Cancer risk and tumour spectrum in 172 patients with a germline <i>SUFU</i> pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group.

Abstract

Little is known about risks associated with germline <i>SUFU</i> pathogenic variants (PVs) known as a cancer predisposition syndrome. To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline <i>SUFU</i> PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with <i>SUFU</i> PV (89 patients) using the Nelson-Aalen estimator. Overall, 117/172 (68%) <i>SUFU</i> PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire <i>SUFU</i> gene and inherited in 73% of cases in which inheritance could be evaluated. Germline <i>SUFU</i> PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.