Despite recent progress in understanding the cancer genome, there is still a relative delay in understanding the full aspects of the glycome and glycoproteome of cancer. Glycobiology has been instrumental in relevant discoveries in various biological and medical fields, and has contributed to the deciphering of several human diseases. Glycans are involved in fundamental molecular and cell biology processes occurring in cancer, such as cell signalling and communication, tumour cell dissociation and invasion, cell-matrix interactions, tumour angiogenesis, immune modulation and metastasis formation. The roles of glycans in cancer have been highlighted by the fact that alterations in glycosylation regulate the development and progression of cancer, serving as important biomarkers and providing a set of specific targets for therapeutic intervention. This Review discusses the role of glycans in fundamental mechanisms controlling cancer development and progression, and their applications in oncology.

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Glycosylation in cancer: mechanisms and clinical implications

The glycome describes the complete repertoire of glycoconjugates composed of carbohydrate chains, or glycans, that are covalently linked to lipid or protein molecules. Glycoconjugates are formed through a process called glycosylation and can differ in their glycan sequences, the connections between them and their length. Glycoconjugate synthesis is a dynamic process that depends on the local milieu of enzymes, sugar precursors and organelle structures as well as the cell types involved and cellular signals. Studies of rare genetic disorders that affect glycosylation first highlighted the biological importance of the glycome, and technological advances have improved our understanding of its heterogeneity and complexity. Researchers can now routinely assess how the secreted and cell-surface glycomes reflect overall cellular status in health and disease. In fact, changes in glycosylation can modulate inflammatory responses, enable viral immune escape, promote cancer cell metastasis or regulate apoptosis; the composition of the glycome also affects kidney function in health and disease. New insights into the structure and function of the glycome can now be applied to therapy development and could improve our ability to fine-tune immunological responses and inflammation, optimize the performance of therapeutic antibodies and boost immune responses to cancer. These examples illustrate the potential of the emerging field of ‘glycomedicine’. Glycosylation refers to the addition of carbohydrate chains to proteins and lipids. In this Review, the authors discuss the broad role of glycans in immunity, cancer, xenotransplantation and glomerular filtration and the potential of ‘glycomedicine’.

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Glycosylation in health and disease.

We examined plasma microRNA (miRNA) concentrations from patients with gastric cancers (GCs) to assess their clinical application for diagnosing and monitoring diseases. We initially investigated the appropriateness of plasma miRNA assay, and then compared plasma miRNA results with the expressions in cancer tissues from eight GC patients, and also compared plasma miRNAs between pre- and post-operative paired samples from 10 GC patients. Then, plasma miRNAs (miR-17-5p, miR-21, miR-106a, miR-106b and let-7a) were analysed in 69 GC patients and 30 healthy volunteers in total. The initial analysis showed that miRNAs were stable and detectable in all plasma samples, and the plasma miRNA levels reflected the tumour miRNAs in most cases. The levels of these miRNAs were significantly reduced in post-operative samples. In large-scale analysis, the plasma concentrations of miRNAs (miR-17-5p, miR-21, miR-106a, miR-106b) were significantly higher in GC patients than controls (P=0.05, 0.006, 0.008 and <0.001 respectively), whereas let-7a was lower in GC patients (P=0.002). The values of the area under the receiver-operating characteristic curve were 0.721 for the miR-106b assay and 0.879 for the miR-106a/let-7a ratio assay. Detection of circulating miRNAs might provide new complementary tumour markers for GC.

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Circulating microRNAs in plasma of patients with gastric cancers

https://cyberleninka.org/article/n/777302.pdf

Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria

Glycoconjugates constitute a major class of biomolecules which include glycoproteins, glycosphingolipids and proteoglycans. Glycans are involved in several physiological and pathological conditions, such as host-pathogen interactions, cell differentiation, migration, tumour invasion and metastisation, cell trafficking and signalling. Cancer is associated with glycosylation alterations in glycoproteins and glycolipids. This review describes various aspects of protein glycosylation with the focus on alterations associated with human cancer. The application of these glycosylation modifications as biomarkers for cancer detection in tumour tissues and serological assays is summarised.

Alterations in glycosylation as biomarkers for cancer detection

The prognostic value of preoperative serum levels of CEA, CA 19-9 and CA 72-4 tumor markers was investigated in 153 patients resected for gastric cancer. The positivity rates for CEA, CA 19-9 and CA 7

Prognostic significance of CEA, CA 19-9 and CA 72-4 preoperative serum levels in gastric carcinoma.

Background: The aim of this longitudinal study was to evaluate the effectiveness of the serum tumor markers CEA, CA 19-9, and CA 72-4 in the early diagnosis of recurrence of gastric cancer. Methods: One hundred and thirty-three patients who had undergone potentially curative surgery were considered. Serum samples were obtained preoperatively, 1 week after surgery, and at every follow-up examination. Mean follow-up time for the entire patient population was 41 ± 33 months, and 71 ± 27 months for patients classified as disease-free. Results: Preoperative positivity was 16% for CEA, 35% for CA 19-9, and 20% for CA 72-4. Recurrence of disease was found in 75 patients (56%). Marker sensitivity in recurrent cases was 44% for CEA, 56% for CA 19-9, and 51% for CA 72-4; the combined use of the three markers increased sensitivity to 87%, which reached 100% in patients with positive preoperative levels. Marker specificity, evaluated in 58 disease-free patients, was 79% for CEA, 74% for CA 19-9, and 97% for CA 72-4. Conclusions: The combined assay of CEA, CA 19-9, and CA 72-4 may be useful for early diagnosis of recurrence of gastric cancer; however, only CA 72-4 positivity should be considered a specific predictor of tumor recurrence.

Clinical utility of CEA, CA 19-9, and CA 72-4 in the follow-up of patients with resectable gastric cancer

The clinical role of microsatellite instability (MSI) in gastric cancer (GC) is controversial. A large series of patients submitted to respective surgery for primary GC with a long follow-up time was evaluated. 472 patients with prospectively collected frozen samples of normal mucosa and tumor tissue stored in a biological tissue bank were included. Microsatellite analysis was evaluated using 5 quasi monomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27). The presence of MSI in 2 or more loci was classified as MSI-H, whereas all other cases were included in the microsatellite-stable (MSS) group. MSI-H phenotype was found in 111 of 472 patients (23.5 %). MSI-H status was related significantly with older age, female gender, non-cardia location, WHO histotype, non-cardia Lauren intestinal type, and less advanced stages. Cancer-related 5-year survival was significantly higher in MSI-H versus MSS group (67.6 % vs. 35 %, p < 0.001). Stratified analysis revealed a significant impact of MSI on prognosis in non-cardia tumors of intestinal type or tubular/poorly differentiated histology, particularly in stages II and III; multivariate Cox regression analysis confirmed MSS status as a strong predictor of poor prognosis (hazard ratio 2.65, 95 % CI 1.56–4.51, p < 0.001) in non-cardia intestinal type. No prognostic value of MSI in the diffuse-mixed type and signet-ring cell/mucinous histotypes was observed. MSI was confirmed as a significant predictor of long term outcome in a large series of GC with a long follow-up time, but the prognostic value is limited to selected histotypes of non-cardia tumors.

Strong Prognostic Value of Microsatellite Instability in Intestinal Type Non-cardia Gastric Cancer.

BACKGROUND: Recent studies have suggested that Helicobacter pylori (H. pylori) infection may be related to better prognosis in patients with gastric cancer, but to the authors’ knowledge, this finding has not yet been validated. In the current study, the association between H. pylori status and clinical outcome was investigated in a large cohort of patients. METHODS: Frozen non-neoplastic gastric mucosa and serum samples obtained from 297 patients who underwent surgery for primary gastric cancer between 1988 and 2004 were retrieved from the serum and tissue bank of the study department. H. pylori status was defined by means of polymerase chain reaction (PCR) analysis for the vacA gene in gastric mucosa and by serologic assay of H. pylori and CagA antibodies. Univariate and multivariate analyses were used for the association between clinicopathologic variables and long-term outcome. RESULTS: Positivity for H. pylori infection was observed in 256 of 297 patients (86%), whereas in 41 patients (14%), PCR for vacA and both serologic tests were negative. Negative H. pylori status was found to be significantly associated with cardia location, advanced pT classification, noncurative surgery, and a lower 5-year survival rate after R0 resection (24% vs 57%; P < .001). Multivariate survival analysis confirmed H. pylori status as a significant prognostic factor (hazards ratio, 2.47; 95% confidence interval, 1.40-4.35 [P ¼ .002]). The influence of H. pylori status on long-term survival was observed in patients with early as well as advanced pT classifications. CONCLUSIONS: Negative H. pylori status appears to be an indicator of poor prognosis in patients with gastric cancer, and is independent of other well-known clinical and pathologic prognostic variables. Cancer 2009;115:2071–80. V C 2009 American Cancer Society.

Negative Helicobacter pylori status is associated with poor prognosis in patients with gastric cancer.

Background The aim of this study was to evaluate the risk of liver metastases after radical surgical treatment for gastric cancer, the potential risk factors involved, and the sensitivity of serum tumor markers during followup. Study design A total of 208 patients who had undergone curative resection for primary gastric cancer and a prospective followup protocol were studied. The association between clinicopathologic variables and hepatic recurrence was investigated using standard univariate methods and multivariate Cox regression analysis. Results Mean followup time (± SD) for the entire patient population was 51 ± 38 months (median 52 months) and was 88 ± 24 months (median 81 months) for disease-free patients. Recurrence of gastric cancer was documented in 109 of 208 patients (52.4%). Liver metastases were found in 28 of 208 patients (13.5%); in most of these patients (82.1%) diagnosis was made within 2 years after surgical treatment. The estimated cumulative risk of liver metastases after 5 years was 16.4%. Cox regression analysis identified lymph node involvement (adjusted relative risk [RR] = 6.28, 95% confidence interval [CI] = 2.11 to 18.70, p=0.001), preoperative positivity for CEA, CA 19-9, or CA 72-4 (RR = 5.18, 95% CI=1.75 to 15.37, p=0.003), and intestinal histotype (RR = 3.08, 95% CI=1.06 to 8.96, p=0.039) as independent predictors of hepatic recurrence. In 27 of 28 cases hepatic recurrence was associated with an increase in CEA, CA 19-9, or CA 72-4 serum levels above the cutoff, either before or at the time of the clinical diagnosis (sensitivity 96.4%). Conclusions Preoperative positivity for serum tumor markers, lymph node involvement, and intestinal histotype are risk factors for liver metastases after radical surgical treatment for gastric cancer. Postoperative measurement of serum tumor markers may be useful for an early diagnosis of hepatic recurrence during followup.

https://www.journalacs.org/article/S1072-7515(03)00987-6/pdf

Risk factors for liver metastases after curative surgical procedures for gastric cancer: a prospective study of 208 patients treated with surgical resection

Lorenzo Garosi

Papers

Prognostic significance of CEA, CA 19-9 and CA 72-4 preoperative serum levels in gastric carcinoma.

Clinical utility of CEA, CA 19-9, and CA 72-4 in the follow-up of patients with resectable gastric cancer

Strong Prognostic Value of Microsatellite Instability in Intestinal Type Non-cardia Gastric Cancer.

Negative Helicobacter pylori status is associated with poor prognosis in patients with gastric cancer.

Risk factors for liver metastases after curative surgical procedures for gastric cancer: a prospective study of 208 patients treated with surgical resection