Abstract
BackgroundColorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard treatment for patients with locally advanced non-metastatic rectal cancer is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU) followed by surgery, but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance.MethodsFrom twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic rectal cancer patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-three patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups.ResultsWe have highlighted 384 differentially abundant proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially abundant proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Data are available via ProteomeXchange with identifier PXD008440.ConclusionsFrom these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic rectal cancer. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.
Highlights
Colorectal cancer is the third most common and the fourth most lethal cancer in the world
We have developed a protein extraction protocol from formalin-fixed paraffin-embedded (FFPE) biopsies of patients with locally advanced non-metastatic rectal cancer (Fig. 1) which allowed us to extract a satisfactory quantity of proteins identified by mass spectrometry, with an average of 4000 proteins identified by samples (Additional file 7: Table S7)
In conclusion, our retrospective study aims to identify a predictive protein signature of the neoadjuvant radio-chemo‐ therapy (NRCT) response to radiotherapy with 5-FU in patients with locally advanced non-metastatic rectal cancer from FFPE biopsies obtained in pre-treatment
Summary
Colorectal cancer is the third most common and the fourth most lethal cancer in the world. Colorectal cancer (CRC) is the third most common cancer (9.7%) in the world behind lung (13%) and breast (12%) cancers and the fourth most lethal (8.5%) behind lung (19%), liver (9.1%) and stomach (8.8%) cancers [1] This high mortality can be explained by a late detection of the cancer, so patients are often diagnosed with locally advanced tumor completely invading the wall of the rectum (T3) or peripheral tissues or organs (T4), and often regional lymph node metastases are found (N1 or N2). Considering the severe secondary effects observed such as radiodermatitis and proctitis, there is a strong need in clinic to have reliable biomarkers in order to predict the outcome of the treatment and to identify the sub-group of patients with resistant phenotype, permitting to avoid long, costly and ineffective procedures but with an adequate personalized treatment
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