Differential cancer risk and survival in Indian oral cancer patients with genic region FAS and FASL polymorphisms.

OBJECTIVE: To investigate the association of genic region polymorphisms of FAS and FASL in Indian patients with oral cancer. STUDY DESIGN: The study included 960 consenting control participants and patients with oral cancer. Genotyping was performed using Polymerase Chain Reaction -Restriction Fragment Length Polymorphism (PCR-RFLP). Cancer risk, 5-year survival, and hazards ratio (HRs), with respect to risk and clinical factors, were estimated using Fisher's exact test, Kaplan-Meier analysis, and Cox proportional hazards models. RESULTS: FASL IVS2nt-124 'AG' increased risk in males with buccal mucosa cancer (BMC) but decreased risk in females. FAS 21196 'CT' decreased risk of tongue cancer (TC) and BMC in females. The survival of the patients also differed between sexes in TC and BMC. FAS 21196 'CT' increased HR by 23-fold in females with BMC when adjusted for age, stage, grade, LVS, PNI, tobacco use, and alcohol. 'TT' genotype increased the HR in females with BMC when adjusted for age, stage, grade, lymphovascular spread (LVS), perineural invasion (PNI), and perinodal spread (PNS). Our bioinformatic study revealed the presence of CTCF binding regions and CpG islands near FAS and FASL. CONCLUSIONS: These single nucleotide polymorphisms (SNPs) altered the risk and survival of BMC and TC patients differentially that varied with clinical and risk factors.

Polymorphic variants of drug-metabolizing enzymes alter the risk and survival of oral cancer patients.

The present study investigated the prevalence of CYP2D6*4, CYP3A5*3 and SULT1A1*2, using PCR-RFLP, in normal and oral cancer (OC) patients that were stratified by OC subtype and gender. The risk of cancer, 5-year cumulative survival and hazard's ratio (HR) with respect to risk factors and clinical factors were estimated using Fisher's exact test, Kaplan-Meier analysis, and Cox proportional hazards models. CYP2D6*4 'GA' lowered the risk of buccal mucosa cancer (BMC) in males (OR = 0.37), whereas, 'G' allele of CYP3A5*3 increased risk of tongue cancer (TC) (OR = 1.67). SULT1A1*2 'GA' increased the risk of TC (OR = 2.36) and BMC (OR = 3.25) in females. The 5-year survival of the patients depended on factors like age, lymphovascular spread (LVS), perinodal spread (PNS), recurrence, tobacco, and alcohol. CYP3A5*3 'AG' and 'GG' had decreased the hazard ratio (HR) for BMC females when inflammatory infiltrate alone or along with other covariates, LVS, PNI, PNS, metastasis, recurrence, and relapse was adjusted. Similarly, CYP3A5*3 'AG' decreased the risk of death (HR = 0.05) when the grade was adjusted. SULT1A1*2 'GA' had decreased HR for TC males (HR = 0.08) after adjusting for inflammatory infiltrate, LVS, perineural invasion (PNI), PNS, metastasis, recurrence, and relapse. Further, our bioinformatics study revealed the presence of a CpG island within the CYP2D6 and a CTCF binding site upstream of CYP2D6. Interestingly, three CpG islands and two CTCF binding sites were also identified near the SULT1A1. In conclusion, the SNPs altered risk and survival of BMC and TC differentially in a gender specified manner, that varied with clinical and risk factors.

Susceptibility to oral cancers with CD95 and CD95L promoter SNPs may vary with the site and gender.

We investigated risk association of oral cancers (tongue and buccal mucosa cancers) with FAS (-1377G > A and FAS -670 A > G) and FASL (-844 T > C) SNPs, in males and females. A case-control study of 535 oral cancer and 525 control subjects was performed. SNPs were detected in the genomic DNA isolated from peripheral blood using PCR-RFLP. We report FASL -844 T > C SNPs increased risk for buccal mucosa cancer in females but not in males. On the other hand, FAS genotypes did not alter the risk of the cancers in both females and males. However, co-occurrence of FAS -1377 GA and -670 GG, FAS -1377 AA and -670 GG genotypes, and combined genotypes of FAS and FASL (FAS -1377 AA + FAS -670 GG + FASL -844 CC) alter male susceptibility towards tongue cancer. In females, combined genotypes of FAS (-1377GA and -670 AA) were found to be a risk factor of buccal mucosa cancer (OR = 3.27, CI = 1.28-8.36; P ≤ 0.01). FASL variants (GA and AA) increased tongue cancer risk in females who were tobacco users compared to non-tobacco users. In conclusion, SNPs of the FAS and FASL might alter risk of tongue and buccal mucosa cancers differentially, in a gender-dependent manner.

Promoter polymorphism of FASL confers protection against female-specific cancers and those of FAS impact the cancers divergently.

We investigated risk association of FAS (-1377 G>A and -670 A>G) and FASL (-844 T>C) promoter polymorphisms with breast, ovarian, cervical, and endometrial cancers and report that the FASL -844 CC genotype was protective against breast, ovarian, cervical, and endometrial cancers (P ≤ 0.01). On the other hand, FAS -1377 GA and AA variants increased risk of breast cancer. However, the GA variant of FAS -1377 was also found to be a risk factor for cervical cancer. In contrast, FAS -670 AG variant significantly lowered risk of breast cancer. Further, we also observed that risk association of co-occurrence of FAS and/or FASL variants with the cancers varied as compared to the presence of individual polymorphisms. Although risk and protective haplotypes of FAS SNPs were observed across the cancer phenotypes, the association of the haplotypes was significant for breast cancer alone with a 3-fold enhanced risk. The protective effect of the FASL CC genotype seen in this study suggests that similar biomolecular mechanisms involving FASL might play a role in female-specific cancers.