Gene Variants That Affect Levels of Circulating Tumor Markers Increase Identification of Patients With Pancreatic Cancer

Abe, Toshiya; Koi, Chiho; Kohi, Shiro; Song, Ki Byung; Tamura, Koji; Macgregor-Das, Anne M.; Kitaoka, Naoki; Chuidian, Miguel; Ford, Madeline; Dbouk, Mohamad; Borges, Michael; He, Jin; Burkhart, Richard A.; Wolfgang, Christopher L.; Klein, Alison P.; Eshleman, James R.; Hruban, Ralph H.; Canto, Marcia Irene; Goggins, Michael

doi:10.1016/j.cgh.2019.10.036

Cited by 43 publications

(31 citation statements)

References 36 publications

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“…In 10 patients among them, the CA 19-9 remained consistently high without causative disease during the follow-up period. It is well known that the Lewis (FUT3) and Secretor (FUT2) genes regulate CA 19-9 secretion [39][40][41] . Lewis inactivity rarely leads to secretion of CA 19-9, and Secretor inactivity can increase CA 19-9 secretion.…”

Section: Discussionmentioning

confidence: 99%

Carbohydrate antigen 19-9 elevation without evidence of malignant or pancreatobiliary diseases

Kim

Park

Seo

et al. 2020

Sci Rep

101

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Although carbohydrate antigen 19-9 (CA 19-9) may be elevated in benign diseases, elevated CA 19-9 may cause a fear of cancer and unnecessary follow-up studies. Research on how to approach systematically in this case is very limited. The purpose of this study was to analyze the clinical features and the causes of CA 19-9 elevation without evidence of malignant or pancreatobiliary diseases. We retrospectively reviewed the medical records of patients who had CA 19-9 elevation (≥80 U/mL) and were found to be unrelated to cancer after follow-up. After exclusion, 192 patients were included in this study. The median level of CA 19-9 was 136.5 U/mL. The causes of CA 19-9 elevation were determined in 147 (76.6%) patients, and that was unknown in 45 (23.4%). The estimated causative diseases were hepatic diseases in 63 patients, pulmonary diseases in 32, gynecologic diseases in 38, endocrine diseases in 13, and spleen disease in 1. Of 45 patients with unknown cause, 35 had normalization of CA 19-9 and 10 had persistently elevated CA 19-9. In conclusion, CA 19-9 elevation without malignancies or pancreatobiliary diseases should be systematically evaluated and followed up. We suggest an algorithm to investigate the causes and follow up these patients. Tumor markers are useful for screening and diagnosis of cancer in high-risk patients, evaluating the response to cancer treatment and detecting the recurrence of cancer. As health checkups are becoming widely available, tumor markers are being checked in asymptomatic healthy people for screening purposes. Among the many tumor markers, carbohydrate antigen 19-9 (CA 19-9) has a relatively high sensitivity and specificity for pancreatic and biliary tract tumors 1,2. According to previous studies, the sensitivity of CA 19-9 in diagnosing pancreatic cancer ranges between 79% and 95%, and the specificity ranges between 82% and 91% 3,4. CA 19-9 has its diagnostic value when the patient has symptoms such as weight loss, abdominal pain, and jaundice or when imaging studies indicate a tumor. However, in asymptomatic patients, there is little evidence of its clinical value in screening for cancer 5-8. In a study conducted with 70,940 asymptomatic individuals, the positive predictive value of CA 19-9 was only 0.9% including ineffectiveness in screening for pancreatic cancer 8. CA 19-9 is synthesized in the normal pancreatic parenchyma and biliary tract. It is also produced from the epithelial cells of the gastric, colonic, and uterine mucosa, as well as the salivary glands 9. From a malignant tumor perspective, CA 19-9 has been reported to be increased in stomach, colorectal, lung, thyroid, as well as biliary and pancreatic cancer 10. CA 19-9 is often elevated in benign pancreatobiliary diseases such as cholangitis, obstructive jaundice and pancreatitis 11,12. Additionally, it has been reported that elevated CA 19-9 levels can be found in other non-malignant conditions such as pulmonary and thyroidal diseases, diabetes mellitus, and gynecologic diseases 5,13,14. In patients with an elevated...

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Section: Discussionmentioning

confidence: 99%

Carbohydrate antigen 19-9 elevation without evidence of malignant or pancreatobiliary diseases

Kim

Park

Seo

et al. 2020

Sci Rep

101

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“…Null alleles of FUT3 and FUT2 are present in the human population, and their genomic dosage affects the amounts of individual antigens expressed, including circulating CA19.9 [75][76][77][78]. FUT3 −/− subjects are known to lack any type 1 chain Lewis antigen, while FUT3 +/+ /FUT2 −/− individuals are candidates for higher expression of CA19.9 than FUT3 −/+ /FUT2 +/+ individuals.…”

Section: A Proposed Model Of Circulating Ca199 and Type 1 Chain Lewimentioning

confidence: 99%

Complementary Use of Carbohydrate Antigens Lewis a, Lewis b, and Sialyl-Lewis a (CA19.9 Epitope) in Gastrointestinal Cancers: Biological Rationale towards a Personalized Clinical Application

Indellicato

Zulueta

Caretti

et al. 2020

Cancers

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Carbohydrate antigen 19.9 (CA19.9) is used as a tumor marker for clinical and research purposes assuming that it is abundantly produced by gastrointestinal cancer cells due to a cancer-associated aberrant glycosylation favoring its synthesis. Recent data has instead suggested a different picture, where immunodetection on tissue sections matches biochemical and molecular data. In addition to CA19.9, structurally related carbohydrate antigens Lewis a and Lewis b are, in fact, undetectable in colon cancer, due to the down-regulation of a galactosyltransferase necessary for their synthesis. In the pancreas, no differential expression of CA19.9 or cognate glycosyltransferases occurs in cancer. Ductal cells only express such Lewis antigens in a pattern affected by the relative levels of each glycosyltransferase, which are genetically and epigenetically determined. The elevation of circulating antigens seems to depend on the obstruction of neoplastic ducts and loss of polarity occurring in malignant ductal cells. Circulating Lewis a and Lewis b are indeed promising candidates for monitoring pancreatic cancer patients that are negative for CA19.9, but not for improving the low diagnostic performance of such an antigen. Insufficient biological data are available for gastric and bile duct cancer. Studying each patient in a personalized manner determining all Lewis antigens in the surgical specimens and in the blood, together with the status of the tissue-specific glycosylation machinery, promises fruitful advances in translational research and clinical practice.

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“…Interestingly, as an O-glycosyltransferases, the single nucleotide polymer-phisms (SNPs) of B3GNT3 also might affect levels of circulating tumor biomarkers including CA19-9, CEA and AFP. By SNP-de ned ranges for each tumor marker, diagnostic speci city and sensitivity of CA19-9 were improved in the identi cation of patients with PAAD [26,27]. As is known, CA19-9 shows many shortcomings of unsatisfactory diagnostic accuracy in the routine management of PAAD.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of B3GNT3 Correlates With Poor Prognosis and Decreased Immune Cell Infiltration In Pancreatic Adenocarcinoma

Chen¹,

Zhai²,

Wang³

et al. 2021

Preprint

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While previous studies have suggested that B3GNT3 is associated with tumorigenesis and progression of several tumors, its expression level and clinical significance in pancreatic adenocarcinoma (PAAD) remains unclear. Our study aimed to investigate the role of B3GNT3 in PAAD. B3GNT3 RNA sequencing and clinicopathological data were collected from the TCGA, GEO and GTEx databases. We assessed the expression and prognostic value of B3GNT3 in PAAD using R program and attached packages. Additionally, we investigate the correlation between B3GNT3 expression and tumor-infiltrating immune cells using CIBERSORT and the “correlation” module of GEPIA. Finally, gene set enrichment analysis (GSEA) was used to elucidate B3GNT3 related signaling pathways in PAAD. Results showed that B3GNT3 expression was significantly higher in tumor tissues compared to normal tissues (P <0.05). Increased B3GNT3 expression was correlated with advanced histologic grade and stage (Ⅰ Vs Ⅱ). Patients with high B3GNT3 expression had a worse OS (HR = 1.713, P = 0.0005). Moreover, a negative correlation between increased B3GNT3 expression and immune infiltrating level of naive B cells, CD8 T cells, and CD4 memory activated T cells was revealed by CIBERSORT analysis. Then, further analysis verified the correlation using the “correlation” module of GEPIA. Finally, GSEA suggested that functional enrichment of B3GNT3 was mainly involved in pathways in cancer, p53 signaling pathway, TGF beta signaling pathway, catabolic and transport processes of proteins, etc. Collectively, these results suggested that overexpression of B3GNT3 might affect the infiltration of immune cells and could act as a potential prognostic biomarker of PAAD.

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Gene Variants That Affect Levels of Circulating Tumor Markers Increase Identification of Patients With Pancreatic Cancer

Cited by 43 publications

References 36 publications

Carbohydrate antigen 19-9 elevation without evidence of malignant or pancreatobiliary diseases

Carbohydrate antigen 19-9 elevation without evidence of malignant or pancreatobiliary diseases

Complementary Use of Carbohydrate Antigens Lewis a, Lewis b, and Sialyl-Lewis a (CA19.9 Epitope) in Gastrointestinal Cancers: Biological Rationale towards a Personalized Clinical Application

Upregulation of B3GNT3 Correlates With Poor Prognosis and Decreased Immune Cell Infiltration In Pancreatic Adenocarcinoma

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