Targeted Molecular and Immunohistochemical Analyses of Endometrial Clear Cell Carcinoma Show that POLE Mutations and DNA Mismatch Repair Protein Deficiencies are Uncommon

Nick Baniak, Oluwole Fadare, Martin Köbel, John Decoteau, Vinita Parkash, Jonathan L. Hecht, Krisztina Z. Hanley, Katja Gwin, Wenxin Zheng, Charles M. Quick, Elke A. Jarboe, Sharon X. Liang, Mary Kinloch

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16%) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10%; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59%, 22/37), followed by KRAS (13%, 2/15) and PIK3CA (13%, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.

Original languageEnglish (US)
JournalAmerican Journal of Surgical Pathology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Protein Deficiency
DNA Mismatch Repair
Carcinoma
Mutation
Immunohistochemistry
Exonucleases
Atlases
Virulence
Turcot syndrome
Genome
Databases
Genes
Neoplasms
Proteins

Keywords

  • classification
  • endometrial clear cell carcinoma
  • molecular
  • POLE

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Targeted Molecular and Immunohistochemical Analyses of Endometrial Clear Cell Carcinoma Show that POLE Mutations and DNA Mismatch Repair Protein Deficiencies are Uncommon. / Baniak, Nick; Fadare, Oluwole; Köbel, Martin; Decoteau, John; Parkash, Vinita; Hecht, Jonathan L.; Hanley, Krisztina Z.; Gwin, Katja; Zheng, Wenxin; Quick, Charles M.; Jarboe, Elke A.; Liang, Sharon X.; Kinloch, Mary.

In: American Journal of Surgical Pathology, 01.01.2018.

Research output: Contribution to journalArticle

Baniak, Nick ; Fadare, Oluwole ; Köbel, Martin ; Decoteau, John ; Parkash, Vinita ; Hecht, Jonathan L. ; Hanley, Krisztina Z. ; Gwin, Katja ; Zheng, Wenxin ; Quick, Charles M. ; Jarboe, Elke A. ; Liang, Sharon X. ; Kinloch, Mary. / Targeted Molecular and Immunohistochemical Analyses of Endometrial Clear Cell Carcinoma Show that POLE Mutations and DNA Mismatch Repair Protein Deficiencies are Uncommon. In: American Journal of Surgical Pathology. 2018.
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title = "Targeted Molecular and Immunohistochemical Analyses of Endometrial Clear Cell Carcinoma Show that POLE Mutations and DNA Mismatch Repair Protein Deficiencies are Uncommon",
abstract = "Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16{\%}) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10{\%}; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59{\%}, 22/37), followed by KRAS (13{\%}, 2/15) and PIK3CA (13{\%}, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.",
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AU - Fadare, Oluwole

AU - Köbel, Martin

AU - Decoteau, John

AU - Parkash, Vinita

AU - Hecht, Jonathan L.

AU - Hanley, Krisztina Z.

AU - Gwin, Katja

AU - Zheng, Wenxin

AU - Quick, Charles M.

AU - Jarboe, Elke A.

AU - Liang, Sharon X.

AU - Kinloch, Mary

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AB - Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16%) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10%; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59%, 22/37), followed by KRAS (13%, 2/15) and PIK3CA (13%, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.

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