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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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.
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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Cancer Gene Census: https://cancer.sanger.ac.uk/census
Mutagenesis protocol: http://mutagenetix.utsouthwestern.edu
- 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.
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.
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.
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.
Genes in different species that evolved from a common ancestral gene by speciation. Usually, orthologues retain the same function in the course of evolution.
The likelihood that a person who has a certain disease-causing mutation in a gene will show signs and symptoms of the disease.
Molecular complexes involved in removing introns (intervening sequences between coding sequences) from the primary RNA transcript.
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