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Homozygous deletions of UGT2B17 modifies effects of smoking on TP53-mutations and relapse of head and neck carcinoma.

Mafune A, Hama T, Suda T, Suzuki Y, Ikegami M, Sakanashi C, Imai S, Nakashima A, Yokoo T, Wada K, Kojima H, Urashima M - BMC Cancer (2015)

Bottom Line: For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17.Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method.These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan. mafu0218@yahoo.co.jp.

ABSTRACT

Background: Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse.

Methods: We conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively.

Results: UGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method.

Conclusions: These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.

No MeSH data available.


Related in: MedlinePlus

Kaplan-Meier curves of relapse-free rates in 234 patients with HNSCC. Differences in time until relapse were compared among combinations of p16 (+) tumors, disruptive TP53-mutations, and homozygous UGT2B17 deletions. The group of both UGT2B17-deletion and a disruptive TP53-mutation in the primary tumors is indicated as green-colored line, the group of both p16 (+) and no disruptive TP53-mutation in the primary tumors is indicated as blue-colored line and the other groups are indicated as red-colored line. p16 (+): p16-positive tumor; p16 (-): p16- negative tumor; dTP53 (+): presence of disruptive TP53-mutations; dTP53 (-): no disruptive TP53-mutations or wild-type TP53; UGT2B17 (+): UGT2B17-deletion: homozygous deletion of UGT2B17; UGT2B17 (-): UGT2B17-presence: one or two copies of UGT2B17.
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Fig1: Kaplan-Meier curves of relapse-free rates in 234 patients with HNSCC. Differences in time until relapse were compared among combinations of p16 (+) tumors, disruptive TP53-mutations, and homozygous UGT2B17 deletions. The group of both UGT2B17-deletion and a disruptive TP53-mutation in the primary tumors is indicated as green-colored line, the group of both p16 (+) and no disruptive TP53-mutation in the primary tumors is indicated as blue-colored line and the other groups are indicated as red-colored line. p16 (+): p16-positive tumor; p16 (-): p16- negative tumor; dTP53 (+): presence of disruptive TP53-mutations; dTP53 (-): no disruptive TP53-mutations or wild-type TP53; UGT2B17 (+): UGT2B17-deletion: homozygous deletion of UGT2B17; UGT2B17 (-): UGT2B17-presence: one or two copies of UGT2B17.

Mentions: Using backward elimination for 13 candidate prognostic factors (Table 3), we found that disruptive TP53-mutations and UGT2B17-deletion interacted to significantly increase the risk of relapse (HR, 2.22; 95% CI, 1.30 to 3.80, P = 0.004); however, either TP53-mutations or UGT2B17-deletion alone did not significantly affect the risk. Notably, p16 (+) was a better prognostic factor than p16 (-) (HR, 0.53; 95% CI, 0.29 to 0.99, P = 0.047). Thus, we analyzed three grouping of the 234 patients based on combinations of three factors—p16 (+) tumors, presence of disruptive TP53-mutations, and UGT2B17-deletions. During a median follow-up period of 1.5 years (interquartile range, 1.0 to 2.5 years), relapse occurred in 89 of 232 patients (38%) in this study. Based on Kaplan-Meier curves, patients harboring both UGT2B17-deletion and a disruptive TP53-mutation in the primary tumors had the highest relapse rates among the three groups, and the group comprising patients with p16 (+) tumors and lacking any disruptive TP53-mutation in the primary tumors had the lowest relapse rates (Figure 1). Relapse was occurred in 21 of 35 patients in the group of both UGT2B17-deletion and a disruptive TP53-mutation in the primary tumors (indicated as green-colored line in Figure 1), 16 of 59 patients in the group of both p16 (+) and no disruptive TP53-mutation in the primary tumors (indicated as blue-colored line in Figure 1) and 48 of 131 patients in the other groups (indicated as red-colored line in Figure 1). We also analyzed overall survival by Kaplan-Meier curves. Although patients with p16 (+) tumors and lacking any disruptive TP53-mutation in the primary tumors had the highest survival rates than the other groups (P = 0.0190, figure was not shown), there was no significant effect among these three factors; status of disruptive TP53-mutation, p16 and UGT2B17.Table 3


Homozygous deletions of UGT2B17 modifies effects of smoking on TP53-mutations and relapse of head and neck carcinoma.

Mafune A, Hama T, Suda T, Suzuki Y, Ikegami M, Sakanashi C, Imai S, Nakashima A, Yokoo T, Wada K, Kojima H, Urashima M - BMC Cancer (2015)

Kaplan-Meier curves of relapse-free rates in 234 patients with HNSCC. Differences in time until relapse were compared among combinations of p16 (+) tumors, disruptive TP53-mutations, and homozygous UGT2B17 deletions. The group of both UGT2B17-deletion and a disruptive TP53-mutation in the primary tumors is indicated as green-colored line, the group of both p16 (+) and no disruptive TP53-mutation in the primary tumors is indicated as blue-colored line and the other groups are indicated as red-colored line. p16 (+): p16-positive tumor; p16 (-): p16- negative tumor; dTP53 (+): presence of disruptive TP53-mutations; dTP53 (-): no disruptive TP53-mutations or wild-type TP53; UGT2B17 (+): UGT2B17-deletion: homozygous deletion of UGT2B17; UGT2B17 (-): UGT2B17-presence: one or two copies of UGT2B17.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig1: Kaplan-Meier curves of relapse-free rates in 234 patients with HNSCC. Differences in time until relapse were compared among combinations of p16 (+) tumors, disruptive TP53-mutations, and homozygous UGT2B17 deletions. The group of both UGT2B17-deletion and a disruptive TP53-mutation in the primary tumors is indicated as green-colored line, the group of both p16 (+) and no disruptive TP53-mutation in the primary tumors is indicated as blue-colored line and the other groups are indicated as red-colored line. p16 (+): p16-positive tumor; p16 (-): p16- negative tumor; dTP53 (+): presence of disruptive TP53-mutations; dTP53 (-): no disruptive TP53-mutations or wild-type TP53; UGT2B17 (+): UGT2B17-deletion: homozygous deletion of UGT2B17; UGT2B17 (-): UGT2B17-presence: one or two copies of UGT2B17.
Mentions: Using backward elimination for 13 candidate prognostic factors (Table 3), we found that disruptive TP53-mutations and UGT2B17-deletion interacted to significantly increase the risk of relapse (HR, 2.22; 95% CI, 1.30 to 3.80, P = 0.004); however, either TP53-mutations or UGT2B17-deletion alone did not significantly affect the risk. Notably, p16 (+) was a better prognostic factor than p16 (-) (HR, 0.53; 95% CI, 0.29 to 0.99, P = 0.047). Thus, we analyzed three grouping of the 234 patients based on combinations of three factors—p16 (+) tumors, presence of disruptive TP53-mutations, and UGT2B17-deletions. During a median follow-up period of 1.5 years (interquartile range, 1.0 to 2.5 years), relapse occurred in 89 of 232 patients (38%) in this study. Based on Kaplan-Meier curves, patients harboring both UGT2B17-deletion and a disruptive TP53-mutation in the primary tumors had the highest relapse rates among the three groups, and the group comprising patients with p16 (+) tumors and lacking any disruptive TP53-mutation in the primary tumors had the lowest relapse rates (Figure 1). Relapse was occurred in 21 of 35 patients in the group of both UGT2B17-deletion and a disruptive TP53-mutation in the primary tumors (indicated as green-colored line in Figure 1), 16 of 59 patients in the group of both p16 (+) and no disruptive TP53-mutation in the primary tumors (indicated as blue-colored line in Figure 1) and 48 of 131 patients in the other groups (indicated as red-colored line in Figure 1). We also analyzed overall survival by Kaplan-Meier curves. Although patients with p16 (+) tumors and lacking any disruptive TP53-mutation in the primary tumors had the highest survival rates than the other groups (P = 0.0190, figure was not shown), there was no significant effect among these three factors; status of disruptive TP53-mutation, p16 and UGT2B17.Table 3

Bottom Line: For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17.Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method.These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan. mafu0218@yahoo.co.jp.

ABSTRACT

Background: Smoking induces oncogenic TP53-mutations in head and neck squamous cell carcinomas (HNSCCs). Disruptive mutations of TP53-gene and expression of p16 protein [p16 (+)] in tumor tissue associate with worse and better prognosis, respectively. UDP-glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17) detoxifies smoking-related metabolites. Differences among ethnic groups in UGT2B17 are extremely high. Homozygous deletions of UGT2B17 gene (UGT2B17-deletion) are a common copy number variant (CNV) among Japanese, but not a common CNV among Africans and Europeans. Thus, we examined Japanese patients with HNSCC to explore if UGT2B17-deletion and/or p16 (+) modify effects of smoking on TP53-mutations and affect relapse.

Methods: We conducted a posthoc analysis of a prospective cohort. Polymerase chain reaction, immunohistochemistry, and direct sequencing were used to determine UGT2B17-deletion, p16 (+), and detailed TP53-mutations, respectively.

Results: UGT2B17-deletion was observed in 80% of this study population. For this 80%, TP53-mutations were significantly more common among smokers than non-smokers (P = 0.0016), but this difference between smokers and nonsmokers was not significant for the 20% with UGT2B17. In patients with UGT2B17-deletion and p16 (+), simultaneously, TP53-mutations were much more common among smokers than among non-smokers (81% versus 17%; P = 0.0050). Patients with both UGT2B17-deletion and disruptive TP53-mutations had higher relapse rates than other patients (hazard ratio, 2.22; 95% confidence interval, 1.30 to 3.80, P = 0.004) in a stepwise method.

Conclusions: These results suggest that UGT2B17-deletion interacting with p16 (+) may modify effects of smoking on TP53-mutations and may further interact with the disruptive TP53-mutations to raise relapse rates among Japanese patients with HNSCC.

No MeSH data available.


Related in: MedlinePlus