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Genotype, phenotype and cancer: Role of low penetrance genes and environment in tumour susceptibility

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Abstract

Role of heredity and lifestyle in sporadic cancers is well documented. Here we focus on the influence of low penetrance genes and habits, with emphasis on tobacco habit in causing head and neck cancers. Role of such gene-environment interaction can be well studied in individuals with multiple primary cancers. Thus such a biological model may elucidate that cancer causation is not solely due to genetic determinism but also significantly relies on lifestyle of the individual.

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Abbreviations

HNSCC:

Head and neck squanous cell carcinoma

MMR:

mismatch repair

NAT :

N-acetyltransferase

SNP:

single nucleotide polymorphism

UADT:

upper aero-digestive tract

XME:

Xenobiotic metabolizing enzyme

References

  • Aka P, Mateuca R, Buchet J P, Thierens H and Kirsch-Volders M 2004 Are genetic polymorphisms in OGG1, XRCC1 and XRCC3 genes predictive for the DNA strand break repair phenotype and genotoxicity in workers exposed to low dose ionising radiations?Mutat. Res. 556 169–181

    Article  CAS  PubMed  Google Scholar 

  • Balmain A, Gray J and Ponder B 2003 The Genetics and Genomics of Cancer;Nature Genet. 33 238

    Article  CAS  PubMed  Google Scholar 

  • Barcellos-Hoff M H 2001 It takes a tissue to make a tumor: epigenetics, cancer and the microenvironment;J. Mammary Gland Biol. Neoplasia 6 213–221

    Article  CAS  PubMed  Google Scholar 

  • Bhowmick N A, Chytil A, Plieth D, Gorska A E, Dumont N, Shappell S, Washington M K, Neilson E G and Moses H L 2004 TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia;Science 303 848–851

    Article  CAS  PubMed  Google Scholar 

  • Bostwick D G, Burke H B, Djakiew D, Euling S, Ho S M, Landolph J, Morrison H, Sonawane B, Shifflett T, Waters D J and Timms B 2004 Human prostate cancer risk factors;Cancer Oct. 19

  • Brennan P 2002 Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it?Carcinogenesis 23 381–387

    Article  CAS  PubMed  Google Scholar 

  • Buch S C, Notani P N and Bhisey R A 2002 Polymorphism at GSTM1, GSTM3 and GSTT1 gene loci and susceptibility to oral cancer in an Indian population;Carcinogenesis 23 803–807

    Article  CAS  PubMed  Google Scholar 

  • Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane C R, Lim E P, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley G Q and Lander E S 1999 Characterization of single nucleotide polymorphisms in coding regions of human genes;Nature Genet. 22 231–238

    Article  CAS  PubMed  Google Scholar 

  • Chen Q, Lipkina G, Song Q and Kramer R H 2004 Promoter methylation regulates cadherin switching in squamous cell carcinoma;Biochem. Biophys. Res. Commun. 315 850–856

    Article  CAS  PubMed  Google Scholar 

  • Chow E, Thirlwell C, Macrae F and Lipton L 2004 Colorectal cancer and inherited mutations in base-excision repair;Lancet Oncol. 5 600–606

    Article  CAS  PubMed  Google Scholar 

  • Costello J F and Plass C 2001 Methylation matters;J. Med. Genet. 38 285–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cybulski C, Huzarski T, Gorski B, Masojc B, Mierzejewski M, Debniak T, Gliniewicz B, Matyjasik J, Zlowocka E, Kurzawski G, Sikorski A, Posmyk M, Szwiec M, Czajka R, Narod S A and Lubinski J 2004 A novel founder CHEK2 mutation is associated with increased prostate cancer risk;Cancer Res. 64 2677–2679

    Article  CAS  PubMed  Google Scholar 

  • Day G L, Blot W J, Shore R E, McLaughlin J K, Austin D F, Greenberg R S, Liff J M, Preston-Martin S, Sarkar S and Schoenberg J Bet al 1994 Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol;J. Natl. Cancer Inst. 86 131–137

    Article  CAS  PubMed  Google Scholar 

  • Doll R 1975 Pott and the path to prevention;Arch. Geschwulstforsch. 45 521–531

    CAS  PubMed  Google Scholar 

  • Etze C J, Amos C I and Spitz M R 2003 Risk for smokingrelated cancer among relatives of lung cancer patients;Cancer Res. 63 8531–8535

    Google Scholar 

  • Evan G I and Vousden K H 2001 Proliferation, cell cycle and apoptosis in cancer;Nature (London) 411 342–348

    Article  CAS  Google Scholar 

  • Fan R, Wu M T, Miller D, Wain J C, Kelsey K T, Wiencke J K and Christiani D C 2000 The p53 codon 72 polymorphism and lung cancer risk;Cancer Epidemiol. Biomarkers Prev. 9 1037–1042

    CAS  PubMed  Google Scholar 

  • Fearon E R 1997 Human cancer syndromes: clues to the origin and nature of cancer;Science 278 1043–1050

    Article  CAS  PubMed  Google Scholar 

  • Fujita M, RudoltzM S, Canady D J, Patel P, Machtay M, PittardM Q, Mohiuddin M and Regine W F 1998 Second malignant neoplasia in patients with T1 glottic cancer treated with radiation;Laryngoscope 108 1853–1855

    Article  CAS  PubMed  Google Scholar 

  • Futreal P, Andrew, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N and Stratton M R 2004 A census of human cancer genes;Nature Rev. Cancer 4 177

    Article  CAS  Google Scholar 

  • Han D F, Zhou X, Hu M B, Wang C H, Xie W, Tan X D, Zheng F and Liu F 2004 Sulfotransferase 1A1 (SULT1A1) polymorphism and breast cancer risk in Chinese women;Toxicol. Lett. 150 167–177

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D and Weinberg R A 2000 The hallmarks of cancer;Cell 100 57–70

    Article  CAS  PubMed  Google Scholar 

  • Hashibe M, Brennan P, Strange R C, Bhisey R, Cascorbi I, Lazarus P, Oude Ophuis M B, Benhamou S, Foulkes W D, Katoh T, Coutelle C, Romkes M, Gaspari L, Taioli E and Boffetta P 2003 Metaand pooled analyses of GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes and risk of head and neck cancer;Cancer Epidemiol. Biomarkers Prev. 12 1509–1517

    CAS  PubMed  Google Scholar 

  • Hein D W, Doll M A, Fretland A J, Leff M A, Webb S J, Xiao G H, Devanaboyina U S, Nangju N A and Feng Y 2000 Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms;Cancer Epidemiol. Biomarkers Prev. 9 29–42

    CAS  PubMed  Google Scholar 

  • Hemminki K and Shields P G 2002 Skilled use of DNA polymorphisms as a tool for polygenic cancers;Carcinogenesis 23 379–380

    Article  CAS  PubMed  Google Scholar 

  • Houlston R S and Peto J 2004 The search for low-penetrance cancer susceptibility alleles;Oncogene 23 6471–6476

    Article  CAS  PubMed  Google Scholar 

  • Howe J R, Roth S, Ringold J C, Summers R W, Jarvinen H J, Sistonen P, Tomlinson I P, Houlston R S, Bevan S, Mitros F A, Stone E M and Aaltonen L A 1998 Mutations in the SMAD4/ DPC4 gene in juvenile polyposis;Science 280 1086–1088

    Article  CAS  PubMed  Google Scholar 

  • Hsieh F I, Pu Y S, Chern H D, Hsu L I, Chiou H Y and Chen C J 1999 Genetic polymorphisms of N-acetyltransferase 1 and 2 and risk of cigarette smoking-related bladder cancer;Br. J. Cancer 81 537–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imyanitov E N, Togo A V and Hanson K P 2004 Searching for cancer-associated gene polymorphisms: promises and obstacles;Cancer Lett. 204 3–14

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa T, Ide F, Qin X, Zhang S, Takahashi Y, Sekiguchi M, Tanaka K and Nakastsuru Y 2001 Importance of DNA repair in Carcinogenesis: evidence from transgenic and gene targeting studies;Mutat. Res. 477 41–49

    Article  CAS  PubMed  Google Scholar 

  • Jhavar S, Sarin R, Mulherkar R, Benner A, Agarwal J P and Dinshaw K 2004 Glutathione S-transferase M1 or T1 null genotype as a risk factor for developing multiple primary neoplasms in the upper aero-digestive tract, in Indian males using tobacco;Oral Oncol. 40 84–91

    Article  CAS  PubMed  Google Scholar 

  • Kinzler K W and Vogelstein B 1998 Landscaping the cancer terrain;Science 15 1036–1037

    Article  Google Scholar 

  • Knudson A G 2002 Cancer Genetics;Am. J. Med. Genet. 111 96–102

    Article  PubMed  Google Scholar 

  • Lander E S, Linton L M, Birren Bet al 2001 Initial sequencing and analysis of the human genome;Nature (London) 409 860–921

    Article  CAS  Google Scholar 

  • Lichtenstein P, Holm N V, Verkasalo P K, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A and Hemminki K 2000 Environmental and heritable factors in the causation of cancer — analyses of cohorts of twins from Sweden, Denmark, and Finland;N. Engl. J. Med. 343 78–85

    Article  CAS  PubMed  Google Scholar 

  • London S J, Yuan J-M, Coetzee G A, Gao Y T, Ross R K and YuM C 2000CYP1A1 I462V Genetic Polymorphism and Lung Cancer Risk in a Cohort of Men in Shanghai, China;Cancer Epidemiol. Biomarkers Prevention 9 987–991

    CAS  Google Scholar 

  • Marth G, Yeh R, Minton M, Donaldson R, Li Q, Duan S, Davenport R, Miller R D and Kwok P Y 2001 Single-nucleotide polymorphisms in the public domain: how useful are they?Nat. Genet. 27 371–372

    Article  CAS  PubMed  Google Scholar 

  • Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans D G, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang H X, Szabo C, Devilee P, Goldgar D, Futreal P A, Nathanson K L, Weber B, Rahman N and Stratton M R 2002 CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations;Nat. Genet. 31 55–59

    Article  CAS  PubMed  Google Scholar 

  • Miller D P, Liu G, De Vivo I, Lynch T J, Wain J C, Su L and Christiani D C 2002 Combinations of the variant genotypes ofGSTP1, GSTM1, and p53 are associated with an increased lung cancer risk;Cancer Res. 62 2819–2823

    CAS  PubMed  Google Scholar 

  • Mitrunen K and Hirvonen A 2003 Molecular epidemiology of sporadic breast cancer the role of polymorphic genes involved in oestrogen biosynthesis and metabolism;Mutat. Res. 544 9–41

    Article  CAS  PubMed  Google Scholar 

  • Nishimoto I N, Pinheiro N A, Rogatto S R, Carvalho A L, de Moura R P, Caballero O L, Simpson A and Kowalski L P 2004 Alcohol dehydrogenase 3 genotype as a risk factor for upper aerodigestive tract cancers;Arch. Otolaryngol Head Neck Surg. 130 78–82

    Article  PubMed  Google Scholar 

  • Park J, Chen L, Tockman M S, Elahi A and Lazarus P 2004 The human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) DNA repair enzyme and its association with lung cancer risk;Pharmacogenetics 14 103–109

    Article  CAS  PubMed  Google Scholar 

  • Paul L, Holm N V, Verkasalo P K, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A and Hemminki K 2000 Environmental and Heritable Factors in the Causation of Cancer — Analyses of Cohorts of Twins from Sweden, Denmark, and Finland;N. Engl. J. Med. 343 78–85

    Article  Google Scholar 

  • Peto J 2001 Cancer epidemiology in the last century and the next decade;Nature (London) 411 390–395

    Article  CAS  Google Scholar 

  • Peto J and Houlston R S 2001 Genetics and the common cancers;Eur. J. Cancer 37 S88-S96

    Article  CAS  PubMed  Google Scholar 

  • Potter J D 1999 Colorectal cancer: molecules and populations;Natl. Cancer Inst. 91 916–932

    Article  CAS  Google Scholar 

  • Risch A, Wallace D M, Bathers S and Sim E 1995 Slow Nacetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer;Hum. Mol. Genet. 4 231–236

    Article  CAS  PubMed  Google Scholar 

  • Ross R K, Jones P A and Yu M C 1996 Bladder cancer epidemiology and pathogenesis;Semin. Oncol. 23 536–545

    CAS  PubMed  Google Scholar 

  • Seow A, Zhao B, Lee E J, Poh W T, Teh M, Eng P, Wang Y T, Tan W C and Lee H P 2001 Cytochrome P4501A2 (CYP1A2) activity and lung cancer risk: a preliminary study among Chinese women in Singapore;Carcinogenesis 22 673–677

    Article  CAS  PubMed  Google Scholar 

  • Shekhar M P, Pauley R and Heppner G 2003 Host microenvironment in breast cancer development: extracellular matrixstromal cell contribution to neoplastic phenotype of epithelial cells in the breast;Breast Cancer Res. 5 130–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen H, Xu Y, Qian Y, Yu R, Qin Y, Zhou Let al 2000 Polymorpism of the DNA repair gene XRCC1 and risk of gastric cancer in Chinese population;Int. J. Cancer 88 601–606

    Article  CAS  PubMed  Google Scholar 

  • Shu X O, Cai Q, Gao Y T, Wen W, Jin F and Zheng W 2003 A population-based case-control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer;Cancer Epidemiol. Biomarkers Prev. 12 1462–1467

    CAS  PubMed  Google Scholar 

  • Slattery M L, Samowtiz W, Ma K, Murtaugh M, Sweeney C, Levin T R and Neuhausen S 2004 CYP1A1, cigarette smoking, and colon and rectal cancer;Am. J. Epidemiol. 160 842–852

    Article  PubMed  Google Scholar 

  • Smits K M, Benhamou S, Garte S, Weijenberg M P, Alamanos Y, Ambrosone C, Autrup H, Autrup J L, Baranova Het al 2004 Association of metabolic gene polymorphisms with tobacco consumption in healthy controls;Int. J. Cancer 110 266–270

    Article  CAS  PubMed  Google Scholar 

  • Sparks R, Ulrich C M, Bigler J, Tworoger S S, Yasui Y, Rajanm K B, Porter P, Stanczyk F Z, Ballard-Barbash R, Yuan X, Lin M G, McVarish L, Aiello E J and McTiernan A 2004 UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumour receptor status in breast cancer patients;Breast Cancer Res. 6 R488-R498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sturgis E M, Castillo E J, Li L, Zheng R, Eicher S A, Clayman G L, Strom S S, Spitz M R and Wei Q 1999 polymorphism of DNA repair genes XRCC1 in squamous cell carcinima of head and neck;Carcinogenesis 20 2125–2129

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama T 2004 Development of gastric cancer associated with Helicobacter pylori infection;Cancer Chemother Pharmacol. Aug. 7

  • Thompson P A and Ambrosone C 2000 Molecular Epidemiology of Genetic Polymorphisms in Estrogen Metabolizing Enzymes in Human Breast Cancer;J. Natl. Cancer Inst. Monogr. 27 125–134

    Article  CAS  Google Scholar 

  • Tiemersma E W, Bunschoten A, Kok F J, Glatt H, de Boer S Y and Kampman E 2004 Effect of SULT1A1 and NAT2 genetic polymorphism on the association between cigarette smoking and colorectal adenomas;Int. J. Cancer 108 97–103

    Article  CAS  PubMed  Google Scholar 

  • Tomatis L 1990Cancer: causes, occurrence and control (Lyon: International Agency for Research on Cancer)

    Google Scholar 

  • Tworoger S S, Chubak J, Aiello E J, Ulrich C M, Atkinson C, Potter J D, Yasui Y, Stapleton P L, Lampe J W, Farin F M, Stanczyk F Z and McTiernan A 2004 Association of CYP17, CYP19, CYP1B1, and COMT polymorphisms with serum and urinary sex hormone concentrations in postmenopausal women;Cancer Epidemiol. Biomarkers Prev. 13 94–101

    Article  CAS  PubMed  Google Scholar 

  • van der Hel O L, Peeters P H, Hein D W, Doll M A, Grobbee D E, Kromhout D and Bueno de Mesquita H B 2003 NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women;Pharmacogenetics 13 399–407

    Article  PubMed  Google Scholar 

  • Varley J and Haber D A 2003 Familial breast cancer and the hCHK21 100delC mutation: assessing cancer risk;Breast Cancer Res. 5 123–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venter J C, Adams M D, Myers E W and Li P Wet al 2001 The sequence of the human genome;Science 291 1304–1351

    Article  CAS  PubMed  Google Scholar 

  • Warnakulasuriya K A A S, Robinson D and Evans H 2003 Multiple primary tumours following head and neck cancer in southern England during 1961-98;J. Oral Path. Med. 32 443

    Article  CAS  Google Scholar 

  • Wogan G N, Hecht S S, Felton J S, Conney A H and Loeb L A 2004 Environmental and chemical carcinogenesis;Semin. Cancer Biol. 14 473–486

    Article  CAS  PubMed  Google Scholar 

  • Woodford-Richens K, Williamson J, Bevan S, Young J, Leggett B, Frayling I, Thway Y, Hodgson S, Kim J C, Iwama T, Novelli M, Sheer D, Poulsom R, Wright N, Houlston R and Tomlinson I 2000 Allelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescencein situ hybridization to demonstrate clonal origin of the epithelium;Cancer Res. 60 2477–2482

    CAS  PubMed  Google Scholar 

  • Wu X, Zhao H, Suk R and Christiani D C 2004 Genetic susceptibility to tobacco-related cancer;Oncogene 23 6500–6523

    Article  CAS  PubMed  Google Scholar 

  • Xing D, Qi J, Miao X, Lu W, Tan W and Lin D 2002 Polymorphisms of DNA repair genes XRCC1 and XPD and their associations with risk of esophageal squamous cell carcinoma in a Chinese population;Int. J. Cancer 100 600–605

    Article  CAS  PubMed  Google Scholar 

  • Yager J D 2000 Endogenous estrogens as carcinogens through metabolic activation;J. Natl. Cancer Inst. Monogr. 27 67–73

    Article  CAS  Google Scholar 

  • Yang G, Scherer S J, Shell S S, Yang K, Kim M, Lipkin M, Kucherlapati R, Kolodner R D and Edelmann W 2004 Dominant effects of an Msh6 missense mutation on DNA repair and cancer susceptibility;Cancer Cell 6 139–150

    Article  CAS  PubMed  Google Scholar 

  • Zhu Y, Spitz M R, Amos C I, Lin J and Schabath M B 2004 An evolutionary perspective on Single-Nucleotide Polymorphism screening in molecular cancer epidemiology;Cancer Res. 64 2251–2257

    Article  CAS  PubMed  Google Scholar 

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  1. Genetic Engineering, ACTREC, Tata Memorial Centre, Kharghar, 410 208, Navi Mumbai, India

    Ashwin Kotnis, Rajiv Sarin & Rita Mulherkar

  2. Tata Memorial Hospital, Parel, 400 012, Mumbai, India

    Rajiv Sarin

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  1. Ashwin Kotnis
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Kotnis, A., Sarin, R. & Mulherkar, R. Genotype, phenotype and cancer: Role of low penetrance genes and environment in tumour susceptibility. J Biosci 30, 93–102 (2005). https://doi.org/10.1007/BF02705154

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