Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement

Abstract

Background Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions. Methods A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions. Results Thirty‐three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician‐based counseling and testing by those who have experience with hereditary RCC. Conclusions In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment. Lay Summary The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

“…In rare cases, characteristic histopathological features may suggest an underlying inherited disorder (e.g. SDH-deficient RCC, hybrid chromophobe-oncocytic and BHD syndrome), but, in general, in the absence of family history or multicentric disease, age at diagnosis seems to be the most practical approach (with 70% general consensus) ( 38 ) for stratifying genetic testing. Based on our results, testing a further 106 participants presenting between 45 and 50 years of age would enable detection of an extra 5 participants ( Supplementary Material, Table S4 ) .Therefore, we suggest that genetic testing should be extended to <50 years of age and that the small clinical gene panels currently used in the UK to be expanded to include CHEK2 , SDHA , SDHC and SDHD .…”

“…Though most centres offer testing to patients with features of an inherited cancer syndrome, there is less consensus for testing isolated non-syndromic cases. Within the UK, testing is offered to patients <40 years of age (or <50 years of age for pRCC), but internationally, it has been suggested that an age cut-off <46 years (equivalent to the 10th percentile) would maximize the sensitivity and specificity and an age cut-off of 50 has also been recommended (20,(36)(37)(38)(39). However, in our cohort, only 23.3% (14/60) of those with an RCC-CSG variant, were aged <46 years.…”

Family History and Risk of Renal Cell Carcinoma: A National Multiregister Case-Control Study

“…3,14,15 In a recently published consensus statement by Bratslavsky et al, 70% believed that age should be a single criterion for genetic investigation. 16 This is reasonable, given the strong association with hereditary RCC syndromes, but one must be aware, given the results of our study, that many investigations will be negative. In the same consensus statement, 90% considered a patient with RCC and concurrent RCC in a FDR to undergo generic investigation regardless of age.…”

Guidelines on Germline Testing for Urologic Tumor Syndromes

“…Many consensus recommendations based on expert opinion align with those of the AUA and NCCN related to multifocal tumors, family members with syndromic manifestations suggestive of a renal cancer syndrome, documented history of a renal cancer syndrome, and histology suggestive of renal cancer syndromes. Of note, consensus was not reached regarding a specific age at which to recommend genetic testing [12].…”