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

Abstract

Purpose: Approximately 5% to 8% of renal cell carcinoma (RCC) is hereditary. No guidelines exist for patient selection for RCC germline mutation testing. We evaluate how age of onset could indicate the need for germline mutation testing for detection of inherited forms of kidney cancer.

Patients and methods: We analyzed the age distribution of RCC cases in the SEER-17 program and in our institutional hereditary kidney cancer population. The age distributions were compared by sex, race, histology, and hereditary cancer syndrome. Models were established to evaluate the specific age thresholds for genetic testing.

Results: The median age of patients with RCC in SEER-17 was 64 years, with the distribution closely approaching normalcy. Statistical differences were observed by race, sex, and subtype (P < .05). The bottom decile cutoff was ≤ 46 years of age and slightly differed by sex, race, and histology. The mean and median ages at presentation of 608 patients with hereditary kidney cancer were 39.3 years and 37 years, respectively. Although age varied by specific syndrome, 70% of these cases were found to lie at or below the bottom age decile. Modeling age-based genetic testing thresholds demonstrated that the 10th percentile maximized sensitivity and specificity.

Conclusion: Early age of onset might be a sign of hereditary RCC. Even in the absence of clinical manifestations and personal/family history, an age of onset of 46 years or younger should trigger consideration for genetic counseling/germline mutation testing and may serve as a useful cutoff when establishing genetic testing guidelines.

Fig 1.

Distribution of the age of onset of kidney cancer in SEER-17 from 1990 to 2008 for 106,224 patients. The distribution approaches a normal curve; skewness and kurtosis are −0.223 and −0.272, respectively.

Fig 2.

A normalized distribution of the age of onset of kidney cancer in SEER-17 compared with National Cancer Institute patients with hereditary kidney cancer (blue, hereditary cases; gold, SEER cases).

Fig 3.

Renal cell carcinoma histology and National Cancer Institute patients with hereditary kidney cancer. (A) Box plot analysis and (B) normalized distribution analysis. UOB, Urologic Oncology Branch.

Fig 3.

Renal cell carcinoma histology and National Cancer Institute patients with hereditary kidney cancer. (A) Box plot analysis and (B) normalized distribution analysis. UOB, Urologic Oncology Branch.

Fig 4.

Box plot of age of onset for National Cancer Institute Urologic Oncology Branch hereditary renal cell carcinoma (RCC) syndromes. BHD, Birt-Hogg-Dubé syndrome; HLRCC, hereditary leiomyomatosis and RCC; HPRC, hereditary papillary RCC; SDHB, succinate dehydrogenase B renal cell carcinoma; VHL, von Hippel-Lindau syndrome.

Fig 5.

Statistical models demonstrating the ability of age threshold alone to enrich selection for renal cell carcinoma (RCC) genetic counseling germline mutation testing. (A) Receiver operating characteristic curve of sensitivity versus 100%−specificity, considering age threshold testing at the 2.5th, 10th, 25th, and 50th percentiles. For this analysis, a 1% incidence of hereditary RCC was used. (B) Number needed to test approximated on the basis of various estimates of the incidence of hereditary, monogenic RCC syndrome.