KRAS mutations in cell-free DNA from preoperative and postoperative sera as a pancreatic cancer marker: a retrospective study

Nakano, Yuichi; Kitago, Minoru; Matsuda, Sachiko; Nakamura, Yuki; Fujita, Yusuke; Imai, Shoichi; Shinoda, Masahiro; Yagi, Hiroshi; Abe, Yuta; Hibi, Taizo; Fujii-Nishimura, Yoko; Takeuchi, Ayano; Endo, Yutaka; Itano, Osamu; Kitagawa, Yuko

doi:10.1038/bjc.2017.479

Cited by 77 publications

(78 citation statements)

References 24 publications

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“…Recently, blood‐based tests, also known as liquid biopsy, serve as potential alternative measures to radiological tests and tissue biopsies. In particular, ctDNA reflects disease status and holds advantages for the diagnosis, prognosis and monitoring of several cancers . Recently, targeted analyses of specific cancer‐associated genes in plasma cfDNA obtained satisfactory clinical applicability for several cancers .…”

Section: Discussionmentioning

confidence: 99%

“…In particular, ctDNA reflects disease status and holds advantages for the diagnosis, prognosis and monitoring of several cancers. 16,[33][34][35] Recently, targeted analyses of specific cancer-associated genes in plasma cfDNA obtained satisfactory clinical applicability for several cancers. 36 cfDNA analysis can include not only somatic mutations but also fragment size, a metric that has received comparatively scant attention.…”

Section: Discussionmentioning

confidence: 99%

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Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

et al. 2019

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Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. The present study aims to clarify the clinical utility of ctDNA for RCC. Fifty‐three patients histologically diagnosed with clear cell RCC were enrolled. Targeted sequencing was carried out using plasma cell‐free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR (ddPCR) to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics‐based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50‐166 bp) to large (167‐250 bp) cfDNA fragments. Association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log‐rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%. We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P = .033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer‐specific survival (P < .001, P = .011). In conclusion, our study shows the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

et al. 2019

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“…Based on these similar mutation types, it was suggested that the mutation of TP53 in this cohort might be a potential biomarker for predicting prognosis in Chinese patients with CCA. KRAS, the main subtype of the RAS gene family, has been reported to promote a variety of lethal human tumors, such as lung, colon and pancreatic cancer (36,37). Several studies have reported KRAS as a tumor biomarker (37)(38)(39) and that the co-mutation of TP53 and KRAS in many tumors (30,40).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genomic profile of cholangiocarcinomas in China

Shi

Liu

et al. 2020

Oncol Lett

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Cholangiocarcinoma (CCA) is a primary malignancy, which is often diagnosed as locally advanced or metastatic. Previous studies have revealed genomic characteristics of CCA in Western patients, however comprehensive genomic features of CCA in Chinese patients have not been well understood. To explore the specific genomic characteristics of Chinese patients with CCA, a total of 66 patients with CCA, including 44 intrahepatic CCA (iCCA) and 22 extrahepatic CCA (exCCA) cases, were studied. The most commonly altered genes in CCAs were TP53 (62.12%, 41/66), KRAS (36.36%, 24/66), SMAD4 (24.24%, 16/66), TERT (21.21%, 14/66), ARID1A (19.70%, 13/66), CDKN2A (19.70%, 13/66), KMT2C (9.09%, 6/66) and RBM10 (9.09%, 6/66), ERBB2 (7.58%, 5/66) and BRAF (7.58%, 5/66). Many gene mutations, including STK11, CCND1 and FGF19, were only found in iCCA. RBM10 mutations were found to be significantly higher in exCCA. The gene mutations of neurofibromin 1, STK11, CCND1 and FBXW7 specifically occurred in males, whereas gene mutations of ERBB2, AXIN2 and CREBBP specifically occurred in females. ERBB2 mutations were significantly associated with the sex of patients with CCA. Mutations in PIK3CA, FGFR2 and ZNF750 were significantly associated with the age of patients with CCA and TERT mutations were significantly associated with tumor differentiation. Alterations in KMT2C, PBRM1, AXIN2, MAGI2, BRCA2 and SPTA1 were associated with tumor mutational burden. The findings of the present study suggest that targeted sequencing, using next-generation sequencing technology, provides comprehensive and accurate information on genomic alterations, which will provide novel potential biomarkers for the diagnosis of CCA and may guide precise therapeutic strategies for Chinese patients with CCA.

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“…In addition, subtype analysis revealed that patients with Kras G12D mutation had an extremely poor prognosis with a median OS of 15.3 months in resectable pancreatic cancer, while other studies showed different results . Change of Kras mutation in ctDNA could also be used to monitor treatment response in metastatic pancreatic cancer and Kras mutation detected in ctDNA after surgery is associated with early recurrence and metastasis . Two patterns (G12V and G12D) of Kras mutation account for about 90% of all mutations in pancreatic cancer and both mutation rates range from 30% to 50%.…”

Section: Discussionmentioning

confidence: 99%

“…22,23 Change of Kras mutation in ctDNA could also be used to monitor treatment response in metastatic pancreatic cancer and Kras mutation detected in ctDNA after surgery is associated with early recurrence and metastasis. 8,24 Two patterns (G12V and G12D) of Kras mutation account for about 90% of all mutations in pancreatic cancer and both mutation rates range from 30% to 50%. Therefore, in this study, we detected these two mutation sites in ctDNA of advanced pancreatic cancer, and found that both Kras G12D mutation and Kras G12V mutation were associated with poor prognosis, which was consistent with other studies.…”

Section: Discussionmentioning

confidence: 99%

Kras mutation correlating with circulating regulatory T cells predicts the prognosis of advanced pancreatic cancer patients

Luo

Jin

et al. 2020

Cancer Medicine

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Purpose Kras mutation and abnormal immune status are associated with pancreatic cancer development and progression. In this study, we evaluated the Kras mutation status in circulating tumor DNA and circulating T cell subsets in a cohort of advanced pancreatic cancer patients. Methods Samples were retrospectively obtained from a series of 210 pathological advanced pancreatic cancer patients between 2012 and 2014. The Kras mutation status was detected in cell‐free circulating tumor DNA (ctDNA) by ddPCR and circulating T cell subsets were analyzed by flow cytometry. Results Univariate analysis found that tumor node metastasis (TNM) stage, chemotherapy, circulating regulatory T cells, CA19‐9 levels, CA125 levels, and KrasG12D and KrasG12V mutations were significantly related to overall survival in advanced pancreatic cancer patients. Multivariate analysis identified that TNM stage (P = .03, HR:1.422), Tregs (P = .004, HR:1.522), CA19‐9 levels (P = .009, HR:1.488), KrasG12D mutation (P = .044, HR:1.353), and KrasG12V mutation (P = .001, HR:1.667) were independent prognostic markers. Furthermore, we found that KrasG12V mutation in ctDNA was correlated with high circulating proportion of Tregs, and patients with both KrasG12V mutation and high levels of Tregs were associated with extremely poor survival in advanced pancreatic cancer. Conclusion KrasG12V mutation was associated with high circulating regulatory T cell levels, and both of them predicted worse prognosis in advanced pancreatic cancer patients.

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KRAS mutations in cell-free DNA from preoperative and postoperative sera as a pancreatic cancer marker: a retrospective study

Abstract: Changes in KRAS mutation status between preoperative and postoperative cfDNA may be a useful predictive biomarker for survival and treatment response.

Cited by 77 publications

References 24 publications

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

Comprehensive genomic profile of cholangiocarcinomas in China

Kras mutation correlating with circulating regulatory T cells predicts the prognosis of advanced pancreatic cancer patients

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