Disertasi

Model Prediksi Status Mutasi KRAS pada Adenokarsinoma Kolorektal Tipe Serrated Berdasarkan Gambaran Histomorfologik serta Ekspresi P53 dan Bcl-2. = Prediction Model of KRAS Mutation Status in Colorectal Serrated Adenocarcinoma Based on Histomorphological Features and Expression of P53 and Bcl-2.

Kanker kolorektal (KKR) dianggap sebagai masalah kesehatan utama, salah satu jenis kanker yang paling sering terjadi serta penyebab kematian kedua terbesar di negara barat dan di Indonesia. Adenokarsinoma kolorektal serrated (AKS) merupakan salah satu tipe dari KKR. Salah satu jalur karsinogenesis kolorektal adalah jalur serrated yang diketahui melibatkan mutasi gen KRAS. Penanda tumor lain yang juga terlibat dalam proses karsinogenesis adalah P53 dan Bcl-2. Gambaran histomorfologik yang ditemukan oleh Tuppurainen dkk. saat ini digunakan sebagai penanda AKS. Terbatasnya sarana laboratorium patologi molekular di Indonesia, menekankan pentingnya membuat model skoring gambaran histomorfologik AKS dan atau ekspresi protein P53 serta Bcl-2 untuk memprediksi mutasi KRAS. Penelitian potong lintang terhadap 39 kasus AKS didapatkan dari Arsip Departemen Patologi Anatomik FKUI/RSCM selama tahun 2013–2015. Setiap kasus dikumpulkan data klinisnya, dan dinilai ulang karakteristik histomorfologik dan penanda tumor (Bcl2 dan P53), serta dilakukan pemeriksaan status KRAS. Penelitian histomorfologik dilakukan per kasus dan per contoh yaitu terhadap 100 kelenjar/kasus. Pada penelitian ini, kasus AKS ditemukan paling banyak pada laki-laki (51,3%), usia ≥ 40 tahun (71,8%), lokasi di kolon kiri (84,6%), tidak memiliki metastasis (92,3%), status mutasi KRAS (71,8%). Ekspresi protein P53 didapatkan pada 69,2% dan protein Bcl-2 51,3%, tidak didapatkan hubungan bermakna ekspresi protein tersebut dengan status KRAS. Gambaran histomorfologik status KRAS didapatkan hubungan pada epitel serrated, lokasi inti sel, kondisi inti, sitoplasma dan musin. Odds ratio tertinggi ditemukan pada epitel serrated (OR 2,7; IK 95% 2,30–3,07) dan musin (OR 2,0; IK 95%, 1,15–3,65). Berdasarkan uji statistik didapatkan model nilai skoring yang terdiri dari epitel serrated, keadaan lokasi inti, kondisi inti dan adanya musin (CI 95% antara 61–65%). Nilai sensitivitas dan spesifisitas berdasarkan nilai titik potong pada angka 16 sensitivitasnya sebesar 72% dan spesifisitasnya sebesar 48%. Simpulan: Didapatkan model sistem skor dengan titik potong 16 untuk memprediksi adanya mutasi KRAS berdasarkan, epitel serrated, lokasi inti sel, kondisi inti, dan adanya musin.
Kata kunci: Adenokarsinoma kolorektal serrated, Bcl-2, jalur serrated, Kanker kolorektal, mutasi KRAS, P53.


Colorectal cancer (CRC) is considered as major health problem, one type of cancer that most often occurs as well as the second largest cause of death in western countries and in Indonesia. Serrated colorectal adenocarcinoma (SA) is one type of CRC. One of colorectal carcinogenesis pathway is serrated pathway that known to involve KRAS gene mutation. Other tumor markers that also involved in the process of its carcinogenesis were P53 and Bcl-2. Histomorphological criteria found by Tuppurainen et al currently used as marker of SA. Limited facilities of molecular pathology laboratory in Indonesia emphasize the needs of making scoring model by using histomorphological features of SA and/or P53 and Bcl-2 protein expression to predict KRAS mutation. A cross sectional study conducted to 39 cases of SA registered in Departement of Anatomical Pathology FMUI/Ciptomangunkusumo Hospital from 2013–2015. All clinical data related to the cases were collected. Each case was reevaluated based on Tuppurainen histomorphological criteria, tumor markers (Bcl-2 and P53), and KRAS status. Histomorphological examination is conducted per case and per instance to 100 nodes/case. Present study showed that most cases of SA was found in male (51.3%), aged ≥ 40 years (71.8%), located in left colon (84.6%), did not have metastasis (92.3% ), with KRAS mutation status (71.8%). P53 and Bcl-2 protein expressions were found in 69.2% and 51.3% respectively, with no significant association with KRAS status. Histomorphological features of KRAS status found in epithelial serration, nucleus location, nucleus condition, cytoplasm and mucin. Epithelial serration has the highest odds ratio (OR 2.7; IK 95% 2.30–3.07) followed by mucin (OR 2.0; IK 95%, 1.15–3.65). Statistical values showed scoring models consisted of epithelial serrations, nucleus location, nucleus condition and presence of mucin (CI 95% between 61–65%). The sensitivity and specificity cut off point located on the number 16, with sensitivity value was 72% and specificity 48%. Conclusion: A scoring system model yielded 16 as cut off score was obtained to predict KRAS mutations based on epithelial serrations, nucleus location, nucleus condition and presence of mucin.
Keywords: Bcl2, Colorectal cancer, colorectal serrated adenocarcinoma, KRAS mutation, P53, serrated pathway.