Evidence for possible non‐canonical pathway(s) driven early‐onset colorectal cancer in India

Ratheesh, Raman; Kotapalli, Viswakalyan; Adduri, Sitaramaraju; Gowrishankar, Swarnalata; Bashyam, Leena; Chaudhary, Ajay Kumar; Vamsy, Mohana; Patnaik, Sujit Chyau; Srinivasulu, Mukta; Sastry, R A; Rao, Subramanyeshwar; Vasala, Anjayneyulu; Kalidindi, NarasimhaRaju; Pollack, Jonathan R.; Murthy, Sudha; Bashyam, Murali D.

doi:10.1002/mc.21976

Cited by 37 publications

(40 citation statements)

References 38 publications

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“…These frequencies also concur with those we reported previously for CAU CRCs [11]. On the other hand, there is evidence that KRAS mutation frequency is lower in early-onset CRC in India (≤50 years, 24%; ≥60 Years, 47%) [27]. Further investigation in BAN CRCs will help to explain the aetiology behind the low KRAS mutations and high mucin percentage.…”

Section: Discussionsupporting

confidence: 90%

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

et al. 2013

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BackgroundPrevalence of colorectal cancer (CRC) in the British Bangladeshi population (BAN) is low compared to British Caucasians (CAU). Genetic background may influence mutations and disease features.MethodsWe characterized the clinicopathological features of BAN CRCs and interrogated their genomes using mutation profiling and high-density single nucleotide polymorphism (SNP) arrays and compared findings to CAU CRCs.ResultsAge of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10-5) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25%; p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN samples. No BRAF mutations was seen in our BAN MSS CRCs (CAU CRCs, 12%; p=0.08). Array data revealed similar patterns of gains (chromosome 7 and 8q), losses (8p, 17p and 18q) and LOH (4q, 17p and 18q) in BAN and CAU CRCs. A small deletion on chromosome 16p13.2 involving the alternative splicing factor RBFOX1 only was found in significantly more BAN (50%) than CAU CRCs (15%) cases (p=0.04). Focal deletions targeting the 5’ end of the gene were also identified. Novel RBFOX1 mutations were found in CRC cell lines and tumours; mRNA and protein expression was reduced in tumours.ConclusionsKRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.

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Section: Discussionsupporting

confidence: 90%

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

et al. 2013

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“…Further, we found significantly lower frequency of KRAS codon 12, 13 mutations in younger patients. Our results were supported by previous findings of low KRAS mutations in young Indian and Bangladeshi population [34,35]. The role of promoter hypermethylation of multiple tumour-related genes is recognised as one of the key events in initiation and progression of colorectal cancer.…”

Section: Discussionsupporting

confidence: 92%

Association of HPV with genetic and epigenetic alterations in colorectal adenocarcinoma from Indian population

et al. 2015

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Several studies from developing countries have shown human papillomavirus to be associated with colorectal cancers, but the molecular characteristics of such cancers are poorly known. We studied the various genetic variations like microsatellite instability (MSI), oncogenic mutations and epigenetic deregulations like CpG island methylation in HPV associated and nonassociated colorectal cancer patients from Indian population. HPV DNA was detected by PCR using My09/My11 and Gp5+/Gp6+ consensus primers and typed using HPV16 and HPV18 specific primers. MSI was detected using BAT 25 and BAT 26 markers, and mutation of KRAS, TP53 and BRAF V600E were detected by direct sequencing. Methyl specific polymerase chain reaction (MSP) was used to determine promoter methylation of the classical CIMP panel markers (P16, hMLH1, MINT1, MINT2 and MINT31) and other tumour-related genes (DAPK, RASSF1, BRCA1 and GSTP1). HPV DNA was detected in 34/93 (36.5 %) colorectal tumour tissues, HPV 18 being the predominant high-risk type. MSI was detected in 7.5 % cases; KRAS codon 12, 13, BRAF V600E and TP53 mutations were detected in 36.5, 3.2 and 37.6 % of the cases, respectively. CIMP-high was observed in 44.08 % cases. HPV presence was not associated with age, stage or grade of tumours, MSI or mutations in KRAS, TP53 or BRAF genes. Higher methylation frequencies of all genes/loci under study except RASSF1, as well as significantly higher CIMP-high characteristics were observed in HPV positive tumours as compared to negative cases. HPV in association with genetic and epigenetic features might be a potent risk factor for colorectal cancer in Indian population.

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“…Although the majority of late-onset CRC is located in the distal colon and microsatellite stable (MSS), some features more characteristic of late-onset CRC include occurrence in the proximal colon, as well as the presence of MSI via MLH1 gene promoter methylation, chromosomal instability, and a high CpG island methylator phenotype, especially when compared with sporadic early-onset CRC11. In addition to these characteristics, constitutively decreased PTEN expression in colon mucosa and p53 were experimentally observed to be associated with a late process of tumorigenesis in CRC192021. Because the PIAS protein family has been known to regulate p5322 and PTEN23, tumor development of CRC may also occur late.…”

Section: Discussionmentioning

confidence: 99%

Common risk variants for colorectal cancer: an evaluation of associations with age at cancer onset

Song

Shin

Park

et al. 2017

Sci Rep

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Common genetic risk variants for colorectal cancer (CRC) have been identified at approximately 40 loci by genome-wide association studies (GWAS). We investigated the association of these risk variants by age at onset of CRC using case-only and case-control analysis. A total of 1,962 CRC cases and 2,668 controls from two independent case-control studies conducted by Korea’s National Cancer Center were included in this study. We genotyped 33 GWAS-identified single-nucleotide polymorphisms (SNPs) associated with CRC risk. The risk allele in SNP rs704017, located at 10q22.3 in the ZMIZ1-AS1 gene, was consistently less frequent among CRC patients aged <50 years than among CRC patients aged ≥50 years in the case-only analysis (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.66–0.92, P = 2.7 × 10−3, in an additive model), although this did not surpass the threshold for multiple testing. The direction of associations between rs704017 and CRC risk differed by age group in the combined case-control analysis (<50 years: OR = 0.77, 95% CI = 0.60–0.98, P = 0.03 and ≥50 years: OR = 1.13, 95% CI = 0.98–1.29, P = 0.09, in a dominant model); the p-values for heterogeneity (Pheterogeneity = 7.5 × 10−3) and for interaction were statistically significant (Pinteraction = 7.8 × 10−3, in the dominant model). Our results suggest that the CRC susceptibility SNP rs704017 has a hereditary effect on onset age of CRC.

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Evidence for possible non‐canonical pathway(s) driven early‐onset colorectal cancer in India

Cited by 37 publications

References 38 publications

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

Association of HPV with genetic and epigenetic alterations in colorectal adenocarcinoma from Indian population

Common risk variants for colorectal cancer: an evaluation of associations with age at cancer onset

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