Over-expression of DNMT3A predicts the risk of recurrent vulvar squamous cell carcinomas.
OBJECTIVE
Cancer initiation and progression has been linked to aberrant expression of the DNA methyltransferases (DNMT), the enzymes which establish and maintain DNA methylation patterns throughout the genome. In this study, we investigated if DNMT expression in vulvar squamous cell carcinomas (VSCC) was related to clinical outcome.


METHODS
DNMT1, DNMT3A and DNMT3B expression was measured in a subset of cases drawn from a cohort of consecutive women treated for primary VSCC at the Pan Birmingham Gynaecological Cancer Centre between 2001 and 2008. Univariable and multivariable competing risk modelling was performed to identify whether DNMT expression was associated with local disease recurrence or disease morbidity.


RESULTS
Over-expression of DNMT3A in the invasive component of the tumour was seen in 44% of tumours and was associated with an increased risk of local vulvar recurrence (LVR) (HR=4.51, p=0.012). This risk was found to increase further after adjustment for disease stage (HR=6.00, p=0.003) and groin node metastasis (HR=4.81, p=0.008). Over-expression of DNMT3B was associated with an increased risk of LVR (HR=5.69 p=0.03), however this ceased to be significant after adjustment for groin node metastasis. In a subset analysis, over-expression of DNMT3A was found to be significantly more common in VSCCs that stained negative for CDKN2A.


CONCLUSIONS
These observations are consistent with the possibility that epigenetic changes contribute to vulvar neoplasia and DNMT3A over-expression may be useful in predicting local disease recurrence.
Institute of Cancer and Genomic Sciences, College of Dental and Medical School, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Sarah
S
Leonard
Institute of Cancer and Genomic Sciences, College of Dental and Medical School, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Merlin
M
Pereira
Cancer Research UK Clinical Trials Unit, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Richard
R
Fox
Institute of Cancer and Genomic Sciences, College of Dental and Medical School, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Naheema
N
Gordon
Institute of Cancer and Genomic Sciences, College of Dental and Medical School, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Jason
J
Yap
Institute of Cancer and Genomic Sciences, College of Dental and Medical School, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Sean
S
Kehoe
Institute of Cancer and Genomic Sciences, College of Dental and Medical School, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
David
D
Luesley
Institute of Cancer and Genomic Sciences, College of Dental and Medical School, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
Ciaran
C
Woodman
Birmingham Women's NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2TG, United Kingdom. Electronic address: Raji.Ganesan@bwnft.nhs.uk.
Raji
R
Ganesan
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis*; D000090205:DNA Methyltransferase 3A; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000209:etiology* / Q000235:genetics; D012306:Risk; D014846:Vulvar Neoplasms / Q000209:etiology* / Q000235:genetics; D000097584:DNA Methyltransferase 3B
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000619380:DNMT1 protein, human
DNA methylation; DNMT expression cancer; Human papillomavirus (HPV); Vulvar cancer