Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex
Background Tuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC fac...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-05-01
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| Series: | The Journal of Clinical Investigation |
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| Online Access: | https://doi.org/10.1172/JCI155858 |
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| author | Katarzyna Klonowska Joannes M. Grevelink Krinio Giannikou Barbara A. Ogorek Zachary T. Herbert Aaron R. Thorner Thomas N. Darling Joel Moss David J. Kwiatkowski |
| author_facet | Katarzyna Klonowska Joannes M. Grevelink Krinio Giannikou Barbara A. Ogorek Zachary T. Herbert Aaron R. Thorner Thomas N. Darling Joel Moss David J. Kwiatkowski |
| author_sort | Katarzyna Klonowska |
| collection | DOAJ |
| description | Background Tuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC facial skin was performed.Methods A multiplex high-sensitivity PCR assay (MHPA) was developed, enabling mutation detection at extremely low (<0.1%) variant allele frequencies (VAFs).Results MHPA assays were developed for both TSC2 and TP53, and applied to 81 samples, including 66 skin biopsies. UV-induced second-hit mutation causing inactivation of TSC2 was pervasive in TSC facial skin with an average of 4.8 mutations per 2-mm biopsy at median VAF 0.08%, generating more than 150,000 incipient facial tumors (subclinical “micro-FAFs”) in the average TSC subject. The MHPA analysis also led to the identification of a refined UV-related indel signature and a recurrent complex mutation pattern, consisting of both a single-nucleotide or dinucleotide variant and a 1- to 9-nucleotide deletion, in cis.Conclusion TSC facial skin can be viewed as harboring a patchwork of clonal fibroblast proliferations (micro-FAFs) with indolent growth, a small proportion of which develop into clinically observable FAF. Our observations also expand the spectrum of UV-related mutation signatures.Funding This work was supported by the TSC Alliance; the Engles Family Fund for Research in TSC and LAM; and the NIH, National Heart, Lung, and Blood Institute (U01HL131022-04 and Intramural Research Program). |
| first_indexed | 2024-04-12T12:33:10Z |
| format | Article |
| id | doaj.art-702bdb854df14b3fa35510627c3d82e1 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-12T12:33:10Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-702bdb854df14b3fa35510627c3d82e12022-12-22T03:32:59ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-05-0113210Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complexKatarzyna KlonowskaJoannes M. GrevelinkKrinio GiannikouBarbara A. OgorekZachary T. HerbertAaron R. ThornerThomas N. DarlingJoel MossDavid J. KwiatkowskiBackground Tuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC facial skin was performed.Methods A multiplex high-sensitivity PCR assay (MHPA) was developed, enabling mutation detection at extremely low (<0.1%) variant allele frequencies (VAFs).Results MHPA assays were developed for both TSC2 and TP53, and applied to 81 samples, including 66 skin biopsies. UV-induced second-hit mutation causing inactivation of TSC2 was pervasive in TSC facial skin with an average of 4.8 mutations per 2-mm biopsy at median VAF 0.08%, generating more than 150,000 incipient facial tumors (subclinical “micro-FAFs”) in the average TSC subject. The MHPA analysis also led to the identification of a refined UV-related indel signature and a recurrent complex mutation pattern, consisting of both a single-nucleotide or dinucleotide variant and a 1- to 9-nucleotide deletion, in cis.Conclusion TSC facial skin can be viewed as harboring a patchwork of clonal fibroblast proliferations (micro-FAFs) with indolent growth, a small proportion of which develop into clinically observable FAF. Our observations also expand the spectrum of UV-related mutation signatures.Funding This work was supported by the TSC Alliance; the Engles Family Fund for Research in TSC and LAM; and the NIH, National Heart, Lung, and Blood Institute (U01HL131022-04 and Intramural Research Program).https://doi.org/10.1172/JCI155858DermatologyGenetics |
| spellingShingle | Katarzyna Klonowska Joannes M. Grevelink Krinio Giannikou Barbara A. Ogorek Zachary T. Herbert Aaron R. Thorner Thomas N. Darling Joel Moss David J. Kwiatkowski Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex The Journal of Clinical Investigation Dermatology Genetics |
| title | Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex |
| title_full | Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex |
| title_fullStr | Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex |
| title_full_unstemmed | Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex |
| title_short | Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex |
| title_sort | ultrasensitive profiling of uv induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex |
| topic | Dermatology Genetics |
| url | https://doi.org/10.1172/JCI155858 |
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