Uterin adenokarsinomda MMR protein ekspresyon kaybı: Sıklığı, klinikopatolojik korelasyonları ve prognostik etkileri
Öz
Amaç: Endometriyal kanser, dünya genelinde en sık görülen jinekolojik malignitedir. Cancer Genome Atlas (TGCA) moleküler sınıflandırması, mutasyon yükü ve kopya sayı değişikliklerine göre dört farklı moleküler alt tip tanımlamıştır. MMR protein ekspresyon kaybı (dMMR), geleneksel histopatolojik özelliklere kıyasla üstün prognostik bilgi sağlayan ve tedavi stratejilerini yönlendiren önemli moleküler belirteçlerden biridir. Bu çalışmanın amacı uterin adenokarsinomlu hastalarda dMMR sıklığını belirlemek ve bunun klinikopatolojik ve prognostik parametrelerle ilişkisini değerlendirmektir. Gereç ve Yöntem: Bu retrospektif çalışmada, Ocak 2019 ile Kasım 2024 tarihleri arasında uterin adenokarsinom/endometrioid karsinom tanısı alan elli hasta analiz edildi. İmmünohistokimyasal değerlendirme MSH1, MSH6, PMS2 ve MLH1 antikorları kullanılarak yapıldı. Hastalar, FIGO 2023 evreleme sistemine göre yeniden evrelendirildi. Bulgular: Yirmi hastada (%40) uyuşmayan onarım (MMR) proteini ekspresyonunda kayıp gözlendi. Çalışma grubunun ortalama yaşı 59,1±8,5 yıldı. İmmünohistokimyasal analiz, 3 hastada (%6) MSH2 kaybı, 4 hastada (%8) MSH6 kaybı, 13 hastada (%26) MLH1 kaybı ve 17 hastada (%34) PMS2 kaybı olduğunu gösterdi. MSI pozitifliği olan hastalar daha genç yaşta tanı aldı, daha yüksek lenfovasküler invazyon oranlarına sahipti ve lenf nodu metastazı açısından daha yüksek risk taşıdı (sırasıyla p:0,18; p:0,32; p:0,40). Sonuç: dMMR değerlendirmesi, endometrial kanserde değerli prognostik bilgi sağlar. Moleküler sınıflandırmanın, gelecekte adjuvan tedavi yaklaşımlarını yönlendirmede ve kişiye özel tedavi stratejileri geliştirmede kilit bir rol oynaması beklenmektedir.
Anahtar Kelimeler
Endometriyal kanser Mikrosatellit instabilitesi İmmünohistokimya
Proje Numarası
25.TU.001
Kaynakça
- Organization WH. International Agency for Research on Cancer. Corpus uteri [Available from: https://gco.iarc.fr/today/data/factsheets/cancers/24-Corpus-uteri-fact-sheet.pdf.
- Anca-Stanciu MB, Manu A, Olinca MV, Coroleucă C, Comandașu DE, Coroleuca CA, et al. Comprehensive Review of Endometrial Cancer: New Molecular and FIGO Classification and Recent Treatment Changes. J Clin Med. 2025;14(4).
- Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
- Rüschoff J, Schildhaus HU, Rüschoff JH, Jöhrens K, Bocker Edmonston T, Dietmaier W, et al. Testing for deficient mismatch repair and microsatellite instability : A focused update. Pathologie (Heidelb). 2023;44(Suppl 2):61-70.
- Nádorvári ML, Lotz G, Kulka J, Kiss A, Tímár J. Microsatellite instability and mismatch repair protein deficiency: equal predictive markers? Pathol Oncol Res. 2024;30:1611719.
- O'Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, et al. Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J Clin Oncol. 2022;40(7):752-61.
- Post CCB, Stelloo E, Smit V, Ruano D, Tops CM, Vermij L, et al. Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer. J Natl Cancer Inst. 2021;113(9):1212-20.
- Loukovaara M, Pasanen A, Bützow R. Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma. Cancers (Basel). 2021;13(13).
- ACOG Practice Bulletin No. 147: Lynch syndrome. Obstet Gynecol. 2014;124(5):1042-54.
- Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021;31(1):12-39.
- Keverline KJ, Hill B, Hom-Tedla M, Jacobs M, Eskander RN. Impact of mismatch repair (MMR) status on recurrence in high intermediate risk endometrial cancer. Gynecol Oncol. 2025;197:116-20.
- Administration USFaD. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication [Internet]. FDA News Release; 2017 May 23 [Available from: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication.
- Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10.
- Horeweg N, Nout RA, Jürgenliemk-Schulz IM, Lutgens L, Jobsen JJ, Haverkort MAD, et al. Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer. J Clin Oncol. 2023;41(27):4369-80.
- Stelloo E, Jansen AML, Osse EM, Nout RA, Creutzberg CL, Ruano D, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2017;28(1):96-102.
- Berg HF, Engerud H, Myrvold M, Lien HE, Hjelmeland ME, Halle MK, et al. Mismatch repair markers in preoperative and operative endometrial cancer samples; expression concordance and prognostic value. Br J Cancer. 2023;128(4):647-55.
Deficient mismatch repair in uterine adenocarcinoma: Frequency, clinicopathological correlations and prognostic implications
Öz
Aim: Endometrial cancer is the most common gynecological malignancy worldwide. The Cancer Genome Atlas (TCGA) molecular classification system has identified four distinct molecular subtypes with mutation burden and copy number alterations. Deficient mismatch repair (dMMR) is an important molecular marker that provides superior prognostic information compared with traditional histopathological features and guides the treatment strategy. This study aimed is to determine the frequency of dMMR in patients with uterine adenocarcinoma and evaluate its relationship with clinicopathological and prognostic parameters. Materials and Methods: This retrospective study analyzed 50 patients diagnosed with uterine adenocarcinoma/endometrioid carcinoma between January 2019 and November 2024. Immunohistochemical evaluation was performed using antibodies against MSH1, MSH6, PMS2, and MLH1 proteins. The patients were restaged according to the Gynecology and Obstetrics International Federation of FIGO 2023 staging system. Results: Loss of mismatch repair (MMR) protein expression was observed in 20 patients (40%). The mean age of the participants was 59.18.5 years old. Immunohistochemical analysis revealed MSH2 loss in three patients (6%), MSH6 loss in four patients (8%), MLH1 loss in 13 patients (26%), and PMS2 loss in 17 patients (34%). Patients with dMMR were diagnosed at a younger age, had higher rates of lymphovascular invasion, and had a greater risk of metastasis (p:0,18; p:0,32; p:0,40 respectively). Conclusion: dMMR provides valuable prognostic information for endometrial cancer. Molecular classification is expected to play a pivotal role in guiding adjuvant treatment approaches and developing personalized therapeutic strategies in the future.
Anahtar Kelimeler
Endometrial cancer Microsatellite instability Immunohistochemistry
Destekleyen Kurum
This study was supported by the Mustafa Kemal University Scientific Research Projects Unit under Project Number 25.TU.001
Proje Numarası
25.TU.001
Teşekkür
This study was supported by the Mustafa Kemal University Scientific Research Projects Unit under Project Number 25.TU.001 Conflict of Interest: Authors declared no conflict of interest
Kaynakça
- Organization WH. International Agency for Research on Cancer. Corpus uteri [Available from: https://gco.iarc.fr/today/data/factsheets/cancers/24-Corpus-uteri-fact-sheet.pdf.
- Anca-Stanciu MB, Manu A, Olinca MV, Coroleucă C, Comandașu DE, Coroleuca CA, et al. Comprehensive Review of Endometrial Cancer: New Molecular and FIGO Classification and Recent Treatment Changes. J Clin Med. 2025;14(4).
- Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
- Rüschoff J, Schildhaus HU, Rüschoff JH, Jöhrens K, Bocker Edmonston T, Dietmaier W, et al. Testing for deficient mismatch repair and microsatellite instability : A focused update. Pathologie (Heidelb). 2023;44(Suppl 2):61-70.
- Nádorvári ML, Lotz G, Kulka J, Kiss A, Tímár J. Microsatellite instability and mismatch repair protein deficiency: equal predictive markers? Pathol Oncol Res. 2024;30:1611719.
- O'Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, et al. Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J Clin Oncol. 2022;40(7):752-61.
- Post CCB, Stelloo E, Smit V, Ruano D, Tops CM, Vermij L, et al. Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer. J Natl Cancer Inst. 2021;113(9):1212-20.
- Loukovaara M, Pasanen A, Bützow R. Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma. Cancers (Basel). 2021;13(13).
- ACOG Practice Bulletin No. 147: Lynch syndrome. Obstet Gynecol. 2014;124(5):1042-54.
- Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021;31(1):12-39.
- Keverline KJ, Hill B, Hom-Tedla M, Jacobs M, Eskander RN. Impact of mismatch repair (MMR) status on recurrence in high intermediate risk endometrial cancer. Gynecol Oncol. 2025;197:116-20.
- Administration USFaD. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication [Internet]. FDA News Release; 2017 May 23 [Available from: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication.
- Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10.
- Horeweg N, Nout RA, Jürgenliemk-Schulz IM, Lutgens L, Jobsen JJ, Haverkort MAD, et al. Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer. J Clin Oncol. 2023;41(27):4369-80.
- Stelloo E, Jansen AML, Osse EM, Nout RA, Creutzberg CL, Ruano D, et al. Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2017;28(1):96-102.
- Berg HF, Engerud H, Myrvold M, Lien HE, Hjelmeland ME, Halle MK, et al. Mismatch repair markers in preoperative and operative endometrial cancer samples; expression concordance and prognostic value. Br J Cancer. 2023;128(4):647-55.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Jinekolojik Onkoloji Cerrahisi, Kadın Hastalıkları ve Doğum |
| Bölüm | Araştırma Makalesi |
| Yazarlar | |
| Proje Numarası | 25.TU.001 |
| Gönderilme Tarihi | 23 Temmuz 2025 |
| Kabul Tarihi | 21 Ekim 2025 |
| Yayımlanma Tarihi | 9 Mart 2026 |
| DOI | https://doi.org/10.19161/etd.1748970 |
| IZ | https://izlik.org/JA83DG26FA |
| Yayımlandığı Sayı | Yıl 2026 Cilt: 65 Sayı: 1 |
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