Folliculin (FLCN) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration
Abstract
:1. Introduction
2. Materials and Methods
2.1. Index Patients
2.2. Database Sources and Case Selection
2.3. Orien-Avatar Dataset
2.4. Publicly Available Datasets
3. Results
3.1. Patient 1
Clinicopathologic Findings
3.2. Patient 2
Clinicopathologic Findings
3.3. Orien Avatar Dataset
3.4. Publicly Available Datasets
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Age at Dx | Sex | Pathologic Dx | FLCN Gene Coverage | Somatic vs. Germline FLCN Alteration | FLCN Alteration | VAF | Variant Reads | Reference Reads | Other Mutations | Family Cancer History | Overall Survival (Months) | Vital Status | T Stage at Dx | N Stage at Dx | Metastases |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
71.8 | M | Oncocytic carcinoma | Germline status only, FLCN not covered on tumor NGS panel | Germline | G319fs | 0.42 | 154 | 214 | Tumor sequenced (FLCN gene not on panel) | “Colon, NOS” | 25 | Living | T3 | N1b | Liver, lung, rib, sternum, clavicle and associated joints, and adrenal gland; lymph nodes of head, face, and neck |
43 | F | PTC, Follicular Variant | Germline and Tumor | Somatic | Biallelic loss | N/A | N/A | N/A | BRAF V600E (known oncogenic; likely GOF), ARID1A E1735* (likely oncogenic; likely LOF) | N/A | 59 | Living | T3 | N0 | N/A |
46 | M | PTC, NOS | Germline and Tumor | Somatic | Biallelic loss | N/A | N/A | N/A | BRAF V600E (known oncogenic; likely GOF) | Lung NOS, Thyroid gland | 62 | Living | T1a | N1a | Rib, sternum, and clavicle and associated joints; lymph nodes of head, face, and neck |
39 | F | PTC, NOS | Germline and Tumor | Somatic | Biallelic loss | N/A | N/A | N/A | No oncogenic point mutations | N/A | 113 | Living | T3 | N0 | N/A |
72 | M | PTC, NOS | Germline and Tumor | Somatic | Biallelic loss in metastasis but not in primary | N/A | N/A | N/A | Primary and lymph node metastasis: BRAF V600E (known oncogenic; likely GOF) | Kidney, NOS, Skin, NOS, Thyroid gland | 51 | Living | T1b | N1b | Lymph nodes of head, face, and neck |
14 | F | PTC, NOS | Germline and Tumor | Somatic | Biallelic loss | N/A | N/A | N/A | BRAF V600E (known oncogenic; likely GOF) | N/A | 80 | Living | T3 | N1a | Lymph nodes of head, face, and neck |
44 | F | PTC, NOS | Germline and Tumor | Somatic | Biallelic loss | N/A | N/A | N/A | BRAF V600E (known oncogenic; likely GOF) | Skin, NOS | 84 | Living | T1b | N1b | Lymph nodes of head, face, and neck |
67 | M | PTC, NOS | Germline and Tumor | Somatic | Biallelic loss | N/A | N/A | N/A | BRAF V600E (known oncogenic; likely GOF) | N/A | 42 | Living | T3 | N1b | Lymph nodes of head, face, and neck |
41 | F | PTC, NOS | Germline and Tumor | Somatic | Biallelic loss in metastasis but not in primary | N/A | N/A | N/A | Primary and lymph node metastasis: BRAF V600E (known oncogenic; likely GOF) | Thyroid Gland | 75 | Living | T3 | N1b | Lymph nodes of head, face, and neck |
23 | F | PTC, NOS | Germline and Tumor | Somatic | Biallelic loss | N/A | N/A | N/A | BRAF V600E (known oncogenic; likely GOF) | N/A | 20 | Living | T2 | N1a | Lymph nodes of head, face, and neck |
Database | Age at Dx | Sex | Pathologic Dx | FLCN Gene Coverage | FLCN Alteration | VAF | Variant Reads | Reference Reads | Other Mutations | Overall Survival (Months) | Vital Status | T Stage at Dx | Metastasis |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | M | ATC | Tumor | Q220* truncating mutation | 0.54 | 22 | 41 | BRAF V600E (oncogenic; gain of function), TP53 M246I (likely oncogenic; likely loss of function), NF2 Q453* (likely oncogenic; likely loss of function) | 4 | Deceased | T4b | Yes (Nodal + Distal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | F | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | TP53 K132N; likely oncogenic; likely loss of function | 1 | Deceased | T4b | Yes (Nodal + Distal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | F | ATC arising in a background of PTC | Tumor | Biallelic loss | N/A | N/A | N/A | BRAF V600E (oncogenic; gain of function) | 4 | Deceased | T4b | Yes (Nodal + Distal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | M | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | BRAF V600E (oncogenic; gain of function), ASXL2 Q1013 (likely oncogenic; likely loss of function) | <1 | Deceased | T4b | Yes (Nodal + Distal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | M | ATC arising in a background of PTC | Tumor | Biallelic loss | N/A | N/A | N/A | BRAF V600E (oncogenic; gain of function), TP53 M246I (likely oncogenic; likely loss of function) | 3 | Deceased | T4b | Yes (Nodal + Distal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | M | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | TP53 Q331H; likely oncogenic; likely loss of function | 23 | Deceased | T4b | N/A |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | Not provided | F | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | No oncogenic point mutations | N/A | N/A | N/A | N/A |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | M | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | NRAS Q61R (oncogenic gain of function), TP53 C135W (likely oncogenic; likely loss of function) | 3 | Deceased | T4b | Yes (Nodal + Distal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | F | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | NF2 E186* (likely oncogenic; likely loss of function) | 11 | Deceased | N/A | Yes (Distal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | F | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | BRAF V600E (oncogenic; gain of function) | 1 | Deceased | N/A | No |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | M | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | STK11 Q220* (likely oncogenic; likely loss of function) | 1 | Deceased | T4b | Yes (Nodal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | F | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | NRAS Q61K (oncogenic; gain of function) + PIK3CA Q546L (likely oncogenic; likely gain of function) | 1 | Deceased | N/A | No |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | M | ATC arising in a background of onocytic carcinoma | Tumor | Biallelic loss | N/A | N/A | N/A | ATR X878_splice in anaplastic (splice; likely oncogenic; likely loss of function); EP400 X2778_splice in oncocytic carcinoma (splice; likely oncogenic; likely loss of function) | 1 | Deceased | N/A | No |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | F | ATC arising in a background of PTC | Tumor | Biallelic loss | N/A | N/A | N/A | PTC component only: BRAF V600E (oncogenic; gain of function), TP53 E285K (likely oncogenic; likely loss of function), BTG1 Q82* (likely oncogenic; likely loss of function) | 3 | Living | N/A | N/A |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | M | ATC arising in a background of oncocytic carcinoma | Tumor | Biallelic loss | N/A | N/A | N/A | Oncocytic carcinoma component only: PTEN W274* (likely oncogenic; likely loss of function) | 6 | Deceased | N/A | No |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | M | ATC arising in a background of poorly differentiated thyroid carcinoma | Tumor | Biallelic loss | N/A | N/A | N/A | No oncogenic point mutations | 19 | Deceased | N/A | No |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | F | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | NRAS Q61R (oncogenic + gain of function), TP53 I195T (likely oncogenic; likely loss of function), EIF1AX G9R (likely oncogenic; likely gain of function) | 1 | Deceased | N/A | No |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | M | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | NRAS Q61R (oncogenic + gain of function) | <1 | Living | N/A | No |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | M | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | BRAF V600E (oncogenic + gain of function), PTEN G129R (oncogenic + gain of function), PICK3CA E453K (oncogenic + gain of function), CHEK2 I157T (oncogenic + gain of function), MUTHY R233* (likely oncogenic; likely loss of function) | 5 | Deceased | T4b | Yes (Nodal + Distal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | M | ATC likely arising out of a follicular carcinoma | Tumor | Biallelic loss | N/A | N/A | N/A | NRAS Q61R (oncogenic + gain of function) | 1 | Living | T4a | Yes (Nodal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | F | ATC | Tumor | Biallelic loss | N/A | N/A | N/A | BRAF V600E (oncogenic + gain of function), RAD51C P21A (likely oncogenic + known biological effect), NF2 Q178* (likely oncogenic; likely loss of function) | 27 | Living | T4b | Yes (Nodal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | F | ATC arising out of a PTC | Tumor | Biallelic loss | N/A | N/A | N/A | No oncogenic point mutations | 3 | Deceased | T4a | Yes (Nodal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | >=70 | M | ATC arising out of a PTC | Tumor | Biallelic loss | N/A | N/A | N/A | TP53 R273C (likely oncogenic; loss of function) in both anaplastic and PTC components | 5 | Deceased | T4a | Yes (Nodal) |
Anaplastic Thyroid Cancers (GATCI, Cell Reports 2024) | <70 | M | ATC arising out of a follicular carcinoma | Tumor | Biallelic loss | N/A | N/A | N/A | NRAS G13R in anaplastic and PTC components (oncogenic + gain of function), EIF1AX X113_splice in follicular carcinoma component only (likely oncogenic + likely gain of function) | 3 | Deceased | T4b | Yes (Distal) |
Thyroid Carcinoma (TCGA, PanCancer Atlas) | 36 | F | PTC with predominantly follicular architecture with oncocytic features and focal tall cell features | Tumor | Biallelic loss | N/A | N/A | N/A | Not profiled for point mutations | 40 | Living | T3 | Yes (Distal, Lung) |
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Hassan, F.A.; Slone, C.; McDonald, R.J.; Dueber, J.C.; Ashraf, A.M.; Windon, M.J.; Fackelmayer, O.J.; Lee, C.Y.; Bocklage, T.J.; Allison, D.B. Folliculin (FLCN) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration. Curr. Oncol. 2025, 32, 224. https://doi.org/10.3390/curroncol32040224
Hassan FA, Slone C, McDonald RJ, Dueber JC, Ashraf AM, Windon MJ, Fackelmayer OJ, Lee CY, Bocklage TJ, Allison DB. Folliculin (FLCN) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration. Current Oncology. 2025; 32(4):224. https://doi.org/10.3390/curroncol32040224
Chicago/Turabian StyleHassan, Faisal A., Camryn Slone, Robert J. McDonald, Julie C. Dueber, Adeel M. Ashraf, Melina J. Windon, Oliver J. Fackelmayer, Cortney Y. Lee, Therese J. Bocklage, and Derek B. Allison. 2025. "Folliculin (FLCN) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration" Current Oncology 32, no. 4: 224. https://doi.org/10.3390/curroncol32040224
APA StyleHassan, F. A., Slone, C., McDonald, R. J., Dueber, J. C., Ashraf, A. M., Windon, M. J., Fackelmayer, O. J., Lee, C. Y., Bocklage, T. J., & Allison, D. B. (2025). Folliculin (FLCN) in Thyroid Tumors: Incidence, Significance, and Role as a Driver Gene and Secondary Alteration. Current Oncology, 32(4), 224. https://doi.org/10.3390/curroncol32040224