Elevation of methylated DNA in KILLIN/PTEN in the plasma of patients with thyroid and/or breast cancer

Around 80% of mutations in the PTEN gene have been reported to be associated with diseases such as Cowden syndrome, which is an autosomal dominant disorder associated with an increased risk of developing breast, thyroid, and endometrial neoplasms. Recent studies have also demonstrated that KILLIN, which is located proximally to PTEN, shares the same transcription start site, and is assumed to be regulated by the same promoter, but is transcribed in the opposite direction. In this regard, we postulate that there may be a connection between KILLIN/PTEN genes and breast and thyroid cancers. Using real-time quantitative polymerase chain reaction (qPCR), we found that expression of KILLIN, but not PTEN, was significantly decreased in 23 Chinese women with a personal history of breast and thyroid cancer or a personal history of breast cancer and a family history of thyroid cancer, or vice versa, and at least two persons in the family with thyroid cancer or at a young age <40 years, when compared with healthy controls (P<0.0001). No PTEN mutations were found in these 23 patients. We then developed a simple methylation-sensitive restriction enzyme digestion followed by real-time quantitative assay to quantify plasma methylated KILLIN/PTEN DNA in these patients. Plasma levels of methylated KILLIN/PTEN DNA were significantly increased in these patients when compared with healthy controls (P<0.05). This study shows that plasma methylated KILLIN/PTEN DNA was significantly elevated, suggesting hypermethylation of the KILLIN/PTEN promoter in breast and thyroid cancer patients.

[1]  Ava Kwong,et al.  Quantitative Analysis and Diagnostic Significance of Methylated SLC19A3 DNA in the Plasma of Breast and Gastric Cancer Patients , 2011, PloS one.

[2]  C. Eng,et al.  Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. , 2010, JAMA.

[3]  D. West,et al.  Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer , 2009, The HUGO Journal.

[4]  S. Chan,et al.  A BRCA2 founder mutation and seven novel deleterious BRCA mutations in southern Chinese women with breast and ovarian cancer , 2009, Breast Cancer Research and Treatment.

[5]  Charis Eng,et al.  Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. , 2008, American journal of human genetics.

[6]  P. Platzer,et al.  Differential expression of PTEN-targeting microRNAs miR-19a and miR-21 in Cowden syndrome. , 2008, American journal of human genetics.

[7]  Peng Liang,et al.  Killin is a p53-regulated nuclear inhibitor of DNA synthesis , 2008, Proceedings of the National Academy of Sciences.

[8]  C. Eng,et al.  Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma , 2007, Nature Clinical Practice Oncology.

[9]  K. Yamazaki,et al.  Association of the polymorphisms in the 5′‐untranslated region of PTEN gene with type 2 diabetes in a Japanese population , 2003, FEBS letters.

[10]  Charis Eng,et al.  PTEN: One Gene, Many Syndromes , 2003, Human mutation.

[11]  J. Ivanovich,et al.  Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. , 2003, American journal of human genetics.

[12]  Charis Eng,et al.  A role for mitochondrial enzymes in inherited neoplasia and beyond , 2003, Nature Reviews Cancer.

[13]  D. Bonneau,et al.  Mutations of the human PTEN gene , 2000, Human mutation.

[14]  C. Eng,et al.  Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. , 2000, Journal of the National Cancer Institute.

[15]  G. Srivastava,et al.  Mutational analysis of the PTEN/MMAC1 gene in primary oesophageal squamous cell carcinomas. , 1999, Molecular pathology : MP.

[16]  F. Couch,et al.  Polymorphisms in PTEN in breast cancer families , 1999, Journal of medical genetics.

[17]  Kenneth M. Yamada,et al.  Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. , 1998, Science.

[18]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[19]  M. Kozak,et al.  At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. , 1987, Journal of molecular biology.