Surveillance for individuals with a strong family history of kidney cancer but no identified heritable disease: a UK consensus

Abstract

Genetic assessment for renal cell carcinoma (RCC) 31 frequently results in an uninformative result, namely, non-identification of a recognised heritable causative genetic variant. In many of these cases, there is a lack of the key features of a syndromic clinical phenotype suggestive of a specific hereditary condition. In this scenario, it is possible that either a combination of shared environmental and genetic risk factors or as yet unidentified monogenetic susceptibility may be responsible for the RCC; thus, the optimal surveillance strategy for the affected person (after RCC follow-up has ceased) and for their relatives in particular, is unclear.

Early detection of RCC is associated with a better prognosis, with 5-year survival of stage I disease in the order of 88.3% compared to 14% for those with stage 4 disease [1]. Imaging tests enabling early detection are widely available and are associated with a shift in stage at diagnosis [2]. For most RCC subtypes, the characteristics of identified renal masses, such as the size and complexity of renal cysts (Bosniak classification), can be used to decide the point at which to intervene. In middle-aged individuals in the general population, the sojourn time between radiologically evident (screen-detectable) kidney cancer and clinically meaningful diagnosis is estimated to be in the order of 3.7–5.8 years, [3] although growth is more rapid, and metastatic potential higher at smaller sizes, in individuals with certain monogenic syndromes predisposing to kidney cancer – most notably FH tumour predisposition syndrome [4].

There is a paucity of data regarding the incidence of RCC in relatives following comprehensive negative genetic assessment in a proband. However, a number of studies have been conducted that estimate the relative risk of RCC in individuals with a family history compared to those without. The largest of these utilised 8513 RCC cases in the Swedish Family Cancer Database [5] and showed a standardised incidence ratio of 1.75 (95% CI 1.49–2.04) in individuals with an affected parent; 2.61 (95% CI 2.00–3.34) in those with an affected sibling and 10.98 (95% CI 4.42–22.63) if both a parent and sibling had RCC. A limitation of estimates such as these is that they may be influenced by the inclusion of individuals with known hereditary conditions. In the aforementioned study, steps were taken to exclude von Hippel-Lindau syndrome (the most common RCC predisposition condition) from analysis, which did not result in a significant difference in findings. These relative risks exceed those observed for other known RCC risk factors, such as smoking (relative risk 1.31 (95% CI 1.22–1.4) for all smokers) [6] and obesity (relative risk 1.77 (95% CI 1.68–1.87)) [7].

Concern over RCC risk in family members of RCC patients assessed by genetics services frequently prompts the suggestion of radiological surveillance in relatives but there is little consensus around the details of execution. A consensus meeting was convened by the UK Cancer Genetics Group (UKCGG) in January 2024 concerning this topic, with representation from specialists with an interest in kidney cancer from the fields of Clinical Genetics, Urology, Nephrology, and General Practice.

In terms of an approach to enhanced surveillance, where indicated, we agreed that it would be reasonable to offer surveillance by ultrasound scanning, at an interval of 2–3 years, determined by comparing the sojourn time of renal cancer development in the general population to that in established monogenic syndromes associated with kidney cancer risk.

We acknowledge that additional interventions, and/or more frequent renal imaging and/or a different modality of renal imaging may be required where a high suspicion of syndromic predisposition to kidney cancer persists after uninformative genetic testing, because of additional phenotypic features in the proband or family members. Where a bespoke approach is required, we agreed that this should be determined following discussion at multidisciplinary team meeting.

The age at which to initiate surveillance is unclear but may be guided by age at diagnosis in the affected individuals, generally 5 years before the earliest diagnosis (e.g., if the affected first-degree relative was diagnosed aged 38 years, screening should commence at age 33 years) and the need for ongoing screening reviewed at age 70 years.

Given that no national RCC screening programme currently exists, the question of which professional group coordinates surveillance is significant. Whilst most Clinical Genetics teams considered themselves to have a role in recommending initiation of serial surveillance for relatives, there is not clear capacity to execute this in Clinical Genetics, Urology, or Primary Care departments. Consequently, recommendations by genetics teams currently need to acknowledge that provision is variable and may require regular prompting by the screened individual themselves.

As Clinical Genetics services are reconfigured to place more emphasis on management and registration of individuals at risk of cancer, there may be opportunities to run RCC surveillance programmes more comprehensively from that setting. Furthermore, some steps are underway to progress kidney cancer screening at population level, starting with the Yorkshire Kidney Screening Trial, [8] which could include a dedicated screening programme for individuals at higher risk (including current and former smokers).

In terms of recommendations for current clinical practice, it should be noted that, as there is a paucity of existing evidence upon which to base more precise guidance, our recommendations are based on expert opinion.

We recommend the following for relevant at-risk individuals (as defined above):

The UKCGG will continue to explore opportunities to facilitate equitable provision of screening for patients who are at higher risk by virtue of an unexplained family history of kidney cancer, accompanied by clinical audit and research.