Influence of location-dependent sex difference on PD-L1, MMR/MSI, and EGFR in colorectal carcinogenesis

Abstract

Background The incidence and mortality rates of colorectal cancer (CRC) has been reported to be strongly associated to sex/gender difference. CRC shows sexual dimorphism, and sex hormones have been shown to affect the tumor immune microenvironment. This study aimed to investigate location-dependent sex differences in tumorigenic molecular characteristics in patients with colorectal tumors, including adenoma and CRC. Methods A total of 231 participants, including 138 patients with CRC, 55 patients with colorectal adenoma, and 38 healthy controls, were recruited between 2015 and 2021 at Seoul National University Bundang Hospital. All patients underwent colonoscopy and acquired tumor lesion samples were further analyzed for programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) expression, deficient mismatch repair (dMMR), and microsatellite instability (MSI) status. This study was registered with ClinicalTrial.gov, number NCT05638542. Results The average of combined positive score (CPS) was higher in serrated lesions and polyps (lesions/polyps) compared to conventional adenomas (5.73 and 1.41, respectively, P < 0.001). No significant correlation was found between sex and PD-L1 expression within the groups, regardless of histopathological diagnosis. In multivariate analysis where each sex was further stratified by tumor location due to their interaction in CRC, PD-L1 expression was inversely correlated with males having proximal CRC with a CPS cutoff of 1 (Odds ratio (OR) 0.28, P = 0.034). Females with proximal CRC showed a significant association with dMMR/MSI-high (OR 14.93, P = 0.032) and high EGFR expression (OR 4.17, P = 0.017). Conclusion Sex and tumor location influenced molecular features such as PD-L1, MMR/MSI status and EGFR expression in CRC, suggesting a possible underlying mechanism of sex-specific colorectal carcinogenesis.

Factors associated with negative colonoscopy in participants with a positive faecal immunochemical test from the Danish Colorectal Cancer Screening Program – a population‐based study

“…However, studies showed that right-sided adenomas are more likely to be missed during colonoscopy [28,29]. Right-sided adenomas are also more common in women than men [30,31]. This could suggest that women have a true positive FIT but a false-negative colonoscopy with missed findings.…”

Sex Difference of Colon Adenoma Pathway and Colorectal Carcinogenesis

“…For example, in recent study in Japan reported that serrated adenoma/polyp (SSA/P) lesions were mostly located in the proximal colon, and SSA/P with dysplasia or invasive carcinoma was more associated with female sex compared with SSA/P without dysplasia [ 152 ]. Furthermore, a recent study in Korea also exhibited the molecular differences such as programmed cell death-ligand 1 (PD-L1), MMR/MSI status and EGFR expression in CRC according to sex and tumor location that females with proximal CRC showed a markedly higher incidence of dMMR/MSI-high status, suggesting a possible underlying mechanism of sex-specific colorectal carcinogenesis [ 153 ]. From these results, the association with SSA/P with dysplasia or invasive carcinoma in proximal colon and female sex is suggested, and additional research focusing on sex differences in molecular pathways is needed.…”

“…A point mutation (V600E) in the BRAF oncogene is known to be mutually exclusive with mutation in KRAS [ 164 ] and associated with a poor prognosis in metastatic [ 165 ] and node-positive CRCs [ 153 159 162 ], shows sex difference. First, sessile SSA/Ps, early precursor lesions in the serrated neoplasia pathway and results in BRAF-mutated CRCs, are known to be associated with advanced age, female sex, and proximal colon [ 152 ].…”

“…0%) in a recent phase II study [ 180 ]. There is also sex difference in dMMR, that tumors with dMMR are reported to be more common in female sex, younger age, right colon, greater tumor burden, and poorer differentiation [ 181 ], and females with proximal CRC showed a significant association with dMMR/MSI-high and high EGFR expression in recent study [ 153 ]. There is differential prognosis by stage between patients with right- and left-sided CRC, that right-sided tumors have a slightly better prognosis in stage II colon cancer, but worse prognosis in stage III and IV colon cancers [ 31 ].…”

“…In another human study, PD-L1 expression was higher in serrated polyps than in conventional adenomas, higher in cancer cells than in normal control or adenoma cells and seemed to be inversely correlated with male proximal CRC patients (OR, 0.28; p=0.034) ( Fig. 10 ) [ 153 ]. Sex differences in expression of ICs are important because they can lead to differences in responses to ICI treatment.…”