Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1
Neurofibromatosis type 1 (NF1) is a multisystem disorder caused by germline heterozygous NF1 loss-of-function variants. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein, which functions by down-regulating RAS/RAF/MAPK-signalling pathways. Somatic NF1 aberrations frequently occur i...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/155620 |
| _version_ | 1811683784736636928 |
|---|---|
| author | Courtney, Eliza Chan, Sock Hoai Li, Shao Tzu Ishak, Diana Merchant, Khurshid Shaw, Tarryn Chay, Wen Yee Chin, Felicia Hui Xian Wong, Wai Loong Wong, Adele Ngeow, Joanne |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Courtney, Eliza Chan, Sock Hoai Li, Shao Tzu Ishak, Diana Merchant, Khurshid Shaw, Tarryn Chay, Wen Yee Chin, Felicia Hui Xian Wong, Wai Loong Wong, Adele Ngeow, Joanne |
| author_sort | Courtney, Eliza |
| collection | NTU |
| description | Neurofibromatosis type 1 (NF1) is a multisystem disorder caused by germline heterozygous NF1 loss-of-function variants. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein, which functions by down-regulating RAS/RAF/MAPK-signalling pathways. Somatic NF1 aberrations frequently occur in sporadic ovarian cancer (OC), but the incidence of OC in NF1 patients is rare. Here we report the germline and somatic findings for two unrelated patients with NF1 and high-grade serous OC. Germline testing revealed a heterozygous NF1 pathogenic variant in each patient, c.7096_7101del (p.Asn2366_Phe2367del) and c.964delA (p.Ile322Leufs*54), respectively. No germline variants in well-established OC predisposition genes were detected, including BRCA1 and BRCA2. Tumor loss-of-heterozygosity analysis demonstrated loss of the wild type NF1 allele for both patients. Biallelic NF1 inactivation occurs as part of OC pathogenesis in NF1 patients. Although the penetrance of NF1-associated OC is insufficient to warrant risk-reducing interventions, our findings highlight the potential for therapies targeting the RAS/RAF/MAPK-signalling pathway for these cases. |
| first_indexed | 2024-10-01T04:18:14Z |
| format | Journal Article |
| id | ntu-10356/155620 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:18:14Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1556202022-03-11T01:41:29Z Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 Courtney, Eliza Chan, Sock Hoai Li, Shao Tzu Ishak, Diana Merchant, Khurshid Shaw, Tarryn Chay, Wen Yee Chin, Felicia Hui Xian Wong, Wai Loong Wong, Adele Ngeow, Joanne Lee Kong Chian School of Medicine (LKCMedicine) Cancer Genetics Services Division of Medical Oncology National Cancer Centre Singapore Department of Pathology and Laboratory KK Women's and Children's Hospital KK Gynaecological Cancer Centre Science::Biological sciences Neurofbromatosis Neurofbromin Neurofibromatosis type 1 (NF1) is a multisystem disorder caused by germline heterozygous NF1 loss-of-function variants. The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein, which functions by down-regulating RAS/RAF/MAPK-signalling pathways. Somatic NF1 aberrations frequently occur in sporadic ovarian cancer (OC), but the incidence of OC in NF1 patients is rare. Here we report the germline and somatic findings for two unrelated patients with NF1 and high-grade serous OC. Germline testing revealed a heterozygous NF1 pathogenic variant in each patient, c.7096_7101del (p.Asn2366_Phe2367del) and c.964delA (p.Ile322Leufs*54), respectively. No germline variants in well-established OC predisposition genes were detected, including BRCA1 and BRCA2. Tumor loss-of-heterozygosity analysis demonstrated loss of the wild type NF1 allele for both patients. Biallelic NF1 inactivation occurs as part of OC pathogenesis in NF1 patients. Although the penetrance of NF1-associated OC is insufficient to warrant risk-reducing interventions, our findings highlight the potential for therapies targeting the RAS/RAF/MAPK-signalling pathway for these cases. National Medical Research Council (NMRC) National Research Foundation (NRF) J.N is funded by the National Research Council Singapore Clinician-Scientist Award (NMRC/CSAINV/0017/2017). Additional funding was provided by the National Research Foundation Singapore under its NMRC Centre Grant Programme (NMRC-CG-RIE 2020 - Project No. NMRC/CG/M003/2017). AstraZeneca provided funding for ovarian cancer research. 2022-03-11T01:41:29Z 2022-03-11T01:41:29Z 2020 Journal Article Courtney, E., Chan, S. H., Li, S. T., Ishak, D., Merchant, K., Shaw, T., Chay, W. Y., Chin, F. H. X., Wong, W. L., Wong, A. & Ngeow, J. (2020). Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1. Familial Cancer, 19(4), 353-358. https://dx.doi.org/10.1007/s10689-020-00184-3 1389-9600 https://hdl.handle.net/10356/155620 10.1007/s10689-020-00184-3 32405727 2-s2.0-85084667240 4 19 353 358 en NMRC/CSAINV/0017/2017 NMRC/CG/M003/2017 Familial Cancer © 2020 Springer Nature B.V. All rights reserved. |
| spellingShingle | Science::Biological sciences Neurofbromatosis Neurofbromin Courtney, Eliza Chan, Sock Hoai Li, Shao Tzu Ishak, Diana Merchant, Khurshid Shaw, Tarryn Chay, Wen Yee Chin, Felicia Hui Xian Wong, Wai Loong Wong, Adele Ngeow, Joanne Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 |
| title | Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 |
| title_full | Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 |
| title_fullStr | Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 |
| title_full_unstemmed | Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 |
| title_short | Biallelic NF1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 |
| title_sort | biallelic nf1 inactivation in high grade serous ovarian cancers from patients with neurofibromatosis type 1 |
| topic | Science::Biological sciences Neurofbromatosis Neurofbromin |
| url | https://hdl.handle.net/10356/155620 |
| work_keys_str_mv | AT courtneyeliza biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT chansockhoai biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT lishaotzu biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT ishakdiana biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT merchantkhurshid biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT shawtarryn biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT chaywenyee biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT chinfeliciahuixian biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT wongwailoong biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT wongadele biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 AT ngeowjoanne biallelicnf1inactivationinhighgradeserousovariancancersfrompatientswithneurofibromatosistype1 |