Genetic alterations in MSS and TMB-H Chinese colorectal cancer patients.

e15524 Background: Efforts by previous study had provided molecular profile of MSS & TMB-H gastrointestinal (GI) cancers, however, Asian patients were underrepresented in this study. We aim to investigate specific molecular features of Chinese MSS & TMB-H colorectal cancer patients. Methods: FFPE tumor samples from 249 Chinese colorectal cancer patients with MSS & TMB-H (Chinese cohort) were sequencing using a panel targeting 539 cancer-related genes of the human genome. Genomic data from our cohort was compared with publicly available data from 508 MSS & TMB-H colorectal cancer patients from the TCGA dataset (TCGA cohort). TMB was calculated on the two cohorts following the same criteria. TMB-H was defined as the top quartile of all TMB values. Results: In total, 48 (19%) MSS & TMB-H patients were found in Chinese cohort, and 55 (10%) were found in TCGA cohort. Based on the analysis of the genetic alteration profile from our cohort, in MSS & TMB-H colorectal cancer patients, APC (85%), TP53 (81%), KRAS (44%), and LRP1B (378%) as the most commonly altered genes. In TCGA cohort, TTN (84%), APC (80%), TP53 (64%), SYNE1 (51%), and MUC16 (51%) as the most commonly altered genes. On the other hand, the most difference genes between MSS & TMB-H group and MSS/TMB-L group in TCGA cohort were TNN (84% vs. 52%; p = 0.000008), SYNE1 (56% vs. 24%; p = 0.000003), MUC16 (51% vs. 23%; p = 0.00006), FAT4 (47% vs. 16%; p = 0.000002), RYR2 (44%vs. 16%; p = 0.00001). Compared with TCGA cohort, LRP1B (38% vs. 13%; p = 0.0005), TCF7L2 (33% vs. 8%; p = 0.00003), SPTA1 (29% vs. 6%; p = 0.00005), PREX2 (19% vs. 3%; p = 0.0006) were the most difference genes between MSS & TMB-H group and MSS/TMB-L group in Chinese cohort. Conclusions: Our study contributes to the understanding of specific genetic alterations harbored by MSS & TMB-H colorectal cancer patients that could potentially be developed as markers of precision medicine.

Download Full-text

Clinicopathological and Molecular Features of Colorectal Cancer Patients With Mucinous and Non-Mucinous Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.620146 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yuan-Tzu Lan ◽

Shih-Ching Chang ◽

Pei-Ching Lin ◽

Chun-Chi Lin ◽

Hung-Hsin Lin ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Colon Cancer ◽

Cancer Patients ◽

Mucinous Adenocarcinoma ◽

Tumor Location ◽

Genetic Alterations ◽

Molecular Features ◽

Poor Differentiation ◽

Colorectal Cancer Patients

BackgroundThe prognosis of mucinous adenocarcinoma (MAC) and non-mucinous adenocarcinoma (NMAC) in colorectal cancer (CRC) is controversial, and the molecular differences between them are unclear.MethodsBetween 2000 and 2010, a total of 1,483 CRC patients were included. Among them, 73 patients (4.9%) were diagnosed with MAC. The clinicopathological features and genetic alterations were compared between MAC and NMAC.ResultsAfter propensity score matching to balance age and sex between MAC and NMAC patients, 292 CRC patients (73 MAC and 219 NMAC) were enrolled in the analysis at a 1:3 ratio. In right-sided colon cancer, patients with MAC were more likely to have Borrmann types 3 and 4 tumors, poor differentiation, and advanced T category and tumor, node, metastasis (TNM) stage, chemotherapy, and a similar 5-year overall survival (OS) rate compared with patients with NMAC. In left-sided colon cancer and rectal cancer, patients with MAC were more likely to have Borrmann types 3 and 4 tumors, poor differentiation, lymphovascular invasion, advanced T and N categories and TNM stages, chemotherapy, and a worse 5-year OS rate than patients with NMAC. Regarding genetic alterations, for NMAC, right-sided colon cancer had more BRAF mutations than left-sided colon cancer and rectal cancer. For MAC, right-sided colon cancer was associated with more microsatellite instability-high tumors and more AKT1 mutations than left-sided colon cancer and rectal cancer.ConclusionThe genetic alterations are distinct between MAC and NMAC in CRC. Tumor location may have an impact on genetic alterations and patient prognosis in MAC and NMAC.

Download Full-text

Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features

International Journal of Cancer ◽

10.1002/ijc.32044 ◽

2019 ◽

Vol 144 (9) ◽

pp. 2161-2168 ◽

Cited By ~ 8

Author(s):

Wu Jiang ◽

Mu-Yan Cai ◽

Shi-Yong Li ◽

Jin-Xin Bei ◽

Fang Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Cancer Patients ◽

Universal Screening ◽

Molecular Features ◽

High Prevalence ◽

Colorectal Cancer Patients

Download Full-text

Prevalence of germline genetic alterations in colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.1577 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 1577-1577 ◽

Cited By ~ 1

Author(s):

Andrea Cercek ◽

Yelena Kemel ◽

Diana Mandelker ◽

Carolyn Stewart ◽

Angela G. Arnold ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Genetic Alterations ◽

Colorectal Cancer Patients

Download Full-text

Detection of allelic variants of the POLE and POLD1 genes in colorectal cancer patients

Balkan Journal of Medical Genetics ◽

10.1515/bjmg-2017-0028 ◽

2017 ◽

Vol 20 (2) ◽

pp. 83-87 ◽

Cited By ~ 1

Author(s):

LA Pätzold ◽

D Bērziņa ◽

Z Daneberga ◽

J Gardovskis ◽

E Miklaševičs

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

High Performance ◽

Genetic Alterations ◽

Hereditary Colorectal Cancer ◽

Allelic Variants ◽

Cancer History ◽

Unknown Significance ◽

Colorectal Cancer Patients ◽

Cancer Syndromes

Abstract Incidence of colorectal cancer is high worldwide and it mostly occurs as an accumulation of environmental factors and genetic alterations. Hereditary colorectal cancer can develop as a part of a hereditary syndrome. There is a suspected correlation between colorectal cancer and allelic variants of the POLE and POLD1 genes. The aim of the present study was to look for associations between the allelic variants in the POLE and POLD1 genes and colorectal cancer. One thousand, seven hundred and forty-nine DNA samples from colorectal cancer patients were collected from 2002 to 2013. Samples were divided in three groups: hereditary colorectal cancer patients, patients with different hereditary cancer syndromes in their families and patients with no cancer history in their families. The DNA samples were screened for allelic variants of POLE rs483352909 and POLD1 rs39751463 using denaturing high performance liquid chromatography (DHPLC). All patients were negative for allelic variants rs483352909 of the POLE gene and rs397514632 of the POLD1 gene. One allelic variant rs373243003 in the POLE gene and one novel duplication of four nucleotides at the excision site between intron and exon (c.1384-5dupCCTA) in the POLD1 gene, was found. We could not detect or confirm the connection between the genetic variants in the POLD1 and POLE genes and colorectal cancer patients, but we detected a novel genetic variant with an unknown significance.

Download Full-text

Prospective study of genetic mutations in matched tumor and plasma specimens in colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.356 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 356-356

Author(s):

G. Perkins ◽

J. Dukes ◽

T. A. Yap ◽

R. Riisnaes ◽

L. Pope ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

The Other ◽

Amplification Refractory Mutation System ◽

Advanced Cancer Patients ◽

Assay Sensitivity ◽

Sequenom Massarray ◽

Pik3ca Mutations ◽

Ffpe Tumor ◽

Colorectal Cancer Patients

356 Background: Circulating free DNA (cfDNA) represents a minimally-invasive resource for detecting mutations in advanced cancer patients. The primary objective of this study was to determine if cfDNA is representative of tumor tissue for multiplex mutation detection utilizing Sequenom MassARRAY. Methods: Samples were spiked with dilutions (10ng/μl to 0.01ng/μl) of HCT116 DNA containing KRAS G13D mutations to determine assay sensitivity and specificity. Metastatic colorectal cancer patients referred to the Drug Development Unit at the Royal Marsden Hospital between 9/09-8/10 gave their consent to provide DNA from matched archival formalin fixed paraffin-embedded (FFPE) tumor and plasma. Samples had ∼200 described gene mutations genotyped using Sequenom MassARRAY (OncoCarta Panel). Results: Serial dilution spiking experiments revealed that the KRAS G13D mutation was reproducibly detectable to 40ng/mL of HCT116 DNA; 26 patient samples were then analyzed. KRAS, BRAF and PIK3CA mutations were detected in 8 (31%), 3 (12%) and 3 (12%) tumor specimens respectively; 100% concordance for KRAS status was observed between multiple FFPE biopsies from the same patient and analysis by Amplification Refractory Mutation System (ARMS)-Scorpion PCR. The median quantity of cfDNA was 353ng/ml (range 106-4603). Concordance between matched FFPE and cfDNA was 88% for KRAS and 100% for BRAF mutations. No patients with wildtype KRAS or BRAF tumor genotypes had mutations in their respective cfDNA confirming the high specificity of cfDNA analysis. Three patients had detectable PIK3CA mutations; 1 patient had a E346K mutation detected in both FFPE tissue and plasma; 1 patient had E545K detected only in FFPE and the other had E542K detected in a liver metastasis but not in the colorectal primary or plasma. The recently reported oncogenic AKT1 E17K mutation was detected in 1 patient in tissue and plasma. No mutations in any of the other tested oncogenes studied were detected. Conclusions: A high concordance in detected mutations was observed between FFPE tumor and matched cfDNA. cfDNA is representative of tumor DNA and may be used for the prospective selection of cancer patients for treatment with targeted therapeutics. No significant financial relationships to disclose.

Download Full-text

“Druggable” alterations detected by ion torrent in metastasis colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e22192 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e22192-e22192

Author(s):

Weijia Fang ◽

Milan Radovich ◽

Anwu Zhou ◽

Yulong Zheng ◽

Peng Zhao ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Pathway Analysis ◽

Cancer Metastasis ◽

Univariate Analysis ◽

Genetic Alterations ◽

Personal Genome ◽

Signal Pathways ◽

Ion Torrent ◽

Colorectal Cancer Patients

e22192 Background: The frequency and poor prognosis of metastasis colorectal cancer (mCRC) emphasizes the need of better markers for both treatment and prognosis. Here we describe an approach of identifying somatic variants in exonic regions of key cancer genes. Methods: Formalin-fixed paraffin embedded (FFPE) tissues biopsied from mCRC patients were collected. DNA was extracted and sequenced on the Ion Torrrent Personal Genome Machine.For targeted amplification, we used the Ion AmpliSeq Cancer Panel which is designed to detect 739 mutations in 604 loci from 46 oncogenes and tumor suppressor genes with as little as 10ng of input DNA.Sequencing results were then analyzed using the Ampliseq Variant Caller plug-in within Ion Torrent Suite Software. Ingenuity Pathway Software was used to do pathway analysis. Cox regression was tested regarding the potential relationship between the alteration numbers and the clinical factors including response rate, disease free survival and overall survival, etc. Results: Among 10 specimens, we identified 66 genetic alterations in 24 genes after excluding the germline mutations according the dbSNP database. 41% of those alterations were also present in the COSMIC database (Catalogue of Somatic Mutations in Cancer). No clinical factor was found to be significantly associated with the alteration numbers by univariate analysis. Notably, there are 11 genes including the expected APC, BRAF, KRAS, PIK3CA and TP53 that were mutated in at least 2 samples. Pathway analysis identified “Colorectal Cancer Metastasis Signaling” as the top mutated canonical pathway. This analysis further revealed mutated genes in the classic signal pathways of Wnt, PI3K/AKT, and TGF-beta/SMAD as significantly present. Interestingly, 90% of specimens harbored at least one “druggable” alteration (range from 1 ~ 6)that has been linked to a target treatment or is currently being investigated in clinical trials. Those pairs of drug and targeted genes are vemurafenib to BRAF; cetuximab to EGFR; palifermin to FGFR2; pazopanib to FGFR3; AEE 788 to KDR and BEZ235 to PIK3CA. Conclusions: DNA deep sequencing of key cancer related genes enables identification of “druggable” mutations for individual colorectal cancer patients.

Download Full-text

Untargeted Metabolomics Reveals Major Differences in the Plasma Metabolome between Colorectal Cancer and Colorectal Adenomas

Metabolites ◽

10.3390/metabo11020119 ◽

2021 ◽

Vol 11 (2) ◽

pp. 119

Author(s):

Tanja Gumpenberger ◽

Stefanie Brezina ◽

Pekka Keski-Rahkonen ◽

Andreas Baierl ◽

Nivonirina Robinot ◽

...

Keyword(s):

Colorectal Cancer ◽

High Risk ◽

Cancer Patients ◽

Molecular Mechanisms ◽

Low Risk ◽

Colorectal Adenomas ◽

Colorectal Carcinogenesis ◽

Sporadic Colorectal Cancer ◽

Molecular Features ◽

Colorectal Cancer Patients

Sporadic colorectal cancer is characterized by a multistep progression from normal epithelium to precancerous low-risk and high-risk adenomas to invasive cancer. Yet, the underlying molecular mechanisms of colorectal carcinogenesis are not completely understood. Within the “Metabolomic profiles throughout the continuum of colorectal cancer” (MetaboCCC) consortium we analyzed data generated by untargeted, mass spectrometry-based metabolomics using plasma from 88 colorectal cancer patients, 200 patients with high-risk adenomas and 200 patients with low-risk adenomas recruited within the “Colorectal Cancer Study of Austria” (CORSA). Univariate logistic regression models comparing colorectal cancer to adenomas resulted in 442 statistically significant molecular features. Metabolites discriminating colorectal cancer patients from those with adenomas in our dataset included acylcarnitines, caffeine, amino acids, glycerophospholipids, fatty acids, bilirubin, bile acids and bacterial metabolites of tryptophan. The data obtained discovers metabolite profiles reflecting metabolic differences between colorectal cancer and colorectal adenomas and delineates a potentially underlying biological interpretation.

Download Full-text