UV rays in sunlight cause DNA damage and sun exposure is a major risk factor in most skin cancers. A recent study from Harvard suggests that sun exposure may also worsen the number and severity of skin lesions found in tuberous sclerosis patients (Tyburczy et al., 2013)
Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary kidney cancer syndrome caused by inactivating mutations in the TSC1 or TSC2 genes. TSC patients are predisposed to develop benign tumours in the eyes, kidney, skin, lungs and brain. The presence of brain tumours can cause neurological symptoms, such as seizures or learning difficulties, to develop during childhood. Roughly 30% of female and 10% of male TSC patients also develop the cystic lung disease lymphangioleiomyomatosis (LAM).
In order to investigate the mechanisms through with skin tumours arise in TSC, Tuburczy et al. took skin biopsies of both skin tumours and unaffected skin tissue from a cohort of 22 TSC patients. They used these samples to culture cell lines, which were subsequently used for next generation sequencing, MLPA and RT-PCR analysis to determine what genetic changes were driving skin tumour development.
Tumour samples from 18/22 (81%) patients had a second inactivating mutation in the TSC1/2 gene. Multiple tumour samples were available for four patients, and showed that different tumours carried different somatic mutations. Together this suggests that somatic loss of the remaining TSC1/2 allele is a significant cause of skin tumour development, and that different mutation events are responsible for different tumours to develop in the same person, consistent with Knudson’s two-hit hypothesis.
Only two of the 19 (10%) second hit mutations found, were due to loss of heterozygosity, in contrast to the situation in tsc-associated renal angiomyolipomas, 70% of which are caused by loss of heterozygosity (Henske et al., 1996).
Half of the point mutations observed were CC>TT mutations, which is a common DNA damage motif caused by UV exposure (Ikehata and Ono, 2011). This type of mutation has never been reported in germline TSC1/2 mutations and was exclusively seen in samples cultured from facial lesions, which would be regularly exposed to sunlight, strongly suggesting that DNA damage after sun exposure has caused these tumours to develop. However, these mutations were found in 6 out of 17 (35%) facial angiofibroma samples, meaning that sun damage might only account for up to a third of the skin tumours found on sun-exposed skin. Therefore, although reducing sun exposure may reduce the number and severity of skin tumours in TSC, it will not completely prevent tumours forming.
One study has shown that BHD skin lesions are not caused by somatic second hits (van Steensel et al., 2007), meaning that FLCN haploinsufficiency is sufficient to for fibrofolliculomas to develop. However, this study only analysed fibrofolliculomas from three patients, and used PCR to amplify DNA from punch biopsies. It would therefore be interesting to analyse skin lesions from a larger cohort of BHD patients using NGS technology, which is more sensitive than traditional PCR, to see if somatic second hits do contribute to the development of fibrofolliculomas. It would also be interesting to find out whether UV exposure contributes to fibrofolliculoma development; if so, reducing sun exposure by staying in the shade or using high factor suncream would be a cheap and safe way to reduce symptoms.
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Henske EP, Scheithauer BW, Short MP, Wollmann R, Nahmias J, Hornigold N, van Slegtenhorst M, Welsh CT, & Kwiatkowski DJ (1996). Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. American journal of human genetics, 59 (2), 400-6 PMID: 8755927
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Ikehata H, & Ono T (2011). The mechanisms of UV mutagenesis. Journal of radiation research, 52 (2), 115-25 PMID: 21436607
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Tyburczy ME, Wang JA, Li S, Thangapazham R, Chekaluk Y, Moss J, Kwiatkowski DJ, & Darling TN (2013). Sun exposure causes somatic second hit mutations and angiofibroma development in Tuberous Sclerosis Complex. Human molecular genetics PMID: 24271014
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van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutiérrez P, Marcus-Soekarman D, Bladergroen RS, Steijlen PM, & van Geel M (2007). Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients. The Journal of investigative dermatology, 127 (3), 588-93 PMID: 17124507
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.