Oncogenomics

The Molecular Genetics Laboratory of Female Reproductive Cancer was established in 2004. We pioneered the elucidation of DNA copy number changes in ovarian cancer using Digital Karyotyping and have since identified several amplified oncogenes, including NOTCH3, CCNE1, RSF1, AKT2, PIK3CA, and the chr12p13 locus, as well as homozygously deleted tumor suppressor genes, including MKK4 and RB1 1-6. We later expanded the DNA copy number analysis to other types of gynecologic malignances, such as ovarian clear cell carcinoma, endometrioid carcinoma, and uterine serous carcinoma 7,8.

With the advancement of next generation sequencing, our team, in collaboration with Drs. Vogelstein and Velculescu at Hopkins, embarked on a project to analyze all coding exomes in gynecologic cancers. Thus far, we have completed whole-exome sequencing on ovarian clear cell carcinoma 9, ovarian low-grade serous carcinoma 10, and uterine serous carcinoma 11. Currently, we are applying genetic biomarkers identified in those studies to early detection and personalized treatment for women with gynecologic malignancies.

References

  1. Wang TL, Maierhofer C, Speicher MR, et al. Digital karyotyping. Proc Natl Acad Sci USA. 2002;99(25):16156-16161.
  2. Wang TL, Rago C, Silliman N, et al. Prevalence of somatic alterations in the colorectal cancer cell genome. Proc Natl Acad Sci USA. Mar 5 2002;99(5):3076-3080.
  3. Wang TL, Diaz LA, Jr., Romans K, et al. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc Natl Acad Sci USA. Mar 2 2004;101(9):3089-3094.
  4. Shih I-M, Sheu JJ, Santillan A, et al. Amplification of a chromatin remodeling gene, Rsf-1/HBXAP, in ovarian carcinoma. Proc Natl Acad Sci USA. Sep 27 2005;102(39):14004-14009.
  5. Nakayama K, Nakayama N, Davidson B, et al. Homozygous Deletion of MKK4 in Ovarian Serous Carcinoma. Cancer Biol Ther. Jun 2006;5(6):630-634.
  6. Nakayama K, Nakayama N, Davidson B, et al. A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival. Proc Natl Acad Sci USA. Dec 5 2006;103(49):18739-18744.
  7. Kuo K, Mao T, Feng Y, et al. DNA copy number profiles in affinity-purified ovarian clear cell carcinoma. Clin Cancer Res. 2010;16(7):1997-2008.
  8. Kuo KT, Guan B, Feng Y, et al. Analysis of DNA copy number alterations in ovarian serous tumors identifies new molecular genetic changes in low-Grade and high-grade carcinomas. Cancer Res. Apr 21 2009;69:4036-4042.
  9. Jones S, Wang TL, Shih Ie M, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science. Oct 8 2010;330(6001):228-231.
  10. Jones S, Wang TL, Kurman RJ, et al. Low-grade serous carcinomas of the ovary contain very few point mutations. J Pathol. Feb 2012;226(3):413-420.
  11. Kuhn E, Wu RC, Guan B, et al. Identification of Molecular Pathway Aberrations in Uterine Serous Carcinoma by Genome-wide Analyses. J Natl Cancer Inst. Oct 3 2012;104(19):1503-1513.