinary , Chromosomes, Mammalian/genetics , Female , Gene Expression , Genetic Association Studies/veterinary , Genetic Variation , Genotype , Male , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Quantitative Trait Loci , RNA, Messenger/biosynthesisABSTRACT
BACKGROUND: This study examined the impact of the Recurrence Score (RS) in Spanish breast cancer patients and explored the associations between clinicopathological markers and likelihood of change in treatment recommendations. PATIENTS AND METHODS: Enrollment was offered consecutively to eligible women with estrogen receptor-positive; human epidermal growth factor receptor 2-negative, node-negative breast cancer. Oncologists recorded treatment recommendation and confidence in it before and after knowing the patient's RS. RESULTS: Treatment recommendation changed in 32% of 107 patients enrolled: in 21% from chemohormonal (CHT) to hormonal therapy (HT) and in 11% from HT to CHT. RS was associated with the likelihood of change from HT to CHT (P < 0.001) and from CHT to HT (P < 0.001). Confidence of oncologists in treatment recommendations increased for 60% of cases. Higher tumor grade (P = 0.007) and a high proliferative index (Ki-67) (P = 0.023) were significantly associated with a greater chance of changing from HT to CHT, while positive progesterone receptor status (P = 0.002) with a greater probability of changing from CHT to HT. CONCLUSIONS: Results from the first prospective European study are consistent with published experience and use of the RS as proposed in European clinical practice guidelines and provide evidence on how Oncotype DX and clinicopathological factors are complementary and patient selection may be improved.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Practice Patterns, Physicians'/statistics & numerical data , Antineoplastic Agents/therapeutic use , Chemotherapy, Adjuvant/statistics & numerical data , Female , Guideline Adherence/statistics & numerical data , Hormone Antagonists/therapeutic use , Humans , Medical Oncology/standards , Medical Oncology/statistics & numerical data , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/genetics , Receptors, Estrogen/biosynthesis , Receptors, Estrogen/genetics , Risk FactorsABSTRACT
BACKGROUND: Poly(ADP-ribose)polymerase-1 (PARP-1) is a highly promising novel target in breast cancer. However, the expression of PARP-1 protein in breast cancer and its associations with outcome are yet poorly characterized. PATIENTS AND METHODS: Quantitative expression of PARP-1 protein was assayed by a specific immunohistochemical signal intensity scanning assay in a range of normal to malignant breast lesions, including a series of patients (N = 330) with operable breast cancer to correlate with clinicopathological factors and long-term outcome. RESULTS: PARP-1 was overexpressed in about a third of ductal carcinoma in situ and infiltrating breast carcinomas. PARP-1 protein overexpression was associated to higher tumor grade (P = 0.01), estrogen-negative tumors (P < 0.001) and triple-negative phenotype (P < 0.001). The hazard ratio (HR) for death in patients with PARP-1 overexpressing tumors was 7.24 (95% CI; 3.56-14.75). In a multivariate analysis, PARP-1 overexpression was an independent prognostic factor for both disease-free (HR 10.05; 95% CI 5.42-10.66) and overall survival (HR 1.82; 95% CI 1.32-2.52). CONCLUSIONS: Nuclear PARP-1 is overexpressed during the malignant transformation of the breast, particularly in triple-negative tumors, and independently predicts poor prognosis in operable invasive breast cancer.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/mortality , Cell Nucleus/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Adult , Aged , Aged, 80 and over , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/diagnosis , Carcinoma, Ductal, Breast/pathology , Cell Nucleus/pathology , Cells, Cultured , Disease Progression , Embryo, Mammalian , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Knockout , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases/genetics , Prognosis , RNA, Small Interfering/pharmacology , Survival Analysis , Up-Regulation/drug effects , Up-Regulation/geneticsABSTRACT
The identification of HER2 alterations in advanced gastric carcinomas is of critical importance in daily clinical practice as such neoplasms require specific treatment with trastuzumab. For these reasons, pathologists and oncologists with expertise in gastric carcinomas and HER2 testing from both organisations (SEAP and SEOM) have endeavoured to discuss and agree on national guidelines for HER2 testing in gastric carcinomas. These guidelines are based on the experience of those who participated in the discussions and also on experience published internationally. These agreed guidelines give the minimum requirements that a pathological anatomy laboratory must fulfil in order to guarantee adequate HER2 testing in daily practice. Any laboratories which do not meet the minimum standards set out in the guidelines must make every effort to achieve compliance (AU)
Subject(s)
Humans , Male , Female , Consensus , Genes, erbB-2/genetics , Genetic Testing/methods , Genetic Testing , Practice Guidelines as Topic , Stomach Neoplasms/genetics , Medical Oncology/legislation & jurisprudence , Medical Oncology/methods , Medical Oncology/organization & administration , Pathology, Molecular/legislation & jurisprudence , Pathology, Molecular/methods , Pathology, Molecular/organization & administration , Societies, Medical/legislation & jurisprudence , Stomach Neoplasms/diagnosis , Stomach Neoplasms/pathology , Biomarkers, Tumor/geneticsABSTRACT
Anticancer drug discovery and development in cancer are currently undergoing of fast transformation. The selection of a therapeutic and effective dose using conventional cytotoxic agents has been based on the consecution of the maximally tolerated dose. However, this principle does not apply for new targeted therapies, where the definition of the optimal biologic dose (OBD) should be preferred. The definition of OBD might be established based on pharmacokinetic endpoints and, ideally, on pharmacodynamic assays by demonstrating directly the biological effect on the target and its downstream molecules in normal or tumor tissues. Normal tissues, such as peripheral blood mononuclear cells, skin or mucosa, may be excellent surrogates for explore the exposure of a drug and the dynamic target inhibition in vivo. In addition, tumor pharmacodynamic assays may determine the biologic effects of a therapy because tumor cells respond in a different way to targeted drugs than normal tissues, and to identify biomarkers that would permit to predict the individual response. In conclusion, these studies provide demonstration of proof of concept for biological and molecular mechanisms of selected drug, to select the appropriate population to be treated, to help the interpretation of clinical data, to inform the identification of optimal dose and schedule, to evaluate the clinical response and to contribute to take decisions for final approval by authorities.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Neoplasms/metabolism , Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Dose-Response Relationship, Drug , Humans , Neoplasms/drug therapyABSTRACT
Anticancer drug discovery and development in cancer are currently undergoing of fast transformation. The selection of a therapeutic and effective dose using conventional cytotoxic agents has been based on the consecution of the maximally tolerated dose. However, this principle does not apply for new targeted therapies, where the definition of the optimal biologic dose (OBD) should be preferred. The definition of OBD might be established based on pharmacokinetic endpoints and, ideally, on pharmacodynamic assays by demonstrating directly the biological effect on the target and its downstream molecules in normal or tumor tissues. Normal tissues, such as peripheral blood mononuclear cells, skin or mucosa, may be excellent surrogates for explore the exposure of a drug and the dynamic target inhibition in vivo. In addition, tumor pharmacodynamic assays may determine the biologic effects of a therapy because tumor cells respond in a different way to targeted drugs than normal tissues, and to identify biomarkers that would permit to predict the individual response. In conclusion, these studies provide demonstration of proof of concept for biological and molecular mechanisms of selected drug, to select the appropriate population to be treated, to help the interpretation of clinical data, to inform the identification of optimal dose and schedule, to evaluate the clinical response and to contribute to take decisions for final approval by authorities (AU)
Subject(s)
Humans , Male , Female , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Clinical Trials as Topic/methods , Clinical Trials as Topic , Drug Screening Assays, Antitumor/methods , Drug Screening Assays, Antitumor , Neoplasms/metabolism , Dose-Response Relationship, Drug , Neoplasms/drug therapyABSTRACT
No disponible
No disponible
Subject(s)
Female , Aged , Humans , Latex Hypersensitivity/complications , Anaphylaxis/chemically induced , Postoperative PeriodABSTRACT
The nuclear factor (NF)-kappaB system is a promising anticancer target due to its role in oncogenesis and chemoresistance in preclinical models. To provide evidence in a clinical setting on the role of NF-kappaB in breast cancer, we aimed to study the value of basal NF-kappaB/p65 in predicting resistance to neoadjuvant chemotherapy, and to characterise the pharmacodynamic changes in NF-kappaB/p65 expression following chemotherapy in patients with locally advanced breast cancer. Pre- and post-chemotherapy tumour specimens from 51 breast cancer patients treated with anthracycline- and/or taxane-containing neoadjuvant chemotherapy were assayed by immunohistochemistry for NF-kappaB/p65 subcellular expression. We studied NF-kappaB/p65, a well-characterised member of the NF-kappaB family that undergoes nuclear translocation when NF-kappaB is activated. Activation of NF-kappaB (i.e. nuclear NF-kappaB/p65 staining in pre-therapy specimens) was linked to chemoresistance. Patients with NF-kappaB/p65 nuclear staining in pre-treatment samples had a 20% clinical response rate, while patients with undetected nuclear staining had a 91% response rate to chemotherapy (P = 0.002). Notably, four patients achieved a complete histological response and none of them had pre-treatment NF-kappaB/p65 nuclear staining. Moreover, the number of patients with NF-kappaB/p65 activation increased after chemotherapy exposure. It is concluded that NF-kappaB/p65 activation assayed by immunohistochemistry is a predictive factor of resistance to neoadjuvant chemotherapy in breast cancer patients. Moreover, NF-kappaB activation was inducible following chemotherapy in a proportion of breast cancer patients. These novel clinical findings strengthen the rationale for the use of NF-kappaB inhibitors to prevent or overcome chemoresistance in breast cancer.
Subject(s)
Breast Neoplasms/therapy , Drug Resistance, Neoplasm , Neoadjuvant Therapy , Transcription Factor RelA/metabolism , Adult , Aged , Anthracyclines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Cytoplasm/chemistry , Female , Humans , Immunohistochemistry , Middle Aged , NF-kappa B/analysis , NF-kappa B/metabolism , Prognosis , Transcription Factor RelA/analysis , Up-RegulationABSTRACT
The pathogenicity of two different genomic profiles of Cryptococcus neoformans var. gattii serotype B isolated from goats that died from cryptococcal pneumonia was assessed in an experimental model of immunocompetent mice. One strain of each randomly amplified polymorphic DNA (RAPD) profile (GR52 and GR56) and three reference C. neoformans isolates representing serotypes B, D and C were used. BALB/c male mice were inoculated by the intraperitoneal route with each strain. After 4 weeks of follow-up, the animals were sacrificed and autopsy specimens of testes, liver, spleen, kidney, lungs and brain were cultured and stained for histopathology. Although spontaneous mortality was only 2% (one animal), all mice except for those inoculated with serotype C showed positive cultures in almost one organ. The strain GR52 isolated from goat showed the highest rate of positive cultures (80%) followed by serotype D (77%). Serotype B reference strain and second goat strain GR56 were both isolated from 70% of samples. Serotype C was recovered in only 33% of organs, and never from brain or lung specimens. GR52 grew abundantly from all lung cultures, and yeast cells with large capsules were seen in histopathology inside the alveoli, peribronchial vessels and interalveolar spaces. They appeared to elicit no inflammatory response. We conclude that intraperitoneally inoculated C. neoformans var. gattii shows high virulence in this immunocompetent mouse model. Strain GR52 was highest in pathogenicity and had marked lung tropism. In contrast, the serotype C reference strain showed the lowest pathogenicity and seemed not to spread outside the abdominal viscera.
Subject(s)
Cryptococcus neoformans/pathogenicity , Animals , Brain/pathology , Cryptococcosis/pathology , DNA, Fungal/analysis , Disease Models, Animal , Immunocompetence , Male , Mice , Mice, Inbred BALB C , Random Amplified Polymorphic DNA Technique , VirulenceABSTRACT
Entendemos la vigilancia de la salud como la recogida, el análisis y la interpretación sistemáticas de datos de salud de los trabajadores con la finalidad de proteger la salud y prevenir la enfermedad. Esta vigilancia, que puede ser individual o colectiva, se limita habitualmente a los exámenes de salud más o menos orientados a los riesgos laborales. Otros instrumentos de la vigilancia, como los cuestionarios o el análisis de la incapacidad laboral por contingencias comunes son, en la práctica, poco utilizados. Este trabajo pretende ser un ejemplo de cómo el análisis de los episodios de incapacidad temporal por contingencias comunes puede ser un buen instrumento en la vigilancia individual y colectiva de la salud de los trabajadores (AU)
Subject(s)
Humans , Surveillance in Disasters , Occupational Health , Occupational RisksSubject(s)
Anesthesia Department, Hospital , Anesthesiology , Medical Staff, Hospital/supply & distribution , Medically Underserved Area , Physicians/supply & distribution , Anesthesiology/education , Data Collection , Forecasting , Hospital Administrators , Humans , Internship and Residency/statistics & numerical data , Middle Aged , Physician Assistants/supply & distribution , Retirement , Spain , Surveys and Questionnaires , WorkforceABSTRACT
BACKGROUND: The aim was to analyse the magnitude, direction and predictors of change in the main hospital discharge diagnosis (HDD) after a clinical expert review, among patients included in a multicentre molecular epidemiologic study of biliopancreatic diseases. METHODS: A total of 602 patients with a suspicion diagnosis of pancreas cancer (PC), cancer of the extrahepatic biliary system (CEBS) or benign biliopancreatic pathologies (BPP) were prospectively recruited at five general hospitals. A structured form was used to collect information from medical records. A panel of experts revised all diagnostic information and established the main clinicopathological diagnosis (CPD) by consensus. RESULTS: Of the 204 cases with a HDD of PC, 176 (86%) were deemed to have a CPD of PC, eight of CEBS, twelve a neoplasm of different origin, four BPP and four syndromic diagnoses. Thus, 28 cases (14%) were false positives. Of the 129 patients with a HDD of CEBS, 15 (12%) were false positives. Nine of the 396 cases with a HDD of non-PC (2%) had a CPD of PC (false negatives), whilst 14 of 471 patients with a HDD of non-CEBS (3%) were deemed to have CEBS. Overall, sensitivity and specificity of HDD for PC were, respectively, 95 and 93%, and for CEBS, 89 and 97%. Cytohistological confirmation and laparotomy were independent predictors of diagnostic change. CONCLUSIONS: Validity of the HDD was high, but its association with some clinical variables suggests that sole reliance on HDD can significantly bias results, and highlights the need to review all HDDs. Alternatively, only patients at high risk of misdiagnosis could be reviewed: primarily, those lacking a cytohistological diagnosis or a laparotomy. No exclusions appear warranted solely on the basis of age, gender or tumour spread.
Subject(s)
Bile Duct Neoplasms/diagnosis , Bile Ducts, Extrahepatic/pathology , Medical Records/statistics & numerical data , Pancreatic Neoplasms/diagnosis , Patient Discharge/statistics & numerical data , Aged , Bile Duct Neoplasms/epidemiology , Epidemiologic Methods , False Positive Reactions , Female , Health Care Surveys , Humans , Male , Middle Aged , Pancreatic Neoplasms/epidemiology , Reproducibility of Results , Spain/epidemiologyABSTRACT
We report the case of an exuberant ulcerative angiomatoid nasal lesion in a cocaine abuser. The lesion was made up of polymorphous endothelial cells with occasional mitoses, arranged in a lobular pattern with infiltrative-looking areas. There were extensive areas of thrombosis with focal recanalization. Intravascular proliferation was not observed. The clinical, radiological, and histological features suggested hemangiosarcoma as the main differential diagnosis, but the lobular architecture of the lesion and the widespread thrombosis favoured the diagnosis of a benign reactive process.
Subject(s)
Angiomatosis/diagnosis , Cocaine-Related Disorders/complications , Hemangiosarcoma/diagnosis , Nasal Septum , Nose Diseases/diagnosis , Adult , Angiomatosis/pathology , Biopsy , Diagnosis, Differential , Humans , Magnetic Resonance Imaging , Male , Nose Diseases/pathologyABSTRACT
BACKGROUND: Organochlorine compounds such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane (p,p'-DDT), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-DDE), and some polychlorinated biphenyls (PCBs) are carcinogenic to animals and possibly also to human beings. Occupational exposure to DDT may increase the risk of pancreas cancer. The high frequency of K-ras mutations in pancreatic cancer remains unexplained. We analysed the relation between serum concentrations of selected organochlorine compounds and mutations in codon 12 of the K-ras gene in patients with exocrine pancreatic cancer. METHODS: Cases were prospectively identified in five hospitals. Mutations in K-ras were analysed by PCR and artificial restriction fragment length polymorphism. Cases of pancreatic cancer with wild-type K-ras (n=17) were frequency matched for age and sex to cases of pancreatic cancer with a K-ras mutation (n=34, case-case study). These 51 cases were further compared with 26 hospital controls (case-control comparison). Serum organochlorine concentrations were measured by high-resolution gas chromatography with electron-capture detection and negative ion chemical ionisation mass spectrometry. FINDINGS: Serum concentrations of p,p'-DDT were significantly higher in pancreatic cancer cases with a K-ras mutation than in cases without a mutation (odds ratio for upper tertile 8.7 [95% CI 1.6-48.5], p for trend=0.005). For p,p'-DDE the corresponding figures were 5.3 (1.1-25.2, p for trend=0.031). These estimates held after adjusting for total lipids, other covariates, and total PCBs. A specific association was observed between a glycine to valine substitution at codon 12 and both p,p'-DDT and p,p'-DDE concentrations (odds ratio 15.9, p=0.044 and odds ratio 24.1, p=0.028; respectively). A similar pattern was shown for the major di-ortho-chlorinated PCBs (congeners 138, 153, and 180), even after adjustment for p,p'-DDE, but without a specific association with spectrum. Concentrations of p,p'-DDT and p,p'-DDE were similar among wild-type cases and controls, but significantly higher for K-ras mutated cases than for controls (p<0.01). INTERPRETATION: Organochlorine compounds such as p,p'-DDT, p,p'-DDE, and some PCBs could play a part in the pathogenesis of exocrine pancreatic cancer through modulation of K-ras activation. The results require replication, but they suggest new roles for organochlorines in the development of several cancers in human beings.