Platinum Priority – Review – Kidney CancerEditorial by Marshall Strother and Alexander Kutikov on pp. 765–766 of this issueFamilial Kidney Cancer: Implications of New Syndromes and Molecular Insights
Introduction
Worldwide, there is an increasing incidence of renal cell carcinoma (RCC), with over 400 000 new cases estimated in 2018 [1]. RCC encompasses many histological subtypes with different molecular drivers [2]. Clear cell RCC (ccRCC) is the most prevalent subtype, accounting for about 75%. The remaining subtypes include papillary, chromophobe, MiT family translocation, and other rare types. Many of these histologies are associated with distinct RCC hereditary syndromes. In 2016, the World Health Organization (WHO) classification of tumours included subtypes specifically associated with genetic syndromes, including hereditary leiomyomatosis and RCC (HLRCC) syndrome, and succinate dehydrogenase (SDH)-deficient RCC [3]. With recent advances in pathological and molecular characterisation, hereditary aetiologies are becoming more evident. Urologists, medical oncologists, and other practitioners play a critical role in identifying familial RCC.
Since the last review in this journal in 2010, there have been advances in our understanding of the genetics of RCC, and several new hereditary syndromes have been described [4]. This review will update genetic and clinical features of the well-characterised and emerging hereditary RCC syndromes. We will discuss contemporary surgical and medical management of bilateral and metastatic familial RCC, and comment on screening and appropriate workup for suspicious cases seen in the clinic.
Section snippets
Evidence acquisition
Data for this review were acquired by searches of PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) and Online Mendelian Inheritance in Man (OMIM; http://www.ncbi.nlm.nih.gov/omim/) using combinations of these terms: hereditary, kidney cancer, clinical criteria, von Hippel-Lindau syndrome, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis RCC, BAP1 RCC, PTEN RCC, hereditary papillary RCC, tuberous sclerosis complex, MITF predisposition to familial RCC, hereditary hyperparathyroidism jaw tumour
Prevalence of hereditary RCC syndromes and recognition of patients with familial renal tumours
Until recently, there were no large-scale studies analysing the prevalence of germline, likely pathogenic or pathogenic, variants (henceforth, referred together as “pathogenic variants”) in RCC cases. With the Cancer Genome Atlas (TCGA) efforts, the germline was also analysed, which provides an estimate in such a population [5]. Of 387 cases of ccRCC, 6% had a germline pathogenic variant. In papillary and chromophobe cases, 9% and 6%, respectively, had a germline pathogenic variant. Although
Conclusions
Hereditary RCC syndromes are caused by several different genetic alterations, and involve a wide spectrum of clinical manifestations and varying incidences of RCC. With advances in sequencing and more widespread applications, new genetic causes of RCC are being uncovered. The molecular pathways involved in the pathogenesis of VHL-associated ccRCC were successfully exploited in the development of anti-VEGF agents now standard for sporadic RCC. Similarly, the last few years have seen exciting
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These authors contributed equally.