Journal of Biosciences

, Volume 30, Issue 1, pp 93–102 | Cite as

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

  • Ashwin Kotnis
  • Rajiv Sarin
  • Rita Mulherkar


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.


Gene-environment interactions low penetrance genes multiple primary cancers SNP 

Abbreviations used


Head and neck squanous cell carcinoma


mismatch repair




single nucleotide polymorphism


upper aero-digestive tract


Xenobiotic metabolizing enzyme


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  1. 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. 556 169–181PubMedGoogle Scholar
  2. Balmain A, Gray J and Ponder B 2003 The Genetics and Genomics of Cancer;Nature Genet. 33 238PubMedCrossRefGoogle Scholar
  3. Barcellos-Hoff M H 2001 It takes a tissue to make a tumor: epigenetics, cancer and the microenvironment;J. Mammary Gland Biol. Neoplasia 6 213–221PubMedCrossRefGoogle Scholar
  4. 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 303 848–851PubMedCrossRefGoogle Scholar
  5. 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. 19Google Scholar
  6. Brennan P 2002 Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it?Carcinogenesis 23 381–387PubMedCrossRefGoogle Scholar
  7. 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 23 803–807PubMedCrossRefGoogle Scholar
  8. 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. 22 231–238PubMedCrossRefGoogle Scholar
  9. Chen Q, Lipkina G, Song Q and Kramer R H 2004 Promoter methylation regulates cadherin switching in squamous cell carcinoma;Biochem. Biophys. Res. Commun. 315 850–856PubMedCrossRefGoogle Scholar
  10. Chow E, Thirlwell C, Macrae F and Lipton L 2004 Colorectal cancer and inherited mutations in base-excision repair;Lancet Oncol. 5 600–606PubMedCrossRefGoogle Scholar
  11. Costello J F and Plass C 2001 Methylation matters;J. Med. Genet. 38 285–303PubMedCrossRefGoogle Scholar
  12. 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 2677–2679PubMedCrossRefGoogle Scholar
  13. 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. 86 131–137PubMedCrossRefGoogle Scholar
  14. Doll R 1975 Pott and the path to prevention;Arch. Geschwulstforsch. 45 521–531PubMedGoogle Scholar
  15. Etze C J, Amos C I and Spitz M R 2003 Risk for smokingrelated cancer among relatives of lung cancer patients;Cancer Res. 63 8531–8535Google Scholar
  16. Evan G I and Vousden K H 2001 Proliferation, cell cycle and apoptosis in cancer;Nature (London) 411 342–348CrossRefGoogle Scholar
  17. 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 1037–1042PubMedGoogle Scholar
  18. Fearon E R 1997 Human cancer syndromes: clues to the origin and nature of cancer;Science 278 1043–1050PubMedCrossRefGoogle Scholar
  19. 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 1853–1855PubMedCrossRefGoogle Scholar
  20. 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 177CrossRefGoogle Scholar
  21. 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. 150 167–177PubMedCrossRefGoogle Scholar
  22. Hanahan D and Weinberg R A 2000 The hallmarks of cancer;Cell 100 57–70PubMedCrossRefGoogle Scholar
  23. 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 1509–1517PubMedGoogle Scholar
  24. 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 29–42PubMedGoogle Scholar
  25. Hemminki K and Shields P G 2002 Skilled use of DNA polymorphisms as a tool for polygenic cancers;Carcinogenesis 23 379–380PubMedCrossRefGoogle Scholar
  26. Houlston R S and Peto J 2004 The search for low-penetrance cancer susceptibility alleles;Oncogene 23 6471–6476PubMedCrossRefGoogle Scholar
  27. 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 1086–1088PubMedCrossRefGoogle Scholar
  28. 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 81 537–541PubMedCrossRefGoogle Scholar
  29. Imyanitov E N, Togo A V and Hanson K P 2004 Searching for cancer-associated gene polymorphisms: promises and obstacles;Cancer Lett. 204 3–14PubMedCrossRefGoogle Scholar
  30. 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 41–49PubMedGoogle Scholar
  31. 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 84–91PubMedCrossRefGoogle Scholar
  32. Kinzler K W and Vogelstein B 1998 Landscaping the cancer terrain;Science 15 1036–1037CrossRefGoogle Scholar
  33. Knudson A G 2002 Cancer Genetics;Am. J. Med. Genet. 111 96–102PubMedCrossRefGoogle Scholar
  34. Lander E S, Linton L M, Birren Bet al 2001 Initial sequencing and analysis of the human genome;Nature (London) 409 860–921CrossRefGoogle Scholar
  35. 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 78–85PubMedCrossRefGoogle Scholar
  36. 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 9 987–991Google Scholar
  37. 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. 27 371–372PubMedCrossRefGoogle Scholar
  38. 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 55–59PubMedCrossRefGoogle Scholar
  39. 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 2819–2823PubMedGoogle Scholar
  40. 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 9–41PubMedCrossRefGoogle Scholar
  41. 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 78–82PubMedCrossRefGoogle Scholar
  42. 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 14 103–109PubMedCrossRefGoogle Scholar
  43. 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 78–85CrossRefGoogle Scholar
  44. Peto J 2001 Cancer epidemiology in the last century and the next decade;Nature (London) 411 390–395CrossRefGoogle Scholar
  45. Peto J and Houlston R S 2001 Genetics and the common cancers;Eur. J. Cancer 37 S88-S96PubMedCrossRefGoogle Scholar
  46. Potter J D 1999 Colorectal cancer: molecules and populations;Natl. Cancer Inst. 91 916–932CrossRefGoogle Scholar
  47. 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. 4 231–236PubMedCrossRefGoogle Scholar
  48. Ross R K, Jones P A and Yu M C 1996 Bladder cancer epidemiology and pathogenesis;Semin. Oncol. 23 536–545PubMedGoogle Scholar
  49. 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 22 673–677PubMedCrossRefGoogle Scholar
  50. 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. 5 130–135PubMedCrossRefGoogle Scholar
  51. 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 88 601–606PubMedCrossRefGoogle Scholar
  52. 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 1462–1467PubMedGoogle Scholar
  53. 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. 160 842–852PubMedCrossRefGoogle Scholar
  54. 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 110 266–270PubMedCrossRefGoogle Scholar
  55. 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-R498PubMedCrossRefGoogle Scholar
  56. 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 2125–2129PubMedCrossRefGoogle Scholar
  57. Sugiyama T 2004 Development of gastric cancer associated with Helicobacter pylori infection;Cancer Chemother Pharmacol. Aug. 7Google Scholar
  58. 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. 27 125–134PubMedGoogle Scholar
  59. 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 97–103PubMedCrossRefGoogle Scholar
  60. Tomatis L 1990Cancer: causes, occurrence and control (Lyon: International Agency for Research on Cancer)Google Scholar
  61. 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 94–101PubMedCrossRefGoogle Scholar
  62. 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 13 399–407PubMedCrossRefGoogle Scholar
  63. Varley J and Haber D A 2003 Familial breast cancer and the hCHK21 100delC mutation: assessing cancer risk;Breast Cancer Res. 5 123–125PubMedCrossRefGoogle Scholar
  64. Venter J C, Adams M D, Myers E W and Li P Wet al 2001 The sequence of the human genome;Science 291 1304–1351PubMedCrossRefGoogle Scholar
  65. 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 443CrossRefGoogle Scholar
  66. Wogan G N, Hecht S S, Felton J S, Conney A H and Loeb L A 2004 Environmental and chemical carcinogenesis;Semin. Cancer Biol. 14 473–486PubMedCrossRefGoogle Scholar
  67. 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 2477–2482PubMedGoogle Scholar
  68. Wu X, Zhao H, Suk R and Christiani D C 2004 Genetic susceptibility to tobacco-related cancer;Oncogene 23 6500–6523PubMedCrossRefGoogle Scholar
  69. 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 100 600–605PubMedCrossRefGoogle Scholar
  70. Yager J D 2000 Endogenous estrogens as carcinogens through metabolic activation;J. Natl. Cancer Inst. Monogr. 27 67–73PubMedGoogle Scholar
  71. 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 6 139–150PubMedCrossRefGoogle Scholar
  72. 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 2251–2257PubMedCrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2005

Authors and Affiliations

  1. 1.Genetic EngineeringACTREC, Tata Memorial CentreNavi MumbaiIndia
  2. 2.Tata Memorial HospitalMumbaiIndia

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