Tumour predisposition and cancer syndromes as models to study gene–environment interactions

Abstract

Cell division and organismal development are exquisitely orchestrated and regulated processes. The dysregulation of the molecular mechanisms underlying these processes may cause cancer, a consequence of cell-intrinsic and/or cell-extrinsic events. Cellular DNA can be damaged by spontaneous hydrolysis, reactive oxygen species, aberrant cellular metabolism or other perturbations that cause DNA damage. Moreover, several environmental factors may damage the DNA, alter cellular metabolism or affect the ability of cells to interact with their microenvironment. While some environmental factors are well established as carcinogens, there remains a large knowledge gap of others owing to the difficulty in identifying them because of the typically long interval between carcinogen exposure and cancer diagnosis. DNA damage increases in cells harbouring mutations that impair their ability to correctly repair the DNA. Tumour predisposition syndromes in which cancers arise at an accelerated rate and in different organs — the equivalent of a sensitized background — provide a unique opportunity to examine how gene–environment interactions influence cancer risk when the initiating genetic defect responsible for malignancy is known. Understanding the molecular processes that are altered by specific germline mutations, environmental exposures and related mechanisms that promote cancer will allow the design of novel and effective preventive and therapeutic strategies.

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Fig. 1: DNA repair pathways and cancer.
Fig. 2: Mechanisms of BAP1 activity in cancer development.
Fig. 3: Xeroderma pigmentosum and Cockayne syndrome as examples of environmental impacts and genetics on DNA damage and repair.
Fig. 4: Using ENU mutagenesis to create and ameliorate disease in mice.

References

  1. 1.

    Tomasetti, C. & Vogelstein, B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Tomasetti, C., Li, L. & Vogelstein, B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355, 1330–1334 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Wu, S., Powers, S., Zhu, W. & Hannun, Y. A. Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016).

    CAS  PubMed  Google Scholar 

  4. 4.

    Wu, S., Zhu, W., Thompson, P. & Hannun, Y. A. Evaluating intrinsic and non-intrinsic cancer risk factors. Nat. Commun. 9, 3490 (2018).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Carbone, M., Klein, G., Gruber, J. & Wong, M. Modern criteria to establish human cancer etiology. Cancer Res. 64, 5518–5524 (2004).

    CAS  PubMed  Google Scholar 

  6. 6.

    Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Huang, K. L. et al. Pathogenic germline variants in 10,389 adult cancers. Cell 173, 355–370 e314 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Rahman, N. Realizing the promise of cancer predisposition genes. Nature 505, 302–308 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    McGee, R. B. & Nichols, K. E. Introduction to cancer genetic susceptibility syndromes. Hematol. Am. Soc. Hematol Educ. Program 2016, 293–301 (2016).

    Google Scholar 

  11. 11.

    Sondka, Z. et al. The COSMIC cancer gene census: describing genetic dysfunction across all human cancers. Nat. Rev. Cancer 18, 696–705 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Carbone, M. et al. A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes. Nat. Rev. Cancer 7, 147–154 (2007).

    CAS  PubMed  Google Scholar 

  13. 13.

    Emri, S. A. The Cappadocia mesothelioma epidemic: its influence in Turkey and abroad. Ann. Transl Med. 5, 239 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Baumann, F., Ambrosi, J. P. & Carbone, M. Asbestos is not just asbestos: an unrecognised health hazard. Lancet. Oncol. 14, 576–578 (2013).

    PubMed  Google Scholar 

  15. 15.

    Alpert, N., Gerwen, Mv. & Taioli, E. Epidemiology of mesothelioma in the 21st century in Europe and the United States, 40 years after restricted/banned asbestos use. Transl Lung Cancer Res. https://doi.org/10.21037/tlcr.2019.11.11 (2019).

    Article  Google Scholar 

  16. 16.

    Carbone, M. et al. Mesothelioma: scientific clues for prevention, diagnosis, and therapy. CA Cancer J. Clin. 69, 402–429 (2019).

    PubMed  Google Scholar 

  17. 17.

    Sluis-Cremer, G. K., Liddell, F. D., Logan, W. P. & Bezuidenhout, B. N. The mortality of amphibole miners in South Africa, 1946–80. Br. J. Ind. Med. 49, 566–575 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Carbone, M. et al. Erionite exposure in North Dakota and Turkish villages with mesothelioma. Proc. Natl Acad. Sci. USA 108, 13618–13623 (2011).

    CAS  PubMed  Google Scholar 

  19. 19.

    Roushdy-Hammady, I., Siegel, J., Emri, S., Testa, J. R. & Carbone, M. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet 357, 444–445 (2001).

    CAS  PubMed  Google Scholar 

  20. 20.

    Carbone, M. et al. BAP1 and cancer. Nat. Rev. Cancer 13, 153–159 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Carbone, M. et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J. Transl Med. 10, 179 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Testa, J. R. et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat. Genet. 43, 1022–1025 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Abdel-Rahman, M. H. et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J. Med. Genet. 48, 856–859 (2011).

    CAS  PubMed  Google Scholar 

  24. 24.

    Yu, M. D., Masoomian, B., Shields, J. A. & Shields, C. L. BAP1 germline mutation associated with bilateral primary uveal melanoma. Ocular Oncol. Pathol. 6, 10–14 (2020).

    Google Scholar 

  25. 25.

    Farley, M. N. et al. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol. Cancer Res. 11, 1061–1071 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Carbone, M. et al. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s. PLoS Genet. 11, e1005633 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Yoshikawa, Y., Emi, M., Nakano, T. & Gaudino, G. Mesothelioma developing in carriers of inherited genetic mutations. Transl Lung Cancer Res. 9 (Suppl. 1), S67–S76 (2019).

    Google Scholar 

  28. 28.

    Haugh, A. M. et al. Genotypic and phenotypic features of BAP1 cancer syndrome: a report of 8 new families and review of cases in the literature. JAMA Dermatol. 153, 999–1006 (2017).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Walpole, S. et al. Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. J. Natl Cancer Inst. 110, 1328–1341 (2018).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Bononi, A. et al. BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 546, 549–553 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Napolitano, A. et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene 35, 1996–2002 (2016).

    CAS  PubMed  Google Scholar 

  32. 32.

    Kadariya, Y. et al. Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations. Cancer Res. 76, 2836–2844 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Hickson, I. D. RecQ helicases: caretakers of the genome. Nat. Rev. Cancer 3, 169–178 (2003).

    CAS  PubMed  Google Scholar 

  34. 34.

    Oshima, J., Sidorova, J. M. & Jr. Monnat, R. J. Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions. Ageing Res. Rev. 33, 105–114 (2017).

    CAS  PubMed  Google Scholar 

  35. 35.

    Killen, M. W., Stults, D. M., Adachi, N., Hanakahi, L. & Pierce, A. J. Loss of Bloom syndrome protein destabilizes human gene cluster architecture. Hum. Mol. Genet. 18, 3417–3428 (2009).

    CAS  PubMed  Google Scholar 

  36. 36.

    Moser, M. J. et al. Genetic instability and hematologic disease risk in Werner syndrome patients and heterozygotes. Cancer Res. 60, 2492–2496 (2000).

    CAS  PubMed  Google Scholar 

  37. 37.

    Boveri, T. Zur Frage der Entstehung maligner Tumoren (Gustav Ficher, 1914).

  38. 38.

    Lauper, J. M., Krause, A., Vaughan, T. L. & Jr. Monnat, R. J. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One 8, e59709 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    German, J. Bloom’s syndrome. XX. The first 100 cancers. Cancer Genet. Cytogenet. 93, 100–106 (1997).

    CAS  PubMed  Google Scholar 

  40. 40.

    Gruber, S. B. et al. BLM heterozygosity and the risk of colorectal cancer. Science 297, 2013 (2002).

    CAS  PubMed  Google Scholar 

  41. 41.

    Goss, K. H. et al. Enhanced tumor formation in mice heterozygous for Blm mutation. Science 297, 2051–2053 (2002).

    PubMed  Google Scholar 

  42. 42.

    Yao, Y. & Dai, W. Genomic instability and cancer. J. Carcinog. Mutagen. 5, 1000163 (2014).

    Google Scholar 

  43. 43.

    Yang, H. et al. Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression. Cell Death Dis. 6, e1786 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Gaudino, G., Xue, J. & Yang, H. How asbestos and other fibers cause mesothelioma. Translational Lung Cancer Res. 9 (Suppl. 1), S39–S46 (2020).

    Google Scholar 

  45. 45.

    Kolodner, R. D. A personal historical view of DNA mismatch repair with an emphasis on eukaryotic DNA mismatch repair. DNA Repair. 38, 3–13 (2016).

    CAS  PubMed  Google Scholar 

  46. 46.

    Graham, V. W. J., Putnam, C. D. & Kolodner, R. D. DNA mismatch repair: mechanisms and cancer genetics. Encycl. Cancer 1, 530–538 (2019).

    Google Scholar 

  47. 47.

    Giorgi, C. et al. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330, 1247–1251 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891–899 (2004).

    CAS  PubMed  Google Scholar 

  49. 49.

    Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011).

    CAS  PubMed  Google Scholar 

  50. 50.

    Kastenhuber, E. R. & Lowe, S. W. Putting p53 in context. Cell 170, 1062–1078 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Yu, H. et al. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc. Natl Acad. Sci. USA 111, 285–290 (2014).

    CAS  PubMed  Google Scholar 

  52. 52.

    Giorgi, C., Bonora, M. & Pinton, P. Inside the tumor: p53 modulates calcium homeostasis. Cell Cycle 14, 933–934 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Zhang, Y. et al. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat. Cell Biol. 20, 1181–1192 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006).

    CAS  PubMed  Google Scholar 

  55. 55.

    Wang, P. Y. et al. Increased oxidative metabolism in the Li-Fraumeni syndrome. N. Engl. J. Med. 368, 1027–1032 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Bononi, A. et al. Germline BAP1 mutations induce a Warburg effect. Cell Death Differ. 24, 1694–1704 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Bougeard, G. et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J. Clin. Oncol. 33, 2345–2352 (2015).

    CAS  PubMed  Google Scholar 

  58. 58.

    Villani, A. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 17, 1295–1305 (2016).

    CAS  PubMed  Google Scholar 

  59. 59.

    Mai, P. L. et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 122, 3673–3681 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Boettcher, S. et al. A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science 365, 599–604 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Giacomelli, A. O. et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat. Genet. 50, 1381–1387 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Gonzalez, K. D. et al. High frequency of de novo mutations in Li-Fraumeni syndrome. J. Med. Genet. 46, 689–693 (2009).

    CAS  PubMed  Google Scholar 

  63. 63.

    Harbour, J. W. et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330, 1410–1413 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Yoshikawa, Y. et al. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc. Natl Acad. Sci. USA 113, 13432–13437 (2016).

    CAS  PubMed  Google Scholar 

  65. 65.

    Nasu, M. et al. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. J. Thorac. Oncol. 10, 565–576 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Jin, S. et al. Comprehensive analysis of BAP1 somatic mutation in clear cell renal cell carcinoma to explore potential mechanisms in Silico. J. Cancer 9, 4108–4116 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Pena-Llopis, S. et al. BAP1 loss defines a new class of renal cell carcinoma. Nat. Genet. 44, 751–759 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Malkin, D. Li-fraumeni syndrome. Genes Cancer 2, 475–484 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Mashtalir, N. et al. Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O. Mol. Cell 54, 392–406 (2014).

    CAS  PubMed  Google Scholar 

  70. 70.

    Bhattacharya, S., Hanpude, P. & Maiti, T. K. Cancer associated missense mutations in BAP1 catalytic domain induce amyloidogenic aggregation: a new insight in enzymatic inactivation. Sci. Rep. 5, 18462 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Heymann, S. et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat. Oncol. 5, 104 (2010).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Ziegler, A. et al. Sunburn and p53 in the onset of skin cancer. Nature 372, 773–776 (1994).

    CAS  PubMed  Google Scholar 

  73. 73.

    Marsella, J. M., Liu, B. L., Vaslet, C. A. & Kane, A. B. Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers. Env. Health Perspect. 105 (Suppl. 5), 1069–1072 (1997).

    Google Scholar 

  74. 74.

    De Flora, S. et al. Molecular alterations and lung tumors in p53 mutant mice exposed to cigarette smoke. Cancer Res. 63, 793–800 (2003).

    PubMed  Google Scholar 

  75. 75.

    Boyle, J. M. et al. Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families. Br. J. Cancer 77, 2181–2192 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Hajkova, N. et al. Germline mutation in the TP53 gene in uveal melanoma. Sci. Rep. 8, 7618 (2018).

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Jiang, W., Ananthaswamy, H. N., Muller, H. K. & Kripke, M. L. p53 protects against skin cancer induction by UV-B radiation. Oncogene 18, 4247–4253 (1999).

    CAS  PubMed  Google Scholar 

  78. 78.

    Ford, J. M. & Hanawalt, P. C. Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc. Natl Acad. Sci. USA 92, 8876–8880 (1995).

    CAS  PubMed  Google Scholar 

  79. 79.

    Kemp, C. J., Wheldon, T. & Balmain, A. p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat. Genet. 8, 66–69 (1994).

    CAS  PubMed  Google Scholar 

  80. 80.

    Nutting, C. et al. A patient with 17 primary tumours and a germ line mutation in TP53: tumour induction by adjuvant therapy? Clin. Oncol. 12, 300–304 (2000).

    CAS  Google Scholar 

  81. 81.

    Hwang, S. J. et al. Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hum. Genet. 113, 238–243 (2003).

    CAS  PubMed  Google Scholar 

  82. 82.

    Zhang, Z. et al. A germ-line p53 mutation accelerates pulmonary tumorigenesis: p53-independent efficacy of chemopreventive agents green tea or dexamethasone/myo-inositol and chemotherapeutic agents Taxol or Adriamycin. Cancer Res. 60, 901–907 (2000).

    CAS  PubMed  Google Scholar 

  83. 83.

    Krais, A. M. et al. The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53+/+, Trp53+/− and Trp53−/− mice. Arch. Toxicol. 90, 839–851 (2016).

    CAS  PubMed  Google Scholar 

  84. 84.

    Tsutsui, T. et al. Aflatoxin B1-induced immortalization of cultured skin fibroblasts from a patient with Li-Fraumeni syndrome. Carcinogenesis 16, 25–34 (1995).

    CAS  PubMed  Google Scholar 

  85. 85.

    Cleaver, J. E., Lam, E. T. & Revet, I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nat. Rev. Gen. 10, 756–768 (2009).

    CAS  Google Scholar 

  86. 86.

    Cleaver, J. E. & Revet, I. Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging. Mech. Ageing Dev. 129, 492–497 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    DiGiovanna, J. J. & Kraemer, K. H. Shining a light on xeroderma pigmentosum. J. Invest. Dermatol. 132, 785–796 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Zheng, C. L. et al. Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes. Cell Rep. 9, 1228–1234 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Zhang, W. R., Garrett, G. L., Arron, S. T. & Cleaver, J. E. Survey of Cockayne patients reports no skin cancers despite DNA repair deficiency. J. Amer Acad. Dermatol. 74, 1270–1272 (2016).

    Google Scholar 

  90. 90.

    Reid-Bayless, K. S., Arron, S. T., Loeb, L. A., Bezrookove, V. & Cleaver, J. E. Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency. Proc. Natl Acad. Sci. USA 113, 10151–101516 (2016).

    Google Scholar 

  91. 91.

    Fujiwara, Y., Ichihashi, M., Kano, Y., Goto, K. & Shimuzu, K. A new human photosensitive subject with a defect in the recovery of DNA synthesis after ultraviolet-light irradiation. J. Investig. Dermatol. 77, 256–263 (1981).

    CAS  PubMed  Google Scholar 

  92. 92.

    Spivak, G. & Hanawalt, P. C. Host cell reactivation of plasmids containing oxidative DNA lesions is defective in Cockayne syndrome but normal in UV-sensitive syndrome fibroblasts. DNA Repair. 5, 13–22 (2006).

    CAS  PubMed  Google Scholar 

  93. 93.

    Cleaver, J. E. et al. Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage. Proc. Natl Acad. Sci. USA 111, 13487–13492 (2014).

    CAS  PubMed  Google Scholar 

  94. 94.

    Crossley, M. P., Bocek, M. & Cimprich, K. A. R-loops as cellular regulators and genomic threats. Mol. Cell 73, 398–411 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Cleaver, J. E. Transcription coupled repair deficiency protects against human mutagenesis and carcinogenesis: personal reflections on the 50th anniversary of the discovery of xeroderma pigmentosum. DNA Repair. 58, 21–28 (2017).

    CAS  PubMed  Google Scholar 

  96. 96.

    Cleaver, J. E. Normal reconstruction of DNA supercoiling and chromatin structure in Cockayne syndrome cells during repair of damage from ultraviolet light. Am. J. Hum. Genet. 34, 566–575 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Tresini, M. et al. The core spliceosome as target and effector of non-canonical ATM signalling. Nature 523, 53–58 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Parris, C. H. & Kraemer, K. H. Ultraviolet-light induced mutations in Cockayne syndrome cells are primarily caused by cyclobutane dimer photoproducts while repair of other photoproducts is normal. Proc. Natl Acad. Sci. USA 90, 7260–7264 (1993).

    CAS  PubMed  Google Scholar 

  99. 99.

    Berg, R. J. et al. Impact of global genome repair versus transcription-coupled repair on ultraviolet carcinogenesis in hairless mice. Cancer Res. 60, 2858–2863 (2000).

    CAS  PubMed  Google Scholar 

  100. 100.

    van Zeeland, A. A. et al. Transcription-coupled repair: impact on UV-induced mutagenesis in cultured rodent cells and mouse skin tumors. Mutat. Res. 577, 170–178 (2005).

    PubMed  Google Scholar 

  101. 101.

    Lynch, H. T., Snyder, C. L., Shaw, T. G., Heinen, C. D. & Hitchins, M. P. Milestones of Lynch syndrome: 1895–2015. Nat. Rev. Cancer 15, 181–194 (2015).

    CAS  PubMed  Google Scholar 

  102. 102.

    Jiricny, J. & Nystrom-Lahti, M. Mismatch repair defects in cancer. Curr. Opin. Genet. Dev. 10, 157–161 (2000).

    CAS  PubMed  Google Scholar 

  103. 103.

    Marsischky, G. T., Filosi, N., Kane, M. F. & Kolodner, R. Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Genes Dev. 10, 407–420 (1996).

    CAS  PubMed  Google Scholar 

  104. 104.

    Srivatsan, A., Bowen, N. & Kolodner, R. D. Mispair-specific recruitment of the Mlh1-Pms1 complex identifies repair substrates of the Saccharomyces cerevisiae Msh2-Msh3 complex. J. Biol. Chem. 289, 9352–9364 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Amin, N. S., Nguyen, M. N., Oh, S. & Kolodner, R. D. exo1-Dependent mutator mutations: model system for studying functional interactions in mismatch repair. Mol. Cell Biol. 21, 5142–5155 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Boland, P. M., Yurgelun, M. B. & Boland, C. R. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J. Clin. 68, 217–231 (2018).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Lynch, H. T. & de la Chapelle, A. Genetic susceptibility to non-polyposis colorectal cancer. J. Med. Genet. 36, 801–818 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Wei, W. et al. Racial differences in MLH1 and MSH2 mutation: an analysis of yellow race and white race based on the InSiGHT database. J. Bioinform Comput. Biol. 8 (Suppl. 1), 111–125 (2010).

    CAS  PubMed  Google Scholar 

  109. 109.

    Park, H. M. et al. Colorectal cancer incidence in 5 Asian countries by subsite: an analysis of cancer incidence in five continents (1998–2007). Cancer Epidemiol. 45, 65–70 (2016).

    PubMed  Google Scholar 

  110. 110.

    Diergaarde, B. et al. Environmental factors and colorectal tumor risk in individuals with hereditary nonpolyposis colorectal cancer. Clin. Gastroenterol. Hepatol. 5, 736–742 (2007).

    PubMed  Google Scholar 

  111. 111.

    Gingras, D. & Beliveau, R. Colorectal cancer prevention through dietary and lifestyle modifications. Cancer Microenviron. 4, 133–139 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378, 2081–2087 (2011).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Burn, J., Mathers, J. C. & Bishop, D. T. Chemoprevention in Lynch syndrome. Fam. Cancer 12, 707–718 (2013).

    CAS  PubMed  Google Scholar 

  114. 114.

    Niraj, J., Farkkila, A. & D’Andrea, A. D. The Fanconi anemia pathway in cancer. Annu. Rev. Cancer Biol. 3, 457–478 (2019).

    PubMed  Google Scholar 

  115. 115.

    Rodriguez, A. & D’Andrea, A. Fanconi anemia pathway. Curr. Biol. 27, R986–R988 (2017).

    CAS  PubMed  Google Scholar 

  116. 116.

    Garaycoechea, J. I. et al. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 489, 571–575 (2012).

    CAS  PubMed  Google Scholar 

  117. 117.

    Langevin, F., Crossan, G. P., Rosado, I. V., Arends, M. J. & Patel, K. J. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 475, 53–58 (2011).

    CAS  PubMed  Google Scholar 

  118. 118.

    Kutler, D. I. et al. Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J. Natl Cancer Inst. 95, 1718–1721 (2003).

    CAS  PubMed  Google Scholar 

  119. 119.

    van Zeeburg, H. J., Snijders, P. J., Joenje, H. & Brakenhoff, R. H. Re: human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J. Natl Cancer Inst. 96, 968 (2004).

    PubMed  Google Scholar 

  120. 120.

    Hira, A. et al. Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients. Blood 122, 3206–3209 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Tyburczy, M. E. et al. Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex. Hum. Mol. Genet. 23, 2023–2029 (2014).

    CAS  PubMed  Google Scholar 

  122. 122.

    Henske, E. P., Jozwiak, S., Kingswood, J. C., Sampson, J. R. & Thiele, E. A. Tuberous sclerosis complex. Nat. Rev. Dis. Prim. 2, 16035 (2016).

    PubMed  Google Scholar 

  123. 123.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Yeung, R. S. et al. Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc. Natl Acad. Sci. USA 91, 11413–11416 (1994).

    CAS  PubMed  Google Scholar 

  125. 125.

    Cook, J. D. et al. Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc. Natl Acad. Sci. USA 102, 8644–8649 (2005).

    CAS  PubMed  Google Scholar 

  126. 126.

    Nickerson, M. L. et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2, 157–164 (2002).

    CAS  PubMed  Google Scholar 

  127. 127.

    Schmidt, L. S. & Linehan, W. M. Molecular genetics and clinical features of Birt-Hogg-Dube syndrome. Nat. Rev. Urol. 12, 558–569 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    de Kock, L., Wu, M. K. & Foulkes, W. D. Ten years of DICER1 mutations: provenance, distribution, and associated phenotypes. Hum. Mutat. 40, 1939–1953 (2019).

    PubMed  Google Scholar 

  129. 129.

    Miniati, D. N. et al. Prenatal presentation and outcome of children with pleuropulmonary blastoma. J. Pediatr. Surg. 41, 66–71 (2006).

    PubMed  Google Scholar 

  130. 130.

    Kurzynska-Kokorniak, A. et al. The many faces of Dicer: the complexity of the mechanisms regulating Dicer gene expression and enzyme activities. Nucleic Acids Res. 43, 4365–4380 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Gross, T. J. et al. A microRNA processing defect in smokers’ macrophages is linked to SUMOylation of the endonuclease DICER. J. Biol. Chem. 289, 12823–12834 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Taeubner, J. et al. Penetrance and expressivity in inherited cancer predisposing syndromes. Trends Cancer 4, 718–728 (2018).

    CAS  PubMed  Google Scholar 

  133. 133.

    Petljak, M. & Alexandrov, L. B. Understanding mutagenesis through delineation of mutational signatures in human cancer. Carcinogenesis 37, 531–540 (2016).

    CAS  PubMed  Google Scholar 

  134. 134.

    Nones, K. et al. Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers. Ann. Oncol. 30, 1071–1079 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Castellsague, E. et al. Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures. Hum. Mutat. 40, 36–41 (2019).

    CAS  PubMed  Google Scholar 

  137. 137.

    Polak, P. et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat. Genet. 49, 1476–1486 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Kucab, J. E. et al. A compendium of mutational signatures of environmental agents. Cell 177, 821–836 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Alexandrov, L. B. et al. Mutational signatures associated with tobacco smoking in human cancer. Science 354, 618–622 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Wild, C. P., Scalbert, A. & Herceg, Z. Measuring the exposome: a powerful basis for evaluating environmental exposures and cancer risk. Env. Mol. Mutagen. 54, 480–499 (2013).

    CAS  Google Scholar 

  141. 141.

    Nik-Zainal, S. et al. The genome as a record of environmental exposure. Mutagenesis 30, 763–770 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Herceg, Z. et al. Roadmap for investigating epigenome deregulation and environmental origins of cancer. Int. J. Cancer 142, 874–882 (2018).

    CAS  PubMed  Google Scholar 

  143. 143.

    Siddeek, B., Mauduit, C., Simeoni, U. & Benahmed, M. Sperm epigenome as a marker of environmental exposure and lifestyle, at the origin of diseases inheritance. Mutat. Res. 778, 38–44 (2018).

    CAS  PubMed  Google Scholar 

  144. 144.

    Johansson, A. et al. Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk. Clin. Epigenetics 11, 66 (2019).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Martin, E. M. & Fry, R. C. Environmental Influences on the epigenome: exposure- associated DNA methylation in human populations. Annu. Rev. Public. Health 39, 309–333 (2018).

    PubMed  Google Scholar 

  146. 146.

    Nik-Zainal, S. et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47–54 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Degasperi, A. et al. A practical framework and online tool for mutational signature analyses show inter-tissue variation and driver dependencies. Nat. Cancer 1, 249–263 (2020).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Turnbull, C. et al. The 100 000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ 361, k1687 (2018).

    PubMed  Google Scholar 

  149. 149.

    Elliott, P., Peakman, T. C. & Biobank, U. K. The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. Int. J. Epidemiol. 37, 234–244 (2008).

    PubMed  Google Scholar 

  150. 150.

    Manolio, T. A. et al. New models for large prospective studies: is there a better way? Am. J. Epidemiol. 175, 859–866 (2012).

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Sullivan, F., McKinstry, B. & Vasishta, S. The “All of Us” research program. N. Engl. J. Med. 381, 1883–1884 (2019).

    PubMed  Google Scholar 

  152. 152.

    Mouse Genome Sequencing Consortium. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

    Google Scholar 

  153. 153.

    Moresco, E. M., Li, X. & Beutler, B. Going forward with genetics: recent technological advances and forward genetics in mice. Am. J. Pathol. 182, 1462–1473 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Arnold, C. N. et al. ENU-induced phenovariance in mice: inferences from 587 mutations. BMC Res. Notes 5, 577 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Wang, T. et al. Real-time resolution of point mutations that cause phenovariance in mice. Proc. Natl Acad. Sci. USA 112, E440–E449 (2015).

    CAS  PubMed  Google Scholar 

  156. 156.

    Mager, L. F. et al. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. J. Clin. Invest. 125, 2579–2591 (2015).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    de Vos tot Nederveen Cappel, W. H. et al. Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis. Colon. Rectum 45, 1588–1594 (2002).

    PubMed  Google Scholar 

  158. 158.

    Jarvinen, H. J. et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118, 829–834 (2000).

    CAS  PubMed  Google Scholar 

  159. 159.

    Schmeler, K. M. et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N. Engl. J. Med. 354, 261–269 (2006).

    CAS  PubMed  Google Scholar 

  160. 160.

    Lynch, H. T., Snyder, C. L., Lynch, J. F., Riley, B. D. & Rubinstein, W. S. Hereditary breast-ovarian cancer at the bedside: role of the medical oncologist. J. Clin. Oncol. 21, 740–753 (2003).

    PubMed  Google Scholar 

  161. 161.

    Kratz, C. P. et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin. Cancer Res. 23, e38–e45 (2017).

    CAS  PubMed  Google Scholar 

  162. 162.

    Vogel, W. H. Li-Fraumeni syndrome. J. Adv. Pract. Oncol. 8, 742–746 (2017).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Pastorino, S. et al. A subset of mesotheliomas with improved survival occurring in carriers of BAP1 and other germline mutations. J. Clin. Oncol. 36, 3485–3494 (2018).

    CAS  PubMed Central  Google Scholar 

  164. 164.

    Baumann, F. et al. Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis 36, 76–81 (2015).

    CAS  PubMed  Google Scholar 

  165. 165.

    Kobrinski, D. A., Yang, H. & Kittaneh, M. BAP1: role in carcinogenesis and clinical implications. Transl Lung Cancer Res. 9 (Suppl. 1), S60–S66 (2019).

    Google Scholar 

  166. 166.

    Wang, P. Y. et al. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. J. Clin. Invest. 127, 132–136 (2017).

    PubMed  Google Scholar 

  167. 167.

    Achatz, M. I., Hainaut, P. & Ashton-Prolla, P. Highly prevalent TP53 mutation predisposing to many cancers in the Brazilian population: a case for newborn screening? Lancet Oncol. 10, 920–925 (2009).

    PubMed  Google Scholar 

  168. 168.

    Achatz, M. I. & Zambetti, G. P. The inherited p53 mutation in the Brazilian population. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a026195 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  169. 169.

    DiGiammarino, E. L. et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat. Struct. Biol. 9, 12–16 (2002).

    CAS  PubMed  Google Scholar 

  170. 170.

    Park, J. H. et al. Mouse homolog of the human TP53 R337H mutation reveals its role in tumorigenesis. Cancer Res. 78, 5375–5383 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Macedo, G. S. et al. Increased oxidative damage in carriers of the germline TP53 p.R337H mutation. PLoS One 7, e47010 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Mouw, K. W., Goldberg, M. S., Konstantinopoulos, P. A. & D’Andrea, A. D. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 7, 675–693 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Reuter, S., Gupta, S. C., Chaturvedi, M. M. & Aggarwal, B. B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med. 49, 1603–1616 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Craven, P. A. & DeRubertis, F. R. Effects of aspirin on 1,2-dimethylhydrazine-induced colonic carcinogenesis. Carcinogenesis 13, 541–546 (1992).

    CAS  PubMed  Google Scholar 

  175. 175.

    Sheng, H. et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J. Clin. Invest. 99, 2254–2259 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Barnes, C. J. & Lee, M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology 114, 873–877 (1998).

    CAS  PubMed  Google Scholar 

  177. 177.

    Beck, S. L. Effects of aspirin on colorectal cancer related to lynch syndrome. J. Adv. Pract. Oncol. 3, 395–398 (2012).

    PubMed  PubMed Central  Google Scholar 

  178. 178.

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Franz, D. N. et al. Long-term use of everolimus in patients with tuberous sclerosis complex: final results from the EXIST-1 study. PLoS One 11, e0158476 (2016).

    PubMed  PubMed Central  Google Scholar 

  180. 180.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03207347 (2020).

  181. 181.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01981525 (2020).

  182. 182.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03448718. (2020).

  183. 183.

    Smith, A. J., Oertle, J. & Prato, D. Environmental carcinogens and the kinds of cancers they cause. Open J. Oncol. (2014).

  184. 184.

    Yoshida, K. et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature 578, 266–272 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Merlino, G. & Noonan, F. P. Modeling gene-environment interactions in malignant melanoma. Trends Mol. Med. 9, 102–108 (2003).

    CAS  PubMed  Google Scholar 

  186. 186.

    Pritchard, C. C. et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375, 443–453 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Panou, V. et al. Frequency of germline mutations in cancer susceptibility genes in Malignant Mesothelioma. J. Clin. Oncol. 36, 2863–2871 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Hassan, R. et al. Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy. Proc. Natl Acad. Sci. USA 116, 9008–9013 (2019).

    CAS  PubMed  Google Scholar 

  189. 189.

    Guerin, A. et al. IRF4 haploinsufficiency in a family with Whipple’s disease. eLife 7, e32340 (2018).

    PubMed  PubMed Central  Google Scholar 

  190. 190.

    Boisson-Dupuis, S. et al. Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant. Sci. Immunol. 3, eaau8714 (2018).

    PubMed  PubMed Central  Google Scholar 

  191. 191.

    Cirulli, E. T. et al. Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts. Nat. Commun. 11, 542 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Ciccia, A. & Elledge, S. J. The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    CAS  PubMed  Google Scholar 

  194. 194.

    Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).

    CAS  PubMed  Google Scholar 

  195. 195.

    Hsu, P. P. & Sabatini, D. M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Warburg, O. On respiratory impairment in cancer cells. Science 124, 269–270 (1956).

    CAS  PubMed  Google Scholar 

  197. 197.

    Porporato, P. E., Filigheddu, N., Pedro, J. M. B., Kroemer, G. & Galluzzi, L. Mitochondrial metabolism and cancer. Cell Res. 28, 265–280 (2018).

    CAS  PubMed  Google Scholar 

  198. 198.

    Peel, J. B. et al. A prospective study of cardiorespiratory fitness and breast cancer mortality. Med. Sci. Sports Exerc. 41, 742–748 (2009).

    PubMed  PubMed Central  Google Scholar 

  199. 199.

    LeBleu, V. S. et al. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16, 1001–1015 (2014).

    Google Scholar 

  200. 200.

    Tan, A. S. et al. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 21, 81–94 (2015).

    CAS  Google Scholar 

  201. 201.

    Sullivan, L. B., Gui, D. Y. & Vander Heiden, M. G. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat. Rev. Cancer 16, 680–693 (2016).

    CAS  PubMed  Google Scholar 

  202. 202.

    Gottlieb, E. & Tomlinson, I. P. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat. Rev. Cancer 5, 857–866 (2005).

    CAS  PubMed  Google Scholar 

  203. 203.

    Sciacovelli, M. & Frezza, C. Oncometabolites: unconventional triggers of oncogenic signalling cascades. Free Radic. Biol. Med. 100, 175–181 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206.

    Inoue, S. et al. Mutant IDH1 downregulates ATM and alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell 30, 337–348 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207.

    Nowicki, S. & Gottlieb, E. Oncometabolites: tailoring our genes. FEBS J. 282, 2796–2805 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208.

    Sabharwal, S. S. & Schumacker, P. T. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat. Rev. Cancer 14, 709–721 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209.

    Sumpter, R. Jr. et al. Fanconi anemia proteins function in mitophagy and immunity. Cell 165, 867–881 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210.

    Weinberg, C. R., Brown, K. G. & Hoel, D. G. Altitude, radiation, and mortality from cancer and heart disease. Radiat. Res. 112, 381–390 (1987).

    CAS  PubMed  Google Scholar 

  211. 211.

    Sung, H. J. et al. Ambient oxygen promotes tumorigenesis. PLoS One 6, e19785 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212.

    Simeonov, K. P. & Himmelstein, D. S. Lung cancer incidence decreases with elevation: evidence for oxygen as an inhaled carcinogen. PeerJ 3, e705 (2014).

    Google Scholar 

  213. 213.

    Sung, H. J. et al. Mitochondrial respiration protects against oxygen-associated DNA damage. Nat. Commun. 1, 1–8 (2010).

    CAS  Google Scholar 

  214. 214.

    Harris, I. S. et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27, 211–222 (2015).

    CAS  PubMed  Google Scholar 

  215. 215.

    Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug. Discov. 12, 931–947 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Funding for travel costs and lodging for the co-authors to meet in person and critically discuss and write the manuscript was provided by a generous donation from the Barry and Virginia Weinman Foundation.

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Authors

Contributions

M.C. researched the data for the article. All authors contributed substantially to discussions of the content. All authors contributed to writing the article and to reviewing and/or editing the manuscript before submission.

Corresponding author

Correspondence to Michele Carbone.

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Competing interests

M.C. and H.Y. report funding from the US National Institute of Environmental Health Sciences (1R01ES030948-01 (M.C and H.Y.)), the US National Cancer Institute (1R01CA237235-01A1 (M.C. and H.Y.) and 1R01CA198138 (M.C.)), the US Department of Defense (CA150671 (M.C. and H.Y.)) and the University of Hawai’i Foundation through donations from Riviera United-4 a Cure (M.C. and H.Y.), the Melohn Family Endowment, Honeywell International Inc., the Germaine Hope Brennan Foundation and the Maurice and Joanna Sullivan Family Foundation (M.C.). M.C. has a patent issued entitled ‘Methods for diagnosing a predisposition to develop cancer’. M.C. and H.Y. have a patent issued entitled ‘Using anti-HMGB1 monoclonal antibody or other HMGB1 antibodies as a novel mesothelioma therapeutic strategy’ and a patent issued entitled ‘HMGB1 as a biomarker for asbestos exposure and mesothelioma early detection’. M.C. is a board-certified pathologist who provides consultation for pleural pathology, including medical–legal consultation. A.D. receives research funding from Eli Lilly and Merck KGaA (EMD Serono), has served on advisory boards for Eli Lilly, Merck KGaA (EMD Serono), Sierra Oncology, Intellia and Formation Biologics and holds equity in Ideaya Inc., Cyteir Therapeutics and Cedilla Therapeutics Inc. I.D.H. is supported by the Danish National Research Foundation (grant no. DNRF115) and by the Nordea Foundation. R.J.M. is supported by grants from the US National Cancer Institute, the US National Heart, Lung and Blood Institute and the Fanconi Anemia Research Fund.. The work of R.J.M. is funded by US National Institutes of Health award NCI P01 077852 and by research awards from the Fanconi Anemia Research Fund and the US Department of Defense Bone Marrow Failure Program. R.J.M. holds equity in bluebird bio and has performed consulting work for Flagship Pioneering. H.I.P. reports funding from the US National Cancer Institute, the US Department of Defense, the US Centers for Disease Control and Prevention, Genentech, and Belluck & Fox. R.D.K. received research support from the US National Institutes of Health (GM26017 and GM50006) and the Ludwig Institute for Cancer Research. He is an inventor on patents covering many aspects of mismatch repair genes, all of which are assigned to the Dana-Farber Cancer Institute. L.S.S. reports funding in part through US federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. J.H.P. is supported by US National Institute of General Medical Science and US National Cancer Institute grants and the Memorial Sloan-Kettering Cancer Center Core Grant P30 CA008748, licenses reagents through Novus Biologicals and is a consultant for ATROPOS Therapeutics. H.I.P and H.Y. received research support for the Early Detection Research Network, US National Cancer Institute (U01CA111295-08). S.T.A., B.B., A.B., W.C., J.E.C., C.M.C., W.D.F., G.G., J.L.G., E.P.H., P.M.H., T.W.M., D.M. and F.N., declare no competing interests.

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Related links

Cancer Gene Census: https://cancer.sanger.ac.uk/census

Mutagenesis protocol: http://mutagenetix.utsouthwestern.edu

Glossary

Asbestos fibres

For regulatory purposes, six of ~400 mineral fibres naturally present in the environment were collectively named ‘asbestos’ and their use was prohibited or severely restricted in the past decades in the USA, Australia and western Europe. The remaining ~394 mineral fibres are not regulated and thus can and have been used and have caused human exposure and mesothelioma, among them erionite.

Base excision repair

(BER). A repair system that removes single-base damage from alkylating agents or reactive oxygen species. One branch consists of a glycosylase that cleaves the base–deoxyribose bond, leaving an apurinic site that is subsequently cleaved and replaced by a small one-to-two-base patch. Formation of a longer patch branch involves the activity of CSB, XRCC1 and PARP1.

Cancer syndromes

Those tumour predisposition syndromes in which close to 100% of carriers develop one or more cancers during their lifetime. Examples include Li–Fraumeni syndrome (~95% of women carriers develop cancer) and BAP1 cancer syndrome (~100% of carriers develop cancer), which are caused by heterozygous autosomal dominant mutations of the TP53 and BAP1 genes, respectively.

DICER1

An endonuclease implicated in microRNA biogenesis and the specific regulation of mRNAs. This mainly cytoplasmic enzyme cleaves precursor hairpin microRNAs to produce mature microRNAs (known as 5′ microRNA and 3′ microRNA, one of which will be loaded onto the RNA-induced silencing complex (RISC), ultimately resulting in downregulation or silencing of the targeted mRNAs).

DNA helicases

Enzymes that unwind the two strands of the DNA helix, a process needed for all aspects of DNA metabolism that in turn is important for DNA replication and repair.

DNA interstrand crosslinks

Covalent bonds between bases on opposite strands of DNA.

Global genome repair

(GGR). A branch of nucleotide excision repair that predominantly occurs in non-transcribed DNA and non-transcribed strands of expressed genes. Damage recognition involves two DNA-binding proteins, xeroderma pigmentosum group C-complementing protein (XPC) and XPE. Subsequent steps involving DNA unwinding, incision, polymerization and ligation are common to GGR and transcription-coupled repair.

Homologous recombination

(HR). This process is essential for the repair of double-strand DNA breaks and consists of an exchange or replacement of a segment of parental DNA with a segment having the homologous sequence from a partner DNA.

Homologues

Genes related to second genes by descent from a common ancestral DNA sequence.

Mitochondrial respiration

Also referred to as oxidative phosphorylation, this is a process that occurs in mitochondria and provides the major source of ATP in aerobic organisms.

Mitophagy

Autophagic removal of damaged mitochondria.

Multiplex ligation-dependent probe amplification

(MLPA). A multiplex polymerase chain reaction method used to detect larger DNA deletions and copy number variations, which are often missed by next-generation sequencing and Sanger sequencing.

Next-generation sequencing

(NGS). A high-throughput sequencing technique that allows rapid simultaneous sequencing of the DNA or RNA of multiple genes. Designed to detect nucleotide-level mutations, it largely replaced manual Sanger sequencing, although this is used to confirm pathogenic mutations detected by NGS.

Non-homologous end joining

(NHEJ). An error-prone DNA double-strand break repair process that entails rejoining of DNA breaks without reliance on a homologous template.

Nucleotide excision repair

(NER). The process by which ultraviolet light-induced DNA lesions and other large adducts, such as those induced by N-2-acetylaminofluorene or benzo[a]pyrene, are repaired.

Orthologues

Genes in different species that evolved from a common ancestral gene by speciation. Usually, orthologues retain the same function in the course of evolution.

Penetrance

The likelihood that a person who has a certain disease-causing mutation in a gene will show signs and symptoms of the disease.

Spliceosomes

Molecular complexes involved in removing introns (intervening sequences between coding sequences) from the primary RNA transcript.

Sumoylation

A process by which proteins are post-translationally modified by the covalent addition of small ubiquitin-like modifier proteins through lysine side chains, resulting in a remodelling of the surface of these proteins, thereby affecting their function in three main ways: through inhibition of the usual interaction between the target of sumoylation and another protein, through provision of a new binding surface and through conformational changes in the target protein.

Targeted NGS

(t-NGS). A commercial or custom gene panel that targets the exons of specific sets of genes (for example, all tumour suppressor genes).

Transcription-coupled repair

(TCR). A branch of nucleotide excision repair that predominantly occurs on the transcribed strand of expressed genes. Damage recognition involves RNA polymerase II arrest at damage in transcribed strands that is relieved by the action of CSA, CSB and UV-stimulated scaffold protein A (UVSSA). Subsequent steps involving DNA incision, polymerization and ligation are common to global genome repair and TCR.

Tumour predisposition syndromes

(TPSs). Affected individuals are predisposed to benign and/or malignant tumours. Depending on the gene that is mutated, a variable fraction of mutation carriers develop one or more tumours during their lifetime. TPSs can be caused by heterozygous (autosomal dominant) or homozygous (autosomal recessive) mutations.

Whole-exome sequencing

(WES). All exons in the genome are sequenced.

Whole-genome sequencing

(WGS). All of the genome including introns is sequenced. Identifies both nucleotide-level deletions and large DNA deletions, but the interpretation of the data requires special expertise and the use of supercomputers that can handle the very large amount of data.

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Carbone, M., Arron, S.T., Beutler, B. et al. Tumour predisposition and cancer syndromes as models to study gene–environment interactions. Nat Rev Cancer 20, 533–549 (2020). https://doi.org/10.1038/s41568-020-0265-y

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