Tuberous sclerosis complex (TSC) is caused by autosomal dominant inactivating mutations in either the TSC1 or TSC2 genes, and patients are predisposed to developing tumours in the brain, eyes, heart, skin, lungs and kidneys throughout their lifetime. While more than 80% of TSC patients develop benign renal angiomyolipoma, only 3% of TSC patients develop renal cell carcinoma (Yang et al., 2014).
Tyburczy et al., (2014) describe two TSC patients who presented with bilateral multifocal renal cell carcinoma.
The first patient received a left nephrectomy to remove 12 tumours at the age of 24. Three years later, a right nephrectomy was required to remove three tumours. Histological analysis showed all tumours to be of TSC-associated papillary renal cell carcinoma (RCC) (Yang et al., 2014).
Fresh frozen tissue was available from four left and one right kidney tumour. Direct sequencing and microsatellite marker analysis showed loss of heterozygosity (LOH) at the TSC2 allele in one tumour sample, but not in the other four tumours. Targeted next generation sequencing found different second hit somatic TSC2 mutations in each of the other four tumours: two nonsense, one frameshift and one missense mutation. Whole exome sequencing of DNA from all five tumours showed an average of four somatic mutations in other genes in each tumour, and no gene was mutated in more than one sample. Furthermore, no copy number changes were observed in any tumour. This suggests that biallelic inactivation of TSC2 is the driving tumorigenic mutation in all five tumours.
The second patient was found to have bilateral, multifocal tumours, and received partial nephrectomy of both kidneys at the age of 36. All tumours showed the same TSC-associated papillary RCC histology. Analysis of three tumours showed no evidence of LOH at the TSC2 allele. Only one tumour sample yielded sufficient DNA for sequencing analysis, and showed a somatic splicing mutation in TSC2, again suggesting that somatic second hits in TSC2 are driving tumorigenesis in this patient.
Both patients carried the same missense R905Q TSC2 mutation, which is associated with a milder presentation of TSC (Jansen et al., 2006). As this mutation is present in fewer than 1% of TSC patients, and only 3% of TSC patients develop RCC, it seems likely this this mutation may predispose patients to developing RCC. Indeed, in a cohort of 19 TSC patients who developed RCC, germline sequencing data was available for three patients who also developed TSC-associated papillary RCC. While none carried the R905Q mutation, all three had non-truncating TSC2 mutations – two missense and one in-frame deletion. This suggests that patients with non-truncating mutations may be at a higher risk of developing RCC (Yang et al., 2014).
Tyburczy et al. calculate the likelikhood of the first patient developing 15 tumours through 15 independent second hit events to be 1 in 3.6 trillion. This suggests that all tumours arose following a single event, which led to a shower of second hit TSC2 mutations occuring in these patients’ kidney tissue. However, the disease mechanism that leads to multiple second hit mutations in in a single gene is currently unknown.
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- Tyburczy ME, Jozwiak S, Malinowska IA, Chekaluk Y, Pugh TJ, Wu CL, Nussbaum RL, Seepo S, Dzik T, Kotulska K, & Kwiatkowski DJ (2014). A shower of second hit events as the cause of multifocal renal cell carcinoma in Tuberous Sclerosis Complex. Human molecular genetics PMID: 25432535
- Yang P, Cornejo KM, Sadow PM, Cheng L, Wang M, Xiao Y, Jiang Z, Oliva E, Jozwiak S, Nussbaum RL, Feldman AS, Paul E, Thiele EA, Yu JJ, Henske EP, Kwiatkowski DJ, Young RH, & Wu CL (2014). Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol, 38 (7), 895-909. PMID: 24832166