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Different prognostic effect of CpG island methylation according to sex in colorectal cancer patients treated with adjuvant FOLFOX.

Lee DW, Han SW, Cha Y, Rhee YY, Bae JM, Cho NY, Lee KH, Kim TY, Oh DY, Im SA, Bang YJ, Jeong SY, Park KJ, Kang GH, Kim TY - Clin Epigenetics (2015)

Bottom Line: CIMP-high (≥5 methylated loci) and concurrent methylation in NEUROG1 and CDKN2A (p16) were found in 5.8 and 7.9 % of patients, respectively.Although CIMP-high status was not associated with survival, concurrent methylation in NEUROG1 and CDKN2A (p16) was associated with shorter OS and DFS.Interaction analysis indicates that the prognostic role is different according to sex.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.

ABSTRACT

Background: Profound methylation of CpG islands constitutes a distinct molecular subtype of colorectal cancer (CRC). The frequencies of methylation in CRC vary according to clinico-pathological characteristics including sex. However, interaction between these characteristics and prognostic influence of methylation status has not been clearly defined. We have investigated the prognostic role of promoter methylation using eight CpG island methylator phenotype (CIMP) markers in 497 stage II or III CRC patients who underwent curative resection followed by adjuvant FOLFOX. Overall survival (OS) and disease-free survival (DFS) were compared between subgroups classified by methylation status, and interactions with clinico-pathological features were analyzed.

Results: CIMP-high (≥5 methylated loci) and concurrent methylation in NEUROG1 and CDKN2A (p16) were found in 5.8 and 7.9 % of patients, respectively. Although CIMP-high status was not associated with survival, concurrent methylation in NEUROG1 and CDKN2A (p16) was associated with shorter OS and DFS. Moreover, the prognostic role of the concurrent methylation was different among sex. The negative prognostic impact was only observed in male but not in female (interaction p value = 0.026 for OS and 0.011 for DFS). In male, the 5-year OS was 61.6 % in concurrent methylation (+) and 91.7 % in concurrent methylation (-) (p < 0.001) whereas it was 95.0 and 92.8 % in female, respectively (p = 0.78).

Conclusions: Concurrent methylation in NEUROG1 and CDKN2A is associated with poor survival in CRC treated with adjuvant FOLFOX. Interaction analysis indicates that the prognostic role is different according to sex.

No MeSH data available.


Related in: MedlinePlus

Kaplan-Meier curves of overall survival (OS) and disease-free survival (DFS) according to concurrent methylation of NEUROG1/CDKN2A (p16) stratified by sex. (a) Male: OS. (b) Female: OS. (c) Male: DFS. (d) Female: DFS. Co-methylation concurrent methylation, N number
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Fig3: Kaplan-Meier curves of overall survival (OS) and disease-free survival (DFS) according to concurrent methylation of NEUROG1/CDKN2A (p16) stratified by sex. (a) Male: OS. (b) Female: OS. (c) Male: DFS. (d) Female: DFS. Co-methylation concurrent methylation, N number

Mentions: We next assessed whether the detrimental effect of concurrent methylation in NEUROG1 and CDKN2A (p16) was different according to clinico-pathological factors, including sex (Fig. 2). The prognostic role of concurrent methylation in NEUROG1 and CDKN2A (p16) was different among sex (interaction p value for OS = 0.026, for DFS = 0.011). It was associated with significantly worse OS and DFS in men (Fig. 3a) (DFS, Fig. 3c). However, there was no prognostic role of concurrent methylation in women (Fig. 3b) (DFS, Fig. 3d). In the multivariate analysis, the poor prognosis associated with concurrent methylation in NEUROG1 and CDKN2A (p16) in male was independent of other clinico-pathologic prognostic factors (adjusted HR for OS 5.23, 95 % CI 2.45–11.17, p < 0.001) (adjusted HR for DFS 3.66, 95 % CI 1.82–7.36, p < 0.001) (Table 3). Other clinico-pathological factors, including tumor location, did not affect the prognostic role of concurrent methylation in NEUROG1 and CDKN2A (p16). Due to the limited number of patients, we could not sub-analyze patients according to BRAF mutation or MSI status.Fig. 2


Different prognostic effect of CpG island methylation according to sex in colorectal cancer patients treated with adjuvant FOLFOX.

Lee DW, Han SW, Cha Y, Rhee YY, Bae JM, Cho NY, Lee KH, Kim TY, Oh DY, Im SA, Bang YJ, Jeong SY, Park KJ, Kang GH, Kim TY - Clin Epigenetics (2015)

Kaplan-Meier curves of overall survival (OS) and disease-free survival (DFS) according to concurrent methylation of NEUROG1/CDKN2A (p16) stratified by sex. (a) Male: OS. (b) Female: OS. (c) Male: DFS. (d) Female: DFS. Co-methylation concurrent methylation, N number
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4495938&req=5

Fig3: Kaplan-Meier curves of overall survival (OS) and disease-free survival (DFS) according to concurrent methylation of NEUROG1/CDKN2A (p16) stratified by sex. (a) Male: OS. (b) Female: OS. (c) Male: DFS. (d) Female: DFS. Co-methylation concurrent methylation, N number
Mentions: We next assessed whether the detrimental effect of concurrent methylation in NEUROG1 and CDKN2A (p16) was different according to clinico-pathological factors, including sex (Fig. 2). The prognostic role of concurrent methylation in NEUROG1 and CDKN2A (p16) was different among sex (interaction p value for OS = 0.026, for DFS = 0.011). It was associated with significantly worse OS and DFS in men (Fig. 3a) (DFS, Fig. 3c). However, there was no prognostic role of concurrent methylation in women (Fig. 3b) (DFS, Fig. 3d). In the multivariate analysis, the poor prognosis associated with concurrent methylation in NEUROG1 and CDKN2A (p16) in male was independent of other clinico-pathologic prognostic factors (adjusted HR for OS 5.23, 95 % CI 2.45–11.17, p < 0.001) (adjusted HR for DFS 3.66, 95 % CI 1.82–7.36, p < 0.001) (Table 3). Other clinico-pathological factors, including tumor location, did not affect the prognostic role of concurrent methylation in NEUROG1 and CDKN2A (p16). Due to the limited number of patients, we could not sub-analyze patients according to BRAF mutation or MSI status.Fig. 2

Bottom Line: CIMP-high (≥5 methylated loci) and concurrent methylation in NEUROG1 and CDKN2A (p16) were found in 5.8 and 7.9 % of patients, respectively.Although CIMP-high status was not associated with survival, concurrent methylation in NEUROG1 and CDKN2A (p16) was associated with shorter OS and DFS.Interaction analysis indicates that the prognostic role is different according to sex.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-Ro, Jongno-Gu, Seoul 110-744 South Korea.

ABSTRACT

Background: Profound methylation of CpG islands constitutes a distinct molecular subtype of colorectal cancer (CRC). The frequencies of methylation in CRC vary according to clinico-pathological characteristics including sex. However, interaction between these characteristics and prognostic influence of methylation status has not been clearly defined. We have investigated the prognostic role of promoter methylation using eight CpG island methylator phenotype (CIMP) markers in 497 stage II or III CRC patients who underwent curative resection followed by adjuvant FOLFOX. Overall survival (OS) and disease-free survival (DFS) were compared between subgroups classified by methylation status, and interactions with clinico-pathological features were analyzed.

Results: CIMP-high (≥5 methylated loci) and concurrent methylation in NEUROG1 and CDKN2A (p16) were found in 5.8 and 7.9 % of patients, respectively. Although CIMP-high status was not associated with survival, concurrent methylation in NEUROG1 and CDKN2A (p16) was associated with shorter OS and DFS. Moreover, the prognostic role of the concurrent methylation was different among sex. The negative prognostic impact was only observed in male but not in female (interaction p value = 0.026 for OS and 0.011 for DFS). In male, the 5-year OS was 61.6 % in concurrent methylation (+) and 91.7 % in concurrent methylation (-) (p < 0.001) whereas it was 95.0 and 92.8 % in female, respectively (p = 0.78).

Conclusions: Concurrent methylation in NEUROG1 and CDKN2A is associated with poor survival in CRC treated with adjuvant FOLFOX. Interaction analysis indicates that the prognostic role is different according to sex.

No MeSH data available.


Related in: MedlinePlus