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FOXL2

MIM.605597 3q23 Entrez:668

Wednesday 18 June 2008

Definition: FOXL2 encodes a forkhead transcription factor. The protein FOXL2 contains a fork-head DNA-binding domain and may play a role in ovarian development and function.

Mutations in FOXL2 are a cause of blepharophimosis syndrome (BPES) and premature ovarian failure type 3 (MIM.608996).

Functions

- FOXL2 represses the transcription of aromatase, cholesterol side-chain cleavage enzyme P450scc and cyclin D2 in granulosa cells.

- FoxL2 plays a key role in activin induction of the FSHbeta gene, by binding to sites conserved across multiple species.

- Human FOXL2 and SF-1 proteins interact in human granulosa cells and that FOXL2 negatively regulates the transcriptional activation of a steroidogenic enzyme, CYP17, by SF-1.

Pathology

- Defects in FOXL2 underlies some types of female infertility and premature ovarian failure. (FOXL2-associated premature ovarian failure)

- FOXL2 germline mutations in

  • blepharophimosis syndrome (BPES), an autosomal dominant syndrome in which an eyelid malformation is associated (type I) or not (type II) with premature ovarian failure (#12529855#) (polyalanine repeat expansion)
  • premature ovarian failure type 3 (MIM.608996)
    • Two mutations in FOXL2 were identified in two familial cases. One was c.855-871dup associated with POF. The other was c.384G>A, a novel mutation that resulted in non-sense changes of the encoded protein.
    • Germline mutations in FOXL2 gene was not common among Chinese patients with POF.

- FOXL2 germline mutations in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES)(MIM.110100)

  • BPES type 1
  • BPES type 2

- Mutation of FOXL2 in adult-type granulosa-cell tumor of the ovary. (#19516027#, #19996294#, #19956657#)

  • FOXL2 showed a p.C134W missense point mutation in 18 of 20 adult granulosa-cell tumors.
  • FOXL2 codon 134 mutation occurs exclusively in granulosa cell tumor (GCT) and thecoma. It suggest the possibility that the development of most GCTs and a fraction of thecomas may be dependent on this mutation.

FOXL2 mutation (402C→G) has been demonstrated in >95% of ovarian adult granulosa cell tumors.

Diagnostic use

- FOXL2 is a sex cord marker.

- Differential diagnosis between diffuse adult granulosa cell tumor and ovarian cellular fibroma

  • Ovarian cellular fibromas are uncommon neoplasms, which may result in considerable diagnostic confusion with diffuse adult granulosa cell tumor.
  • This is an important distinction, as the former usually exhibits benign behavior, whereas the latter is a low-grade malignant neoplasm capable of recurrence and metastasis.
  • FOXL2 mutation (402C→G) has been demonstrated in >95% of ovarian adult granulosa cell tumors, only rarely in other ovarian sex cord-stromal neoplasms, and never in ovarian fibromas.
  • FOXL2 mutation analysis is a useful adjunct in distinguishing between diffuse adult granulosa cell tumor (mutation present) and cellular fibroma (mutation absent).
  • Mutation testing should be considered in problematic cases, as this will provide prognostic information for the patient.

See also

- FOXs

  • FOXLs

References

- Luteinized Thecomas (Thecomatosis) Associated With Sclerosing Peritonitis Exhibit Positive Staining With Sex Cord Markers Steroidogenic Factor-1 (SF-1) and FOXL2. McCluggage WG, Staats PN, Gilks CB, Clement PB, Young RH. Am J Surg Pathol. 2013 Sep;37(9):1458-9. doi:10.1097/PAS.0b013e31829bafee . PMID: #24076780#

- Ovarian Cellular Fibromas Lack FOXL2 Mutations: A Useful Diagnostic Adjunct in the Distinction From Diffuse Adult Granulosa Cell Tumor. McCluggage WG, Singh N, Kommoss S, Huntsman DG, Gilks CB. Am J Surg Pathol. 2013 Jun 14. PMID: #23774170#

- Adult-type granulosa cell tumors and FOXL2 mutation. Köbel M, Gilks CB, Huntsman DG. Cancer Res. 2009 Dec 15;69(24):9160-2. PMID: #19996294#

- The specificity of the FOXL2 c.402C>G Somatic mutation: a survey of solid tumors. Schrader KA, Gorbatcheva B, Senz J, Heravi-Moussavi A, Melnyk N, Salamanca C, Maines-Bandiera S, Cooke SL, Leung P, Brenton JD, Gilks CB, Monahan J, Huntsman DG. PLoS One. 2009 Nov 24;4(11):e7988. PMID: #19956657#

- The forkhead factor FOXL2: A novel tumor suppressor? Benayoun BA, Kalfa N, Sultan C, Veitia RA. Biochim Biophys Acta. 2009 Sep 10. PMID: #19747961#

- The new molecular biology of granulosa cell tumors of the ovary. Kalfa N, Veitia RA, Benayoun BA, Boizet-Bonhoure B, Sultan C. Genome Med. 2009 Aug 25;1(8):81. PMID: #19725933#

- Mutation of FOXL2 in granulosa-cell tumors of the ovary. Shah SP, Köbel M, Senz J, Morin RD, Clarke BA, Wiegand KC, Leung G, Zayed A, Mehl E, Kalloger SE, Sun M, Giuliany R, Yorida E, Jones S, Varhol R, Swenerton KD, Miller D, Clement PB, Crane C, Madore J, Provencher D, Leung P, DeFazio A, Khattra J, Turashvili G, Zhao Y, Zeng T, Glover JN, Vanderhyden B, Zhao C, Parkinson CA, Jimenez-Linan M, Bowtell DD, Mes-Masson AM, Brenton JD, Aparicio SA, Boyd N, Hirst M, Gilks CB, Marra M, Huntsman DG. N Engl J Med. 2009 Jun 25;360(26):2719-29. PMID: #19516027#

- FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary. Al-Agha OM, Huwait HF, Chow C, Yang W, Senz J, Kalloger SE, Huntsman DG, Young RH, Gilks CB. Am J Surg Pathol. 2011 Apr;35(4):484-94. PMID: #21378549#

- FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). Hersmus R, Kalfa N, de Leeuw B, Stoop H, Oosterhuis JW, de Krijger R, Wolffenbuttel KP, Drop SL, Veitia RA, Fellous M, Jaubert F, Looijenga LH. J Pathol. 2008 May;215(1):31-8. PMID: #18348162#

- Adult-type granulosa cell tumors and FOXL2 mutation. Köbel M, Gilks CB, Huntsman DG. Cancer Res. 2009 Dec 15;69(24):9160-2. PMID: #19996294#

- A new FOXL2 gene mutation in a woman with premature ovarian failure and sporadic blepharophimosis-ptosis-epicanthus inversus syndrome. Silva Corrêa FJ, Tavares AB, Pereira RW, Abrão MS. Fertil Steril. 2009 Dec 5. PMID: #19969293#

- The specificity of the FOXL2 c.402C>G Somatic mutation: a survey of solid tumors. Schrader KA, Gorbatcheva B, Senz J, Heravi-Moussavi A, Melnyk N, Salamanca C, Maines-Bandiera S, Cooke SL, Leung P, Brenton JD, Gilks CB, Monahan J, Huntsman DG. PLoS One. 2009 Nov 24;4(11):e7988. PMID: #19956657#

- Identification of a Novel Mutation in FOXL2 Gene That Leads to Blepharophimosis Ptosis Epicanthus Inversus and Telecanthus Syndrome in a Tunisian Consanguineous Family. Chouchene I, Derouiche K, Chaabouni A, Cherif L, Amouri A, Largueche L, Abdelhak S, Matri LE. Genet Test Mol Biomarkers. 2009 Nov 23. PMID: #19929410#

- FOXL2 mutations lead to different ovarian phenotypes in BPES patients: Case Report. Méduri G, Bachelot A, Duflos C, Bständig B, Poirot C, Genestie C, Veitia R, De Baere E, Touraine P. Hum Reprod. 2010 Jan;25(1):235-43. Epub 2009 Oct 9. PMID: #19819892#

- The forkhead factor FOXL2: A novel tumor suppressor? Benayoun BA, Kalfa N, Sultan C, Veitia RA. Biochim Biophys Acta. 2009 Sep 10. PMID: #19747961#

- The new molecular biology of granulosa cell tumors of the ovary. Kalfa N, Veitia RA, Benayoun BA, Boizet-Bonhoure B, Sultan C. Genome Med. 2009 Aug 25;1(8):81. PMID: #19725933#

- Mutation of FOXL2 in granulosa-cell tumors of the ovary. Shah SP, Köbel M, Senz J, Morin RD, Clarke BA, Wiegand KC, Leung G, Zayed A, Mehl E, Kalloger SE, Sun M, Giuliany R, Yorida E, Jones S, Varhol R, Swenerton KD, Miller D, Clement PB, Crane C, Madore J, Provencher D, Leung P, DeFazio A, Khattra J, Turashvili G, Zhao Y, Zeng T, Glover JN, Vanderhyden B, Zhao C, Parkinson CA, Jimenez-Linan M, Bowtell DD, Mes-Masson AM, Brenton JD, Aparicio SA, Boyd N, Hirst M, Gilks CB, Marra M, Huntsman DG. N Engl J Med. 2009 Jun 25;360(26):2719-29. PMID: #19516027#