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Contribution of environment and genetics to pancreatic cancer susceptibility.

ABSTRACT: Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00 ± 0.05) versus both healthy unrelated and related controls (0.70 ± 0.06, p<0.001 and 0.82 ± 0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA -308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.

SUBMITTER: Hocevar BA

PROVIDER: S-EPMC3961224 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Contribution of environment and genetics to pancreatic cancer susceptibility.

Hocevar Barbara A BA Kamendulis Lisa M LM Pu Xinzhu X Perkins Susan M SM Wang Zheng-Yu ZY Johnston Erica L EL DeWitt John M JM Li Lang L Loehrer Patrick J PJ Klaunig James E JE Chiorean E Gabriela EG

PloS one 20140320 3

Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level ...[more]

PMID: 24651674

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Project description:ImportanceHidradenitis suppurativa is a chronic, inflammatory skin disease in which genetic factors are considered to play a role, with up to 38% of patients reporting a family history. Variations in the γ-secretase genes are found mainly in familial cases with an autosomal dominant pattern of inheritance. These variations are rare in the general population with hidradenitis suppurativa, even in patients who report a family history of the disease.ObjectiveTo assess the heritability of hidradenitis suppurativa in a nationwide Dutch twin cohort.Design, setting, and participantsIn this cross-sectional study on self-reported hidradenitis suppurativa conducted from 2011 to 2016, data were collected from twins participating in the surveys of the nationwide Netherlands Twin Register. All complete twin pairs answering the question on hidradenitis suppurativa in the survey were included: 978 female monozygotic twin pairs and 344 male monozygotic twin pairs and 426 female dizygotic twin pairs, 167 male dizygotic twin pairs, and 428 dizygotic twin pairs of the opposite sex. Statistical analysis was performed from July to November 2019.Main outcomes and measuresThe main outcome is the proportion of susceptibility to hidradenitis suppurativa due to additive genetic factors (narrow-sense heritability), dominant genetic factors, common or shared environmental factors, or unshared or unique environmental factors. The main outcome was evaluated prior to data collection.ResultsThe prevalence of hidradenitis suppurativa among twin pairs was 1.2% (58 of 4686); the mean (SD) age was 32.7 (15.4) years. The narrow-sense heritability of hidradenitis suppurativa was 77% (95% CI, 54%-90%), with the remainder of the variance due to unshared or unique environmental factors based on an age-adjusted model combining additive genetic factors and unshared or unique environmental factors.Conclusions and relevanceThe high heritability found in this study suggests a stronger than previously assumed genetic basis of hidradenitis suppurativa. Environmental factors were also shown to contribute to the susceptibility to hidradenitis suppurativa, supporting a multifactorial cause of the disease. Moreover, the results of this study strongly support the need for a global genome-wide association study in the general population of patients with hidradenitis suppurativa.

Project description:BackgroundGermline variations may contribute to lung cancer susceptibility besides environmental factors. The influence of germline mutations on lung cancer susceptibility and their correlation with somatic mutations has not been systematically investigated.MethodsIn this study, germline mutations from 1,026 non-small cell lung cancer (NSCLC) patients were analyzed with a 58-gene next-generation sequencing (NGS) panel containing known hereditary cancer-related genes, and were categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes.ResultsPlausible genetic susceptibility was found in 4.7% of lung cancer patients, in which 14 patients with pathogenic mutations (P group) and 34 patients with likely-pathogenic mutations (LP group) were identified. The ratio of the first degree relatives with lung cancer history of the P groups was significantly higher than the Non-P group (P=0.009). The ratio of lung cancer patients with history of other cancers was higher in P (P=0.0007) or LP (P=0.017) group than the Non-P group. Pathogenic mutations fell most commonly in BRCA2, followed by CHEK2 and ATM. Likely-pathogenic mutations fell most commonly in NTRK1 and EXT2, followed by BRIP1 and PALB2. These genes are involved in DNA repair, cell cycle regulation and tumor suppression. By comparing the germline mutation frequency from this study with that from the whole population or East Asian population (gnomAD database), we found that the overall odds ratio (OR) for P or LP group was 17.93 and 15.86, respectively, when compared with the whole population, and was 2.88 and 3.80, respectively, when compared with the East Asian population, suggesting the germline mutations of the P and LP groups were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in tumor mutation burden (TMB) among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation frequency of TP53 in the P group was significantly lower than the other two groups, and the copy number variation (CNV) mutation frequency of PIK3CA and MET was significantly higher than the Non-P group. Pathway enrichment analysis found no significant difference in aberrant pathways among the three groups.ConclusionsA proportion of 4.7% of patients carrying germline variants may be potentially linked to increased susceptibility to lung cancer. Patients with pathogenic germline mutations exhibited stronger family history and higher lung cancer risk.

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Contribution of environment and genetics to pancreatic cancer susceptibility.

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Contribution of environment and genetics to pancreatic cancer susceptibility.

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