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