Familial Kidney Cancer: Implications of New Syndromes and Molecular Insights

doi:10.1016/j.eururo.2019.06.015

European Urology

Volume 76, Issue 6, December 2019, Pages 754-764

https://doi.org/10.1016/j.eururo.2019.06.015 Get rights and content

Abstract

Context

Hereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few years.

Objective

To review and summarise the recent preclinical and clinical literature in hereditary renal cancer.

Evidence acquisition

A systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management.

Evidence synthesis

Several autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy.

Conclusions

There are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection.

Patient summary

This review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.

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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Referral patterns and genetic testing outcomes in a contemporary hereditary renal cancer clinic
2024, Urologic Oncology: Seminars and Original Investigations
Multidisciplinary hereditary tumor clinics are a collaborative format to identify and treat patients with genetic cancer predispositions. The hereditary renal cancer clinic at Indiana University is comprised of a urologic oncologist, medical oncologist, clinical geneticist, and genetic counselor. The clinic holds regular tumor board meetings, where patient histories, pedigrees, imaging, pathology, and management plans are collectively reviewed and discussed. Here we report the contemporary experience for our hereditary renal cancer clinic, with description and analysis of referral patterns, patient profiles, and genetic testing outcomes.
A retrospective review of an IRB-approved, prospectively maintained database of patients seen in the hereditary renal cancer clinic was performed. Patient characteristics, genetic testing results, and disease characteristics were reported and analyzed.
A total of 142 patients seen in clinics from January 2018 to June 2023 were included. Patient's median age was between 40 and 49 years old, and 88.7% were Caucasian. The most common reasons for referral were early-onset renal tumors (40%), known hereditary renal cancer syndrome (29%), and hereditary renal cancer syndrome screening (13%). Of those with a tissue diagnosis of renal cell carcinoma, 46.2% were clear cell subtype. The presence of nonrenal syndromic features concerning for hereditary renal tumor syndrome was predictive of pathogenic mutation identification (OR 13.45, P < 0.0001). Patient race and presence of multifocal tumors were not predictive of pathogenic mutation identification. When restricting analysis to patients with an established renal malignancy, high-grade tumor histology was predictive of a pathogenic mutation (OR 8.17, P = 0.012), though higher pathologic stage and nonclear cell histology were not. Referral for early-onset renal tumor (age < 45 years) predicted lower likelihood of pathogenic mutations (OR 0.10, P = 0.0002). FH gene mutations were the most commonly identified pathogenic mutations. Genetic testing of family members (cascade testing) was recommended to 9 patients seen in clinic; a pathogenic mutation was subsequently identified in all but one of these families.
These findings are useful for referring physicians and patients in determining patient referral to hereditary cancer clinics, and for counseling patients undergoing genetic testing. Data from non-Caucasian patients and evolving implications of variants of unclear significance (VUS) may represent future research directions for hereditary renal cancer clinics.
Obesity and renal cell carcinoma: Biological mechanisms and perspectives
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Obesity, defined by body mass index (BMI), is an established risk factor for specific renal cell carcinoma (RCC) subtypes such as clear cell RCC, the most common RCC histology. Many studies have identified an association between obesity and improved survival after diagnosis of RCC, a potential “obesity paradox.” Clinically, there is uncertainty whether improved outcomes observed after diagnosis are driven by stage, type of treatment received, or artifacts of longitudinal changes in weight and body composition. The biological mechanisms underlying obesity’s influence on RCC are not fully established, but multiomic and mechanistic studies suggest an impact on tumor metabolism, particularly fatty acid metabolism, angiogenesis, and peritumoral inflammation, which are known to be key biological hallmarks of clear cell RCC. Conversely, high-intensity exercise associated with increased muscle mass may be a risk factor for renal medullary carcinoma, a rare RCC subtype that predominantly occurs in individuals with sickle hemoglobinopathies. Herein, we highlight methodologic challenges associated with studying the influence of obesity on RCC and review the clinical evidence and potential underlying mechanisms associating RCC with BMI and body composition.
Characterization of protein S-(2-succino)-cysteine (2SC) succination as a biomarker for fumarate hydratase–deficient renal cell carcinoma
2023, Human Pathology
Citation Excerpt :
Additionally, FH staining was retained in all 15 cases of non-FH- deficient RCC, which showed positivity for 2SC (Supplementary Figs. 3B and C). Patients with hereditary kidney cancer harbor various pathogenic germline variants associated with RCC and/or benign renal tumors [8, 20]. These hereditary tumors are frequently bilateral and/or multi-focal and may clinically present in younger individuals.
Fumarate hydratase (FH)–deficient renal cell carcinoma (RCC) is an aggressive, rare genetic disease affecting the kidney and other organ systems. We constructed a specialized multi-institutional cohort of 20 primary FH-deficient RCC cases with aims of characterizing a new commercially available antibody, S-(2-succino)-cysteine (2SC). Herein, we present our findings on the biomarker characterization and performance of 2SC expression by immunohistochemistry (IHC) in FH-deficient RCC and other common and rare RCC subtypes. Morphological assessment revealed characteristic cytomorphologic features and a majority (55%) of FH-deficient RCC had mixed architectural growth patterns. We observed predominantly diffuse and strong cytoplasmic staining with limited nuclear positivity for 2SC staining on IHC. Receiver operating characteristic curves (ROC) for 2SC identified the threshold IHC score (cutoff) as 90, with the sensitivity and specificity being 100% and 91%, respectively. The findings of the present study along with the prior evidence in literature encourage utilization of 2SC as a positive marker along with the loss of FH expression by anti-FH IHC staining as a negative marker, in clinical and/or pathologic scenarios when considering FH-deficient RCC in the differential diagnosis. FH⁻/2SC⁺ may serve as a comprehensive IHC panel in identifying such cases and excluding morphologically similar entities.
European Association of Urology Guidelines Panel on Renal Cell Carcinoma Update on the New World Health Organization Classification of Kidney Tumours 2022: The Urologist's Point of View
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Renal cell carcinoma (RCC) represents a group of diseases arising from renal tubule epithelial cells and constitutes approximately 90% of all kidney cancers. The major socioeconomic impact of this disease continues to grow with its rising incidence worldwide. More than 76,000 new diagnoses of kidney cancer are projected in the United States in 2021, and an estimated 13,780 patient deaths will be attributed to this disease. The majority of patients present with organ-confined RCC, and surgical resection of these tumors has generally resulted in excellent long-term survival outcomes. However, it is reported that up to 30% of newly diagnosed patients present with nodal or distant metastasis. Systemic therapy has historically been reserved for patients in this setting with advanced or metastatic RCC.
Epidemiology of Renal Cell Carcinoma: 2022 Update
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International variations in the rates of kidney cancer (KC) are considerable. An understanding of the risk factors for KC development is necessary to generate opportunities to reduce its incidence through prevention and surveillance.
To retrieve and summarize global incidence and mortality rates of KC and risk factors associated with its development, and to describe known familial syndromes and genetic alterations that represent biologic risk factors.
A systematic review was conducted via Medline (PubMed) and Scopus to include meta-analyses, reviews, and original studies regarding renal cell carcinoma, epidemiology, and risk factors.
Our narrative review provides a detailed analysis of KC incidence and mortality, with significant variations across time, geography, and sex. In particular, while KC incidence has continued to increase, mortality models have leveled off. Among the many risk factors, hypertension, obesity, and smoking are the most well established. The emergence of new genetic data coupled with observational data allows for integrated management and surveillance strategies for KC care.
KC incidence and mortality rates vary significantly by geography, sex, and age. Associations of the development of KC with modifiable and fixed risk factors such as obesity, hypertension, smoking, and chronic kidney disease (CKD)/end-stage kidney disease (ESKD) are well described. Recent advances in the genetic characterization of these cancers have led to a better understanding of the germline and somatic mutations that predispose patients to KC development, with potential for identification of therapeutic targets that may improve outcomes for these at-risk patients.
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^†: These authors contributed equally.

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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

Abstract

Context

Objective

Evidence acquisition

Evidence synthesis

Conclusions

Patient summary

Introduction

Section snippets

Evidence acquisition

Prevalence of hereditary RCC syndromes and recognition of patients with familial renal tumours

Conclusions

Eur Urol

Eur Urol

Eur Urol

Genet Med

Urol Oncol

Urol Clin North Am

J Urol

J Urol

Kidney Int

Hum Pathol

J Urol

J Urol

Lancet Oncol

Ann Oncol

Cancer Cell

Cancer Cell

Cancer Cell

Am J Hum Genet

Am J Pathol

J Urol

Mod Pathol

Am J Hum Genet

Lancet Oncol

Surg Pathol Clin

Am J Surg Pathol

Eur Urol

Lancet

Urology

J Urol

Pediatr Neurol

Eur J Cancer

Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

CA Cancer J Clin

Pathogenic germline variants in 10,389 adult cancers

Cell

Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management

J Clin Oncol

Advances in the diagnosis of hereditary kidney cancer: initial results of a multigene panel test

Cancer

Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma

JAMA Oncol

Genetic predisposition to renal cell carcinoma: implications for counseling, testing, screening, and management

J Clin Oncol

Von Hippel-Lindau disease: genetics and role of genetic counseling in a multiple neoplasia syndrome

J Clin Oncol

Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx Renal

Cell

Patient-specific factors influence somatic variation patterns in von Hippel-Lindau disease renal tumours

Nat Commun

Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype

Hum Mutat

Genotype-phenotype correlations in von Hippel-Lindau disease

Hum Mutat

VHL, the story of a tumour suppressor gene

Nat Rev Cancer

Spectrum of preneoplastic and neoplastic cystic lesions of the kidney

Arch Pathol Lab Med

Clear cell papillary renal cell carcinoma-like tumors in patients with von Hippel-Lindau disease are unrelated to sporadic clear cell papillary renal cell carcinoma

Am J Surg Pathol

Sunitinib treatment for metastatic renal cell carcinoma in patients with von Hippel-Lindau disease

Cancer Res Treat

Platinum Priority – Review – Kidney Cancer
Editorial by Marshall Strother and Alexander Kutikov on pp. 765–766 of this issue
Familial Kidney Cancer: Implications of New Syndromes and Molecular Insights