الفهرس 
Dukes system for CRC stagingOnly 14 pages are availabe for public view
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Abstract
Colorectal carcinoma (CRC) is the most common gastrointestinal malignancy and the third most common cancer globally. In Egypt, CRC represents 6.48% of total malignancies. Despite advances in molecular based cancer therapy, there are resistant cases for therapy. Cancer biology research has helped to elucidate some of the genetic mechanisms leading to colorectal carcinogenesis and may be a cause of resistance to conventional chemotherapy. However, accumulating evidence suggests that tumor progression is governed not only by genetic changes intrinsic to cancer cells but also by tumor microenvironment (TME). Increased understanding of the TME and correlation of it with cancer cells has revealed novel biomarkers that helped in the development of new agents for blockage of all tumors stromal interconnected pathways that promote carcinogenesis. Among the most promising molecules are sterol O-acyltransferase 1 (SOAT1), yes-associated protein 1 (YAP1) and large tumor suppressor 1 (LATS1) in CRC studies showed a wide controversy between being protective or oncogenic. SOAT1 and YAP shared the same proliferative role.
To date, drugs are promising for targeting SOAT1. However, verteporfin was approved by food and drug administration (FDA) as YAP antagonist.
However, a clear consensus has not been reached on the triple relationship of SOAT1, YAP1 and LATS1in CRC. This study aimed to evaluate the role of sterol O-acyltransferase 1 (SOAT1), Yes associated protein1 (YAP1) and LATS1 in pathogenesis of CRC and to assess their prognostic impact on CRC patients.
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This retrospective case control study involved 99 cases, divided into 30 adenoma specimens, 69 CRC specimens retrieved from the archival material of Pathology Departments of Faculty of Medicine, Menoufia University and Tanta Cancer Center during the period between 2019 and 2023. Hematoxylin and eosin (H&E) stained slides of the selected cases’ blocks were examined carefully to identify viable and representative areas of each sample. Tissue microarray technique was performed through sampling of three cores of representative areas of the tumor and stroma from each specimen.
The included 30 colonic adenoma specimens thirteen specimens (43.3%) were of tubular type, 11 specimens (36.7%) were of the tubulovillous type and 6 cases (20%) were of villous type. Sixteen specimens (53.3%) showed low grade dysplasia and 14 cases (46.7%) showed high grade dysplasia.
The included 69 CRC cases, their age ranged between 24 and 82 years with a median of 54 years and a mean±SD of 52.10±14.39 years. Thirty-five cases (50.7%) were males and thirty-four cases (49.3%) were females. Twenty-four cases (34.8%) had the tumor in right colon, 25 cases (36.2%) in distal colon and 20 cases (29%) in rectum.
Tumor size ranged between 2 and 20 cm and with a mean±SD of 6.81 ± 4.27 and a median of 6. Grossly, 31 (44.9%) cases presented as fungating mass, ten cases (14.5%) were infiltrative and 28 cases (40.6%) were ulcerative lesion. Eight cases (11.6%) showed gross perforation. Fifty-five cases (79.8%) were of advanced T stage (T3, T4).
Thirty-two cases (46.4%) showed positive LNs (N1, N2). Sixty-eight cases with available metastatic data showed metastasis (M1) in 15 cases (21.7%) and 37 cases (53.6%) were of early-stage grouping (I, II).
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Regarding the number of positive lymph nodes, it ranged from 0 to 13 lymph nodes with a mean ±SD of 1.78 ± 2.82 and median was 3 lymph nodes. Forty-five cases (65.2%) were conventional adenocarcinoma, 15 cases (21.8%) were adenocarcinoma with mucinous differentiation and 9 cases (13%) were mucinous adenocarcinoma. Forty cases (58%) were of low grade, while 29 cases (42%) were of high grade. Twelve cases (17.4%) showed lympho-vascular invasion and Six cases (8.7%) showed perineural invasion. Necrosis was detected in 11 cases (15.9%). Mitosis ranged from 1 to 17/ 10 HPF with median of 5 and mean ± SD of 6.71 ± 5.55. Thirty-nine cases (56.5%) showed low tumor budding group. Twenty-nine cases (42%) showed a high tumor stroma ratio, while 40 cases (58%) showed a low ratio.
Forty-seven cases (68.1%) showed low and intermediate TIL scores. Thirty-six cases (52.2%) cases were of pushing tumor border configuration, while 33 cases (47.8%) were of infiltrating border.
All 69 CRC cases were available with complete follow-up and survival data. Forty-four cases (63.8%) were alive, 25 cases were dead.
Regarding SOAT1, there was a statistically significant difference between adenoma and malignant cases regarding expression of SOAT1 as 73.4% of malignant cases showed high SOAT1 expression while 52% of adenoma cases showed low expression (P=0.049).
A higher SOAT1 score demonstrated a statistically significant association with poor prognostic factors as younger age group with median 47 years old (P=0.02), poorly differentiated tumors (P=0.042), large number of positive lymph nodes (P=0.02), late AJCC tumor stage (P=0.02) and high-grade tumors (P=0.02). Moreover, there was a statistically significant association between high score and high mitotic count(P= 0.05),
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high tumor budding score (P=0.01), high tumor stromal ratio (P=0.02), and infiltrating tumor borders
(P= 0.005).
Regarding YAP1 There was a highly statistically significant relationship between CRC cases and colonic adenoma cases regarding localization of YAP1 (P=0.005), as 88.9% of adenoma cases showed cytoplasmic staining.
Also, there was a significant relationship between CRC cases and colonic adenoma cases regarding intensity (P=0.011) as thirty-three of CRC cases showed mild expression and 29 cases of CRC cases showed strong intensity.
High YAP1 expression showed significant association poor prognostic factors as young age (P=0.001), right colon located tumor (P=0.023), large tumor size (P=0.007), poorly differentiated tumor (P<0.001), high number of positive lymph nodes (P<0.001) high tumor stage (P<0.001), high lymph nodal staging (P<0.001), presence of distant metastasis (P<0.001), late AJCC staging (P<0.001), high grade cases (P<0.001), mucinous type (P=0.002), high mitotic index and (P<0.001),high tumor budding group as well as high tumor budding number (P<0.001), high tumor stromal ratio (P<0.001), low tumor infiltrating lymphocytes (TIL ) score (P<0.001), infiltrative tumor border (P<0.001).
Regarding LATS1 high score of LATS1 showed significant association with good prognostic factors as old age (P=0.004), rectal located tumor (P=0.002), small tumor size (P=0.017), well differentiated tumor(P<0.001), absence of positive lymph node (P<0.001), low tumor stage (T1,T2) (P=0.001), early lymph nodal staging (P<0.001), absence
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of distant metastasis (P<0.001), early AJCC staging (P<0.001), low grade cases (P<0.001) ,conventional adenocarcinoma type (P=0.026),low mitotic count (P<0.001), low tumor budding group as well as tumor budding number (P<0.001), low tumor stromal ratio (P<0.001), high tumor infiltrating lymphocytes (TIL) score (P<0.001), pushing tumor border configuration (P<0.001).
The positive relationship between SOAT1 and YAP1 expression in CRC suggests that these two proteins may work together to promote tumor growth and metastasis. Both proteins have a role in tumor progression, SOAT1 regulates free cholesterol levels by forming cholesterol esters.
both YAP1 and LATS1 are Hippo pathway proteins, the current study showed an inverse relationship between their expression levels in colorectal carcinoma.
Univariate survival analysis revealed a significant association of Prolonged OS and PFS with low SOAT1 expression, low YAP1 expression and high LATS1 expression.
Multivariate Cox regression analysis showed that nodal metastasis was the only independent prognostic factor affecting OS among the studied clinicopathologic parameters.
In conclusion SOAT1 and YAP1 are bad prognostic markers evidenced by their significant association with bad prognostic clinicopathological parameters, short OS and progression free survival, While LATS1 is a good prognostic marker evidenced by its significant association with favorable prognostic clinicopathological parameters, prolonged OS and progression free survival.