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Methylation and expression of the tumour suppressor, PRDM5, in colorectal cancer and polyp subgroups.

Bond CE, Bettington ML, Pearson SA, McKeone DM, Leggett BA, Whitehall VL - BMC Cancer (2015)

Bottom Line: PRDM5 methylation was associated with advanced stages of presentation (p<0.05) and the methylator phenotype (p=0.03).The polyp subgroups showed less silencing than the cancers, but similar rates were found between the serrated and conventional polyp cohorts (29/59, 49%; 23/40, 58% respectively).Interestingly, PRDM5 protein expression was substantially reduced in all polyp types and more so in cancers which also indicates early and increasing PRDM5 down-regulation with disease progression.

View Article: PubMed Central - PubMed

Affiliation: Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Catherine.Bond@qimrberghofer.edu.au.

ABSTRACT

Background: PRDM5 is an epigenetic regulator that has been recognized as an important tumour suppressor gene. Silencing of PRDM5 by promoter hypermethylation has been demonstrated in several cancer types and PRDM5 loss results in upregulation of the Wnt pathway and increased cellular proliferation. PRDM5 has not been extensively investigated in specific subtypes of colorectal cancers. We hypothesized it would be more commonly methylated and inactivated in serrated pathway colorectal cancers that are hallmarked by a BRAF V600E mutation and a methylator phenotype, compared to traditional pathway cancers that are BRAF wild type.

Methods: Cancer (214 BRAF mutant, 122 BRAF wild type) and polyp (59 serrated polyps, 40 conventional adenomas) cohorts were analysed for PRDM5 promoter methylation using MethyLight technology. PRDM5 protein expression was assessed by immunohistochemistry in cancers and polyps. Mutation of PRDM5 was analysed using cBioPortal's publicly available database.

Results: BRAF mutant cancers had significantly more frequent PRDM5 promoter methylation than BRAF wild type cancers (77/214,36% vs 4/122,3%; p<0.0001). Serrated type polyps had a lower methylation rate than cancers but were more commonly methylated than conventional adenomas (6/59,10% vs 0/40,0%). PRDM5 methylation was associated with advanced stages of presentation (p<0.05) and the methylator phenotype (p=0.03). PRDM5 protein expression was substantially down-regulated in both BRAF mutant and wild type cancer cohorts (92/97,95% and 39/44,89%). The polyp subgroups showed less silencing than the cancers, but similar rates were found between the serrated and conventional polyp cohorts (29/59, 49%; 23/40, 58% respectively). Of 295 colorectal cancers, PRDM5 was mutated in only 6 (2%) cancers which were all BRAF wild type.

Conclusions: Serrated pathway colorectal cancers demonstrated early and progressive PRDM5 methylation with advancing disease. Interestingly, PRDM5 protein expression was substantially reduced in all polyp types and more so in cancers which also indicates early and increasing PRDM5 down-regulation with disease progression. Methylation may be contributing to gene silencing in a proportion of BRAF mutant cancers, but the large extent of absent protein expression indicates other mechanisms are also responsible for this. These data suggest that PRDM5 is a relevant tumour suppressor gene that is frequently targeted in colorectal tumourigenesis.

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PRDM5 immunohistochemistry. A demonstrates the normal pattern of staining in non-neoplastic colonic mucosa. Down arrows indicate strong nuclear and cytoplasmic staining for PRDM5 in scattered cells predominantly in the crypt bases. Up arrowheads indicate incidental melanosis coli in the lamina propria. B is a representative area of a colorectal carcinoma negative for PRDM5. C is a representative area of a colorectal carcinoma positive for PRDM5, showing scattered cells with strong cytoplasmic and/or nuclear staining. (Original magnification: x200).
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Fig1: PRDM5 immunohistochemistry. A demonstrates the normal pattern of staining in non-neoplastic colonic mucosa. Down arrows indicate strong nuclear and cytoplasmic staining for PRDM5 in scattered cells predominantly in the crypt bases. Up arrowheads indicate incidental melanosis coli in the lamina propria. B is a representative area of a colorectal carcinoma negative for PRDM5. C is a representative area of a colorectal carcinoma positive for PRDM5, showing scattered cells with strong cytoplasmic and/or nuclear staining. (Original magnification: x200).

Mentions: Immunohistochemical analysis of PRDM5 protein expression in adjacent normal mucosa showed it was routinely present within the crypt bases. Interestingly, there was substantial loss of protein expression in both the BRAF mutant (92/97, 94.5%) and BRAF wild type (39/44, 88.6%) cancer cohorts (Figure 1).Figure 1


Methylation and expression of the tumour suppressor, PRDM5, in colorectal cancer and polyp subgroups.

Bond CE, Bettington ML, Pearson SA, McKeone DM, Leggett BA, Whitehall VL - BMC Cancer (2015)

PRDM5 immunohistochemistry. A demonstrates the normal pattern of staining in non-neoplastic colonic mucosa. Down arrows indicate strong nuclear and cytoplasmic staining for PRDM5 in scattered cells predominantly in the crypt bases. Up arrowheads indicate incidental melanosis coli in the lamina propria. B is a representative area of a colorectal carcinoma negative for PRDM5. C is a representative area of a colorectal carcinoma positive for PRDM5, showing scattered cells with strong cytoplasmic and/or nuclear staining. (Original magnification: x200).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4318154&req=5

Fig1: PRDM5 immunohistochemistry. A demonstrates the normal pattern of staining in non-neoplastic colonic mucosa. Down arrows indicate strong nuclear and cytoplasmic staining for PRDM5 in scattered cells predominantly in the crypt bases. Up arrowheads indicate incidental melanosis coli in the lamina propria. B is a representative area of a colorectal carcinoma negative for PRDM5. C is a representative area of a colorectal carcinoma positive for PRDM5, showing scattered cells with strong cytoplasmic and/or nuclear staining. (Original magnification: x200).
Mentions: Immunohistochemical analysis of PRDM5 protein expression in adjacent normal mucosa showed it was routinely present within the crypt bases. Interestingly, there was substantial loss of protein expression in both the BRAF mutant (92/97, 94.5%) and BRAF wild type (39/44, 88.6%) cancer cohorts (Figure 1).Figure 1

Bottom Line: PRDM5 methylation was associated with advanced stages of presentation (p<0.05) and the methylator phenotype (p=0.03).The polyp subgroups showed less silencing than the cancers, but similar rates were found between the serrated and conventional polyp cohorts (29/59, 49%; 23/40, 58% respectively).Interestingly, PRDM5 protein expression was substantially reduced in all polyp types and more so in cancers which also indicates early and increasing PRDM5 down-regulation with disease progression.

View Article: PubMed Central - PubMed

Affiliation: Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Catherine.Bond@qimrberghofer.edu.au.

ABSTRACT

Background: PRDM5 is an epigenetic regulator that has been recognized as an important tumour suppressor gene. Silencing of PRDM5 by promoter hypermethylation has been demonstrated in several cancer types and PRDM5 loss results in upregulation of the Wnt pathway and increased cellular proliferation. PRDM5 has not been extensively investigated in specific subtypes of colorectal cancers. We hypothesized it would be more commonly methylated and inactivated in serrated pathway colorectal cancers that are hallmarked by a BRAF V600E mutation and a methylator phenotype, compared to traditional pathway cancers that are BRAF wild type.

Methods: Cancer (214 BRAF mutant, 122 BRAF wild type) and polyp (59 serrated polyps, 40 conventional adenomas) cohorts were analysed for PRDM5 promoter methylation using MethyLight technology. PRDM5 protein expression was assessed by immunohistochemistry in cancers and polyps. Mutation of PRDM5 was analysed using cBioPortal's publicly available database.

Results: BRAF mutant cancers had significantly more frequent PRDM5 promoter methylation than BRAF wild type cancers (77/214,36% vs 4/122,3%; p<0.0001). Serrated type polyps had a lower methylation rate than cancers but were more commonly methylated than conventional adenomas (6/59,10% vs 0/40,0%). PRDM5 methylation was associated with advanced stages of presentation (p<0.05) and the methylator phenotype (p=0.03). PRDM5 protein expression was substantially down-regulated in both BRAF mutant and wild type cancer cohorts (92/97,95% and 39/44,89%). The polyp subgroups showed less silencing than the cancers, but similar rates were found between the serrated and conventional polyp cohorts (29/59, 49%; 23/40, 58% respectively). Of 295 colorectal cancers, PRDM5 was mutated in only 6 (2%) cancers which were all BRAF wild type.

Conclusions: Serrated pathway colorectal cancers demonstrated early and progressive PRDM5 methylation with advancing disease. Interestingly, PRDM5 protein expression was substantially reduced in all polyp types and more so in cancers which also indicates early and increasing PRDM5 down-regulation with disease progression. Methylation may be contributing to gene silencing in a proportion of BRAF mutant cancers, but the large extent of absent protein expression indicates other mechanisms are also responsible for this. These data suggest that PRDM5 is a relevant tumour suppressor gene that is frequently targeted in colorectal tumourigenesis.

Show MeSH
Related in: MedlinePlus