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SOX10

Monday 9 June 2003

Location: 22q13. SRY-BOX 10, SRY-RELATED HMG-BOX GENE 10; SRY-related HMG-box 10 (SOX10) protein

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Definition: SOX10 is a transcription factor known to be crucial in the specification of the neural crest and maintenance of Schwann cells and melanocytes. It is expressed in nuclei of melanocytes and breast myoepithelial cells .

Images

- SOX10 in melanoma

- SOX-10 NEGATIVE in basal cell carcinoma / BCC. The few positive cells seen are normal melanocytes at DEJ.

- SOX-10 stains myoepithelial layer (& some apocrine cells) in hidradenoma papilliferum.

Functions

- transcription factor (as SOXs )

- human connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10 (11734543)

- NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma. (27084744)

Pathology

- SOX10 germline mutations cause Waardenburg syndrome type 4 (auditory-pigmentary abnormalities and Hirschsprung disease, Gene 2014 Jan 16 [Epub ahead of print])
- Mutations within SOX10 enhancers may contribute to isolated Hirschsprung disease (Hum Mutat 2013 Dec 19 [Epub ahead of print])
- Mutations cause Kallman syndrome (anosmia and hypogonadotropic hypogonadism) with deafness (Am J Hum Genet 2013;92:707)

- germline mutations of SOX10 in

  • Waardenburg-Shah type 4 disease (WS4) associating bilateral profound hearing loss, short segment Hirschsprung disease, and pigmentary abnormalities (white hair, blue irides with gray speckles, depigmented skin patches) (MIM.277580)
  • in a developmental neural crest syndrome associating peripheral demyelinating neuropathy, central leukodystrophy, Waardenburg-Shah syndrome and chronic intestinal pseudo-obstruction and deafness (11026454)
  • in yemenite deaf-blind hypopigmentation syndrome (MIM.601706).
    • Truncating heterozygote SOX10 mutations have been identified in patients with WS4, Yemenite deaf-blind-hypopigmentation syndrome and WS2 but also in patients presenting in addition neurological impairment due to central and peripheral dysmyelination.
    • The latter combination is known as PCWH for Peripheral demyelination-Central dysmyelinating leucodystrophy-Waardenburg syndrome and Hirschsprung disease. Genotype–phenotype correlation relies on nonsense-mediated decay being effective (WS4) or not (PCWH).
    • The penetrance of the HSCR trait appears to be high, although sibs sharing a mutation and discordant for HSCR have been described in one family. Therefore, SOX10 is unlikely to be a major gene in isolated HSCR.

Diagnostic use / IHC

SOX10 is a Schwannian and melanocytic marker that is used for the diagnosis of neural crest-derived tumors.

- SOX10 in melanocytic tumors

  • SOX10 is a melanoma marker (100%, Appl Immunohistochem Mol Morphol 2014;22:142)
  • melanocytic nevi are positive (Nat Cell Biol 2012;14:882),
  • desmoplastic melanoma may be only focally positive (Appl Immunohistochem Mol Morphol 2013;21:506)
  • MITF1 and SOX10 can be used to differentiate melanoma in situ from actinic keratosis with melanocytic hyperplasia (Am J Dermatopathol 2013 Jun 18)
  • SOX10 and MART-1 (Melan-A) are used to detect melanoma in sentinel nodes.

- mammary tumors

  • Usually positive nuclear staining in breast basal-like / unclassified triple negative / metaplastic carcinoma (Hum Pathol 2013;44:959)
  • Usually negative / rarely positive staining in breast luminal A/B or HER2+ carcinoma (5% positive), ER-/PR- DCIS (4% positive), phyllodes tumor, fibroadenoma

- MPNST

- salivary gland tumors

  • In major salivary glands, expressed in nuclei of acini and both luminal and abluminal cells of intercalated ducts, but not in other sites (Mod Pathol 2013;26:1041).
  • SOX10+ carcinomas include acinic cell, adenoid cystic (Br J Cancer 2013;109:444), epithelial-myoepithelial, myoepithelial; also pleomorphic adenomas, including the pleomorphic adenoma component of carcinoma

- soft tissue tumors of neural crest origin

  • SOX10 shows an increased specificity for soft tissue tumors of neural crest origin compared with S100 (Appl Immunohistochem Mol Morphol 2012;20:445)

- SOX10 immunohistochemistry in sweat ductal/glandular neoplasms

- granular cell tumor / granular cell tumors : SOX10+

- SOX10 is a marker of acinus and intercalated duct differentiation in salivary gland tumors. (23558573)

- SOX10 expression in salivary gland tumors

  • Salivary adenoid cystic carcinoma (ACC) is an insidious slow-growing cancer with the propensity to recur and metastasise to distant sites.
  • Basal-like breast carcinoma (BBC) is a molecular subtype that constitutes 15-20% of breast cancers, shares histological similarities and basal cell markers with ACC, lacks expression of ER (oestrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2), and, similar to ACC, metastasises predominantly to the lung and brain.
  • SOX10 expression in ACC and BBC appears to be a part of a highly coordinated transcriptional programme characteristic for cancers with basal/myoepithelial features.
  • Comparison between ACC/BBC and other cancers, such as neuroblastoma and MEL, reveals potential molecular markers specific for these cancers that are likely linked to their cell identity.
  • SOX10 is a diagnostic marker for ACC and BBC and provides important molecular insight into their molecular etiology and cell origin.
  • Given that SOX10 was recently described as a principal driver of MEL, identification of conserved elements of the SOX10 signatures may help in better understanding of SOX10-related signalling and development of novel diagnostic and therapeutic tools. (23799842)

- SOX10 negative IHC labelling

Animal models

The last known mouse model for WS4 in human is dominant megalon (Dom), homozygous Dom mutation being embryonic lethal.

The Dom gene is Sox10, a member of the SRY (sex determining factor)-like, high mobility group (HMG) DNA binding proteins.

See also

- Hirschsprung disease genes

RET GDNF NRTN SOX10 EDNRB EDN3 ECE1 ZFHX1B PHOX2B TCF4

MIM.602229

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