Additional file 1: of Construction of quality of life change patterns: example in oncology in a phase III therapeutic trial (FFCD 0307)

Annex 1: The Full EORTC QLQ-C30 version 3 questionnaire with 30 items and their answer options. The physical functioning scale is concerned by items 1 to 5. Annex 2: Construction steps of quality of life change pattern from longitudinal data score, taking into account the presence of missing scores. Annex 3: Listing of the 27 statistical measures of change with in bold case (N°), the measures selected for the classification. Annex 4: The CritCF formula. (DOCX 568 kb

Additional file 1: Table S1. of Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study

SNPs studied and their frequencies in our population. This table contains the description and frequencies of the SNP investigated in the study for ABCB1, UGT, MRP2, SLCO1B1 and SLCO1B2 genes. (DOCX 22 kb

Beta catenin immunostaining in MSS tumors.

<p><b>A.</b> Cross-section of a tumor from an MSS-Old patient shows only membrane staining. <b>B</b>. Cross-section of a tumor from a sporadic EOCRC (MSS–Young) patient shows strong cytoplasmic and nuclear staining with a loss of membrane staining, reflecting Wnt/beta catenin activation.</p

Sporadic Early-Onset Colorectal Cancer Is a Specific Sub-Type of Cancer: A Morphological, Molecular and Genetics Study

<div><p>Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45–60 years were excluded to help define “young” and “old” groups. Thirty-nine cases of sporadic EOCRC (patients≤45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for <i>TP53</i>, <i>KRAS</i>, <i>BRAF</i>, <i>PIK3CA</i> mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of <i>BRAF</i> mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease.</p></div

Clinico-pathological features of each group showing significant differences among the 79 variables studied.

<p>Data are expressed as absolute number and relative percentage. SD: standard deviation, M/F: male/female, UICC: Union for International Cancer Control (2002 classification), CRC: colorectal cancer. *: One case with liver and ovary metastases, 6 cases with liver and lung metastases, one case with liver and brain metastasis and one case with ovary and peritoneum metastasis. **: Two cases presented with liver and peritoneum metastases.</p

Supervised analysis of MSS tumors (n = 54).

<p>The heat map shows the expression of 219 genes. Based on expression levels, genes were grouped into four clusters of highly overexpressed genes (red boxes surrounded by a black border) and one cluster of underexpressed genes in MSS tumors (blue boxes surrounded by a black border) from young patients compared to MSS tumors from older patients. MSS: Microsatellite Stable. MSI: Microsatellite Instability.</p

Overall survival in the four patient groups.

<p>Each group had a specific overall survival profile although none were significantly different from each other (p = 0.15). MSS: Microsatellite stable. MSI: Microsatellite unstable.</p

Consort diagram.

<p>Consort diagram depicting the selection of patients from a single institution, on the basis of available frozen tissue and after applying exclusion criteria. Four groups were defined by taking into account age and MMR status. The study was designed to allow the comparison of MSS early-onset CRC with other well-defined groups of CRC. FAP: Familial Adenomatous Polyposis. IBD: Inflammatory Bowel Disease. MMR status: Mismatch Repair status. MSS: Microsatellite stable. MSI: Microsatellite unstable.</p

Unsupervised analysis of expression profiles of the four patient groups.

<p>Unsupervised classification of expression profiles: dendrogram of the closest clustering to the consensus partition for k = 5. Legend: io, MSI/Old; iy, MSI/Young; so, MSS/Old; sy, MSS/Young; d, deficient MMR; p, proficient MMR; R, right colon; L, left colon; Re, rectum; M, mutated; W, wild-type.</p

Pathway analysis of MSS tumors.

<p>Pathway analysis grouping the 49 most significantly enriched pathways for differential gene expression between sporadic EOCRC and MSS tumors from old patients. Pathways were grouped into five main categories, namely cell adhesion/motility, inflammation/apoptosis, cell proliferation, cell signalling and developmental biology. The distribution of the main canonical pathways among categories is detailed as well as their rank order. This rank order is indicated by the # symbol followed by the row number (# 1 means that this pathway is the most deregulated among the 49 pathways).</p