world cancer report - iarc

linkage studies in high-risk families. More
likely, these loci, which may be associated
with a two or three-fold increased risk of
cancer (or even less), are more amenable to
examination using either population-based or
family-based case-control studies. One alternative
approach is to focus on the fact that
for any given environmental exposure, individual
differences in susceptibility may have
a genetic basis. Knowledge of the specific
genetic polymorphism conferring this susceptibility
should provide more power for the
detection and characterization of the environmental
risk factors through stratification
of the sample according to the underlying
genetic make-up. Likewise, there may be
environmental factors that are associated
with cancer (e.g. smoking and bladder cancer)
in all individuals, but with a much
stronger effect in individuals who have a
reduced capacity to metabolize the relevant
carcinogens (e.g. N-acetyltransferase-2,
NAT2 slow acetylators [7] or glutathione Stransferase,
GSTM1-null individuals [12]).
Two cytochrome P450 enzymes, CYP2D6
and CYP2A6, are associated with nicotine
REFERENCES
1. Knudson AG, Jr. (1971) Mutation and cancer: statistical
study of retinoblastoma. Proc Natl Acad Sci USA, 68: 820-
823.
2. Steel M, Thompson A, Clayton J (1991), Genetic
aspects of breast cancer. Br Med Bull, 47: 504-518.
3. Russo A, Zanna I, Tubiolo C, Migliavacca M, Bazan V,
Latteri MA, Tomasino RM, Gebbia N (2000) Hereditary
common cancers: molecular and clinical genetics.
Anticancer Res, 20: 4841-4851.
4. Gutmann DH (2001) The neurofibromatoses: when less
is more. Hum Mol Genet, 10: 747-755.
5. Fearnhead NS, Britton MP, Bodmer WF (2001) The ABC
of APC. Hum Mol Genet, 10: 721-733.
6. Eeles RA (1999) Screening for hereditary cancer and
genetic testing, epitomized by breast cancer. Eur J Cancer,
35: 1954-1962.
7. Learoyd DL, Delbridge LW, Robinson BG (2000)
Multiple endocrine neoplasia. Aust N Z J Med, 30: 675-
682.
8. Evans JP, Skrzynia C, Burke W (2001) The complexities
of predictive genetic testing. BMJ, 322: 1052-1056.
9. Nathanson KN, Wooster R, Weber BL (2001) Breast
cancer genetics: what we know and what we need. Nat
Med, 7: 552-556.
10. Rebbeck TR, Wang Y, Kantoff PW, Krithivas K,
Neuhausen SL, Godwin AK, Daly MB, Narod SA, Brunet JS,
Vesprini D, Garber JE, Lynch HT, Weber BL, Brown M (2001)
Modification of BRCA1- and BRCA2-associated breast cancer
risk by AIB1 genotype and reproductive history. Cancer
Res, 61: 5420-5424.
metabolism [13,14]. Persons with a genetic
deficiency in these enzymes smoke fewer
cigarettes and can quit smoking more easily
compared to individuals with normal activity
of these enzymes. Drugs that inhibit the
activity of these enzymes reduce a smoker’s
urge for cigarettes [15].
Genes relevant in this regard may be associated
with a particular cancer or may be associated
with basic cellular or physiological
processes and include:
- genes coding for enzymes involved in the
metabolism and detoxification of carcinogens
including the cytochrome P450[16] and
glutathione S-transferase (GST) [17] families;
- genes involved in the repair of DNA damage;
- genes related to cell growth and differentiation
or steroid hormone pathways;
- known high-risk genes, such as p16 INK4A ,
BRCA1 or hMLHI.
It is hoped that a more unified approach to
cancer epidemiology and genetics will identify
those combinations of genetic susceptibility
and environmental exposures that lead to
significant increases in risk at the individual
11. King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K,
Tait J, Ford L, Dunn BK, Costantino J, Wickerham L,
Wolmark N, Fisher B (2001) Tamoxifen and breast cancer
incidence among women with inherited mutations in
BRCA1 and BRCA2: National Surgical Adjuvant Breast and
Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.
JAMA, 286: 2251-2256.
12. Brockton N, Little J, Sharp L, Cotton SC (2000) Nacetyltransferase
polymorphisms and colorectal cancer: a
HuGE review. Am J Epidemiol, 151: 846-861.
13. Nakajima M, Yamagishi S, Yamamoto H, Yamamoto T,
Kuroiwa Y, Yokoi T (2000) Deficient cotinine formation from
nicotine is attributed to the whole deletion of the CYP2A6
gene in humans. Clin Pharmacol Ther, 67: 57-69.
14. Bartsch H, Nair U, Risch A, Rojas M, Wikman H,
Alexandrov K (2000) Genetic polymorphism of CYP genes,
alone or in combination, as a risk modifier of tobacco-related
cancers. Cancer Epidemiol Biomarkers Prev, 9: 3-28.
15. Sellers EM, Kaplan HL, Tyndale RF (2000) Inhibition of
cytochrome P450 2A6 increases nicotine's oral bioavailability
and decreases smoking. Clin Pharmacol Ther, 68:
35-43.
16. Ingelman-Sundberg M (2001) Genetic susceptibility to
adverse effects of drugs and environmental toxicants. The
role of the CYP family of enzymes. Mutat Res, 482: 11-19.
17. Strange RC, Spiteri MA, Ramachandran S, Fryer AA
(2001) Glutathione-S-transferase family of enzymes. Mutat
Res, 482: 21-26.
Fig. 2.69 Women carrying an inherited mutation
in the BRCA1 gene have a greatly increased risk of
developing breast cancer.
and population level. This in turn could lead
to reduction of the cancer burden by lifestyle
modification and avoidance of specific exposures
in genetically susceptible individuals.
WEBSITES
UICC Familial Cancer and Prevention Project:
http://www.uicc.org/programmes/epid/familial.shtml
GeneClinics, a clinical information resource:
http://www.geneclinics.org/
Genetic susceptibility
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