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

Abstract

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.

Does human papillomavirus cause human colorectal cancer? Applying Bradford Hill criteria postulates

“…The HPV positivity ratio reported in these studies was varied between 0% [ 11 , 12 , 17 , 23 , 26 , 32 , 41 , 43 , 45 , 46 , 50 , 59 ] and 100% [ 13 , 54 ]. In most of the case–control studies [ 12 , 17 – 27 , 29 – 32 , 35 – 57 ], the positivity ratio for HPV detection was higher in the cancerous samples as compared to the controls, whereas, in some studies [ 28 , 33 , 34 , 58 ], HPV positivity ratio was higher in the controls as compared to the CRC samples. Possible reasons for such population-specific inequalities in HPV detection could be non-modifiable factors such as genetic makeup and socially controllable factors such as health-seeking behaviour and differential access to the health facilities.…”

“…In India, a single case–control study [ 27 ] has been reported so far to find out the association between HPV and CRC. They analysed 93 CRC samples and 30 adjacent/benign controls using L1 gene-specific primers through the PCR technique and identified 6% HPV detection positivity ratio in normal and 36.5% positivity ratio in the CRC samples.…”

“…The expression of the p16, p53 and some other genes could be used as a surrogate biomarker in HPV-infected CRC patients. Along with HPV detection, these surrogate biomarkers were also analysed by some studies [ 20 , 27 , 37 , 47 , 75 ] to further validate their findings, of which the studies of Laskar et al [ 27 ] and Karbasi et al [ 75 ] have validated their findings by analysing these surrogate biomarkers, whereas the other studies [ 20 , 37 , 47 ] were failed to validate their findings the surrogate biomarkers. Such deviations in the results of previous studies raise a big question mark on the selection of appropriate technique and their sensitivities.…”

The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer

“…BRCA1 methylation is observed in approximately 11–14% of breast cancers and 5%–31% of ovarian cancers [93]. BRCA1 methylation is also found in gastric (1.4%) [89], colorectal (10.75%) [94], non-small cell lung (18.6%) [95], bladder (12.1%) [96] and pancreatic cancers (46%) [97]. BRCA2 methylation is reported in NSCLC (42%) [80].…”

Prevalence of Human Papilloma Virus in Patients With Colorectal Cancer: A Systematic Review and Meta-analysis

“…[1][2][3] There is evidence for the presence of more than 100 types of HPV in the medical literature. In addition, 15 types of HPV (16,18,35,31,39,51,45,56,52,66,59, 69, 68, 82, and 73) are considered to be highly involved in the pathogenesis of genital cancer in women while HPVs responsible for the warts of genitals and skin (HPV 6,11,43,42,40,44,61,54,72,70, and 81) have lower pathogenicity. [4][5][6] Further, HPV is related to other malignancies including anal, oropharyngeal, penile, vulvar, and HPV-related tumors, which together represent 0.7% of carcinomas in both genera.…”