Doctors should consider germline genetic testing in kidney cancer patients under 46

It is estimated that between 5 and 8% of kidney cancers are hereditary (Linehan et al., 2010). There are several clues that help clinicians diagnose these cases: patients who present with multifocal and/or bilateral tumours; who have a family history of the disease; or who are younger than the average age of onset are more likely to have inherited a genetic susceptibility to their cancer.

Correctly diagnosing hereditary cancer cases is important as it may change the chosen treatment pathway, suggest a patient’s prognosis and future risk of recurrence, it allows other family members at risk of developing the disease to be identified, and has implications for family planning.

For some cancers, specific guidelines exist to help doctors identify hereditary cancer cases. For example, in the UK, if a patient, or one of their first degree relatives, presents with breast cancer before the age of 40, the patient should be referred for genetic testing (NICE guidelines, 2013). Currently there are no similar guidelines for hereditary kidney cancers, meaning that referral for genetic testing relies on the patient having a switched on clinician.

A recent study from Dr W. Marston Linehan’s group at the National Cancer Institute (NCI), in the States suggests that germline genetic testing should be considered for all patients who present with kidney cancer before the age of 46 (Shuch et al., 2014).

The authors first analysed the mean age of initial diagnosis in over 100,000 kidney cancer cases from the Surveillance, Epidemiology and End Results (SEER) Program database held at the NCI. The mean age of first kidney cancer diagnosis was found to be 63.4 years old. Subtype analysis of gender, tumour histology, and race showed slight variances in mean age of diagnosis, but these were not significantly different from the overall mean, thus Shuch et al. did not include these factors in their subsequent analyses to define an age threshold for genetic testing.

Next they reviewed the average age of diagnosis of 608 patients with hereditary kidney cancers, recruited through the Clinical Manifestations and Molecular Bases of Heritable Urologic Malignant Disorders trial at the NCI. The dataset comprised 387 VHL patients, 127 BHD patients, 56 HLRCC patients, 25 HPRC patients, and 13 SDH patients, and to be included in the trial, patients needed to have renal cell carcinoma, a clinical diagnosis of one of these syndromes and/or a genetic diagnosis. Overall, the mean age of this cohort’s first kidney cancer diagnosis was 39.2 years, meaning that, on average, patients with hereditary kidney cancers get their first tumour nearly 25 years earlier than patients with sporadic cancers.

In order to define an age threshold before which genetic testing should be performed, Shuch et al. analysed what percentage of hereditary kidney cancer patients would be identified and the number of patients needed to test in order to find a single patient with hereditary kidney cancer. Testing at an earlier age means that while a larger proportion of those tested are hereditary cancer patients, any hereditary cases that develop after that age will be missed. Conversely, testing at a later age means that although more hereditary cases will have had time to manifest, the concomitant increase in sporadic cases means that more patients would have to undergo unnecessary genetic testing in order to identify the hereditary cases.

Thus, the authors found that testing all patients at the age of 46 and under struck an optimal balance between sensitivity whilst ensuring the number of patients tested unnecessarily remained low. With a cut off age of 46, 70% of hereditary cases had manifested by this age, and an estimated 7- 28 individuals are needed to test in order to find a single case of hereditary kidney cancer.

There are a number of confounding factors in this study. The hereditary cancer cohort only included five types of kidney cancer syndrome – and in particular renal cell carcinoma syndromes – meaning that this study is not directly relevant to other kidney cancer syndromes such as TSC. Additionally, it is possible that some cases in the control cohort were undiagnosed cases of familial kidney cancers, which would artificially lower the average age of cancer onset in this cohort. Furthermore, subtype analysis of the hereditary kidney cancer cohort showed that the average age of onset in BHD is later than the others at 50.3, meaning that many BHD cases might not get picked up with routine screening.

Thus, although this study gives clinicians a starting point at which to consider genetic testing in younger kidney cancer patients, a cut of age of 46 should only be considered to be a rough guide.


  • Linehan WM, Srinivasan R, & Schmidt LS (2010). The genetic basis of kidney cancer: a metabolic disease. Nature reviews. Urology, 7 (5), 277-85 PMID: 20448661
  • Shuch B, Vourganti S, Ricketts CJ, Middleton L, Peterson J, Merino MJ, Metwalli AR, Srinivasan R, & Linehan WM (2014). Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 32 (5), 431-7 PMID: 24378414 – the primary online resource for anyone interested in BHD Syndrome.

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