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Assessment of Biological Plausibility in Cancer . Paolo Boffetta IARC, Lyon, France. Characteristics of cancer. Pathology Uncontrolled growth Ability to spread Morphological and functional changes cellular, tissue and organ level Clinics Local compression, infiltration, bleeding, etc.

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assessment of biological plausibility in cancer

Assessment of Biological Plausibility in Cancer

Paolo Boffetta

IARC, Lyon, France

characteristics of cancer
Characteristics of cancer
  • Pathology
    • Uncontrolled growth
    • Ability to spread
    • Morphological and functional changes
      • cellular, tissue and organ level
  • Clinics
    • Local
      • compression, infiltration, bleeding, etc.
    • Systemic
      • adsorption, excretion, metabolism, etc.
underlying mechanisms
Underlying mechanisms
  • Six general mechanisms
    • self-sufficiency in growth signals
    • insensitivity to growth-inhibitory signals
    • evasion of programmed cell death
    • limitless replicative potential
    • sustained angiogenesis
    • ability to invade tissue and metastasis
  • Additional considerations
    • redundancy
    • multiplicity of pathways

Hanahan and Weinberg, 2000

heterogeneity of cancer
Heterogeneity of cancer
  • Types of cancer
    • epithelial neoplasms
      • carcinoma
    • mesenchimal neoplasms
      • sarcoma
    • lymphatic and hematopoietic neoplasms
      • lymphoma, leukemia
  • Individual cases of cancer
criteria for assessing biological plausibility of genetic variants
Criteria for assessing biological plausibility of genetic variants
  • Gene is known to be relevant to one or more steps of the carcinogenic process
  • Variant is known to affect one or more steps in the carcinogenic process
  • Consistency with experimental results
1 gene is known to be relevant to one or more steps of the carcinogenic process
1. Gene is known to be relevant to one or more steps of the carcinogenic process
  • Direct involvement
    • DNA repair; detoxification
  • Indirect involvement
    • tobacco dependence
  • Complexity of carcinogenic pathways
    • imperfect knowledge
early stages in carcinogenesis
Early stages in carcinogenesis

Exogenous carcinogen

Endogenous carcinogen

Dependence

Exposure

Activation

Detoxification

DNA damage

DNA repair

DNA mutation

slide9
Evidence for a genetic role in nicotine addiction

Family and twin studies

Concordance rates higher in monozygotic than dizygotic twins

Estimated heritability rates:

60% - initiation of smoking

70% - maintenance of dependent smoking

Smoking is a complex genetic trait with gene-gene and gene- environmental interactions and phenotypic and genotypic heterogeneity

nicotine dependent individuals adjust smoking behavior to maintain nicotine levels
 80%

NICOTINECOTININE

CYP2A6

Nicotine-dependent individuals adjust smoking behavior to maintain nicotine levels

Nicotine intake

(smoking)

Nicotine removal (metabolism)

cyp2a6 gene duplications increase nicotine clearance
CYP2A6 gene duplications increase nicotine clearance

Duplication (*1x2)

clearance

Inactive alleles (*4)

 clearance

Nicotine-d2 Clearance

(ml/min/kg)

Hukkanen et al., 2005

smoking cessation by cyp2a6 genotype assessment in a bupropion treatment trial
Smoking cessation by CYP2A6 genotype(Assessment in a Bupropion treatment trial)

p=0.03

Ahluwalia et al. 2002

p53 polymorphism and cervical cancer
p53 polymorphism and cervical cancer
  • Interaction between HPV oncogenes and p53 in cervical carcinogenesis
  • Arg/Pro polymorphism at codon 72 of TP53
    • Arg form more vulnerable to binding and degradation by HPV-E6
  • Meta-analysis of association studies
    • LSIL: 18 studies, RR 0.9 (95% CI 0.7-1.1)
    • HSIL: 22 studies, RR 1.0 (95% CI 0.9-1.1)
    • Inv Ca: 24 studies, RR 1.1 (95% CI 0.9-1.3)
    • SqCC: 22 studies, RR 1.5 (95% CI 1.2-1.9)
    • AC: 4 studies, RR 1.7 (95% CI 1.0-2.7)

Koushik et al. 2004

2 variant is known to affect one or more steps in the carcinogenic process
2. Variant is known to affect one or more steps in the carcinogenic process
  • Lack of functional data for many variants
  • Function often depends on interaction with other genes and non-genetic factors
n acetylation in bladder cancer
N-acetylation in bladder cancer
  • N-acetylation of arylamines and hydrazines
    • drugs (isoniazid, caffeine)
    • carcinogens (benzidine, 4-aminobiphenyl, heterocyclic amines)
  • several NAT2 polymorphisms
    • the most common result in decreased activity
slide17
Results of studies of interaction between NAT2 slow polymorphism and tobacco smoking in bladder carcinogenesis

Garcia-Closas et al., 2005

gene environment interaction in lung carcinogenesis itc intake and gst polymorphims
Gene-environment interaction in lung carcinogenesisITC intake and GST polymorphims
  • Green cruciferous vegetables
    • Shown protective against lung cancer
    • Rich in isothiocyanates (ITCs)
      • Experimental studies show ITCs inhibit lung carcinogenesis
      • However, a definite causal association between ITC and decreased risk of any cancer cannot be drawn, due to confounding effect of other nutrients (IARC handbook, 2004)
  • Glutathione S-transferase (GSTs)
    • Promote elimination of ITCs
    • GSTM1 or T1 null: does not have enzyme activity increased ITC levels
    • The distribution of GSTM1 and T1 genotypes is unlikely to be associated with other dietary sources.
  • If ITC is the responsible chemopreventive agents, then the protective effect of cruciferous vegetables should be modified by GSTs genotypes
effects of cruciferous vegetables on lung cancer by gst m1 and t1 polymorphisms
Effects of cruciferous vegetables on lung cancer, by GST M1 and T1 polymorphisms

Adjusted by age, gender, country, education, and tobacco pack-years. – Brennan et al., 2005

3 consistency with experimental results
3. Consistency with experimental results
  • Same gene
    • response on TP53 LOH mice to suspected human carcinogens
  • Comparable gene/pathway
  • Issues
    • target organ, histologic type
    • magnitude of effect (background incidence)
    • limitations of database
biological plausibility in the assessment of cancer genetic associations
Biological plausibility in the assessment of cancer genetic associations
  • Support to results of human studies
  • Generation of specific hypotheses
    • gene-gene and gene-environment interactions
  • Contribution to understanding of human carcinogenesis
    • BRCA1 and BRCA2 as DNA repair genes
conclusions
Conclusions
  • Imperfect knowledge of carcinogenesis
    • lack of biological support to ‘real’ associations
    • generation of a posteriori plausibility
  • Criteria
    • strength of underlying biological data
      • human vs. animal evidence
    • parsimony
chek2 and cancer
CHEK2 and cancer
  • Cell cycle control gene (located on chromosome 22), the product of which can bind to and activate the p53 protein and other cell cycle proteins
  • Risk of 1100delC in breast cancer confirmed, although increase in risk is moderate
  • I157T polymorphism associated with a moderate risk of 6 cancer types from 13 studied
  • Testing the hypothesis of a role of I157T polymorphism on cancer risk
  • Application to a multi-site association study from Central Europe

Nature Genetics, 2002, 31: 55-59

Am.J.Hum.Genet., 2004; 75: 1131-35

chek2 i157t variant
CHEK2 I157T variant
  • rs17879961
  • Results in a replacement of A by G at position 26 in exon 6
  • Evolutionary highly conserved among different species
  • Alteration of the binding site in the protein in a way that, in yeast, prevents the homologous protein from activating the yeast homologue of the p53 protein
chek2 and cancer risk
CHEK2 and cancer risk
  • Opposite effect on different organs
  • Role of CHEK2
  • Quality of functional data
  • Support from experimental studies
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