Histopathologists are often involved in the diagnosis of genetic tumour syndromes (GTS) by flagging up the possibility of these disorders. Some specific tumour types strongly correlate with syndromic diseases, and clustering of multiple tumours or more than one tumour type, or associated non-tumour syndromic features may raise the possibility of a GTS. The appearance of the tumour, clinical presentation, age of the patient and other characteristics can also be important. While the recognition of GTS can sometimes be a rather haphazard process, the importance of recognising such syndromes is increasing as preventative treatment and/or screening becomes available to prevent cancers in affected individuals and their families.1 The management of tumours in patients with GTS may also vary from sporadic tumours. The tumour board/multidisciplinary team meeting can greatly assist the process of coordinating the different specialties involved. While individual GTS may be rare, it is not uncommon for a GTS to be involved in cancers seen by pathologists: approximately 10% of cancers are believed to be associated with genetic predisposition, and this percentage is considerably higher in children and young adults.2 The WHO Classification of Tumours3 has recently produced the classification of GTS to assist this process and provide a framework for future research in the field. Prior to this, GTS were incorporated in many of the volumes of the organ-based classification of tumours, usually in the last chapter. This was increasingly unsatisfactory as it tended to highlight some common syndromes from the perspective of the subject of the volume, rather than allowing a more comprehensive approach. The solution was to have a separate volume on GTS. This then required a classification, for which there was no precedent. After consultation with interested organisations and individuals from the pathology and genetics communities, the WHO Classification of Tumours editorial board approved a hierarchical GTS classification based on the cellular mechanism affected, the molecular pathway altered and the gene(s) mutated. Chapters were sequenced from mechanisms anchored around cell surface molecules, progressing in a cytosolic direction on to intracellular pathways, then into the nucleus with DNA and epigenetic regulation, on to RNA and then protein regulation. Selection of syndromes to include was at times difficult and there were space limitations in this first edition of the GTS classification that precluded some from inclusion. It is expected that the classification will evolve with time to include some that have been omitted or included as subtypes (e.g. MicroRNA processor tumour predisposition syndromes, where two genes, DROSHA and DGCR8, may be regarded as separate syndromes in the future). Syndromes resulting in leukaemia or lymphoma have proven particularly difficult, and these issues are discussed in a separate introduction in the volume; some evolution of the classification in this area is expected in the future. The cellular mechanisms that formed the overarching distinction between families of related GTS comprise the following: Growth factor receptors and related signalling pathways; Oxidative stress response and metabolism; Cell cycle and apoptosis pathways; DNA repair and genomic stability; Telomere maintenance; Epigenetic drivers and chromatin remodelling; RNA regulation; Protein regulation. Within these pathways, specific molecular pathways are readily identified, allowing families of more closely related GTS to be distinguished. Many of the key genes within these pathways have recognised GTS, although there are some notable absences. For instance, syndromes associated with growth factor receptor kinases such as MET and RET are well represented, but there are no known syndromes associated with their ligands. Within the RAS-MAPK pathway, neurofibromatosis is probably the best-known syndrome, while PKA signalling includes Carney complex. The WNT/TGFbeta pathway is involved in cell differentiation. Ten syndromes, including familial adenomatous polyposis due to APC germline pathogenic variants (GPVs), multiple endocrine neoplasia type 1 (MEN1) and Peutz-Jeghers syndrome (due to STK11 GPVs) are part of this family. While there are relatively few syndromes listed under oxidative stress and metabolism, these include the angiogenesis-related Von Hippel-Lindau syndrome (VHL) and the Krebs cycle related SDH-deficient tumour syndromes. The latter is the cause of hereditary phaeochromocytoma-paraganglioma syndromes due to mutation of SDHA, SDHB, SDHC, SDHD or SDHAF2. Cell cycle and apoptosis-related pathways are involved in several well-known syndromes, particularly Li-Fraumeni syndrome, related to TP53 GPVs, and retinoblastoma. DNA repair and genomic stability are related to a large number of syndromes, with all DNA repair pathways represented, as well as those due to alterations of genes involved in DNA polymerisation and chromosomal non-disjunction resulting in aneuploidy. The most common ones are Lynch syndrome and related mismatch repair deficiency syndromes, and the homologous recombination repair pathway genes, particularly BRCA1 and BRCA2. Disorders of telomere biology are responsible for dyskeratosis congenita as well as the POT1 and shelterin-related tumour predisposition syndromes (involving POT1, ACD, TERF2IP and TERT promoter). Epigenetic drivers and chromatin remodelling include IDH1 and IDH2 mutation, responsible for enchondromatosis, while SMARCB1 is involved in rhabdoid tumour predisposition as well as schwannomatosis, and SMARCE1 for clear cell meningioma predisposition. RNA regulation by microRNAs can be disrupted by DICER1 GPVs leading to the formation of a variety of benign and malignant neoplasms involving multiple organ systems, including pleuropulmonary blastoma, thyroid cancers, paediatric cystic nephroma and embryonal rhabdomyosarcoma. These are often first recognised by histopathologists. Finally, only one syndrome is so far included under protein regulation, but this is the important BAP1-related tumour predisposition syndrome, a cause of familial mesothelioma, though also causing a wide variety of other tumour types (e.g. uveal melanoma and clear cell renal carcinoma). The terminology associated with genetics and that used by pathologists sometimes causes issues, and we have taken a pragmatic approach to this, to harmonise the terms used and avoid confusion between disciplines, or indeed in the minds of patients and their families. We have included a small glossary to assist and have reproduced this here (Table 1). The decision to call these disorders ‘genetic tumour predisposition syndromes’ (with ‘genetic tumour syndromes’ as the shortened form), rather than ‘familial’ or ‘hereditary’ was made to allow inclusion of syndromes that are often the result of de novo or post-zygotic mutation. The use of the term ‘predisposition’ is important as not all affected individuals may develop tumours, despite being predisposed. Equally, ‘germline’ was preferred for pathogenic sequence variants rather than ‘constitutional’ as the former is used more widely within PubMed and general literature, and the latter has some linguistic difficulties that may cause confusion with consanguinity. Pathogenic DNA sequence variants (colloquially known as mutations) need to be reported accurately, so we have included a set of guidelines for reporting these which should be used by all disciplines, based on the nomenclature published by the Human Genome Variation Society (HGVS).4-6 However, we recognise that compliance is sometimes difficult due to common usage and have taken the pragmatic approach of citing these as well as ensuring that we provide the correct HGVS nomenclature. The naming of syndromes remains rather arbitrary, although eponymous names are slowly changing towards a dyadic gene-related naming system based on the HGNC (HUGO Gene Nomenclature Committee) gene symbol7 followed by the cancer predisposition (e.g. BAP1-related tumour predisposition syndrome) as recently recommended by the Clinical Genome Resource working with OMIM and Monarch Initiative.8 We have adopted the approach used for tumour types in the 5th edition, citing the most commonly accepted term followed by the name of the primary driver gene(s) between parentheses, while giving the alternative terminology and indicating whether it is regarded by the editors as acceptable, or not recommended. The WHO Classification of GTS represents an important advance in the field, which should assist the collection of high-quality evidence and the future evolution of thinking about genetic tumour predisposition syndromes with consistent nomenclature. The authors and editors very much hope that it will stimulate research to answer questions and fill knowledge gaps, and that it will benefit the surveillance, chemoprevention, risk-reduction and treatment of those who suffer from these conditions. IC conceived and drafted the manuscript, to which all of the authors contributed. This editorial introduces the classification, which has been edited, seen and approved by all authors. We are grateful to all those who contributed to this classification as authors, editors and the WHO Classification of Tumours team at IARC. EB is currently funded by the National Human Genome Research Institute (NHGRI) grant U24HG003345. SP is currently funded by the National Human Genome Research Institute (NHGRI) grant U24HG009649. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no competing interests. The content of this article represents the personal views of the authors and does not represent the views of the authors' employers and associated institutions. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. The open access outline of the WHO Classification of Genetic Tumour Syndromes is available at https://whobluebooks.iarc.fr/structures/genetic-tumour-syndromes/, and the full classification is available to subscribers at https://tumourclassification.iarc.who.int/.
Cree et al. (2026) studied this question.