Uterine (Womb) Cancer molecular biology and genetics

A number of molecular changes are observed in endometrial carcinogenesis but the frequency of these events varies with cancer type. Mutations in the tumour supressor genePTEN are the most commonly reported in type I tumours1,2.

A 3-D model of the structure of a DNA double helix Alterations in this gene are early events in cancer progression and have also been detected in precancerous lesions3. Changes in the oncogeneK-ras have also been observed. Type II carcinomas are characterised by inactivation of the tumour suppressor gene p53 and overexpression of the ErbB oncogene. Aneuploidy is also commonly observed in these tumours.

Microsatellite instability is a feature in around 25% of endometrial cancers, predominantly type I tumours 4. This is due to underlying faults in DNA mismatch repair ( MMR) genes. The exact mechanism by which faults in these genes lead to cancer is unclear, but they may permit an increase in the mutation rate leading to an accumulation of faults in genes important in the cancer pathway.

Endometrial cancer commonly occurs as part of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Individuals with HNPCC syndrome have faults in a MMR gene (most commonly MSH2, MLH1 or MSH6) and female family members have a 60% lifetime risk of uterine cancer 5. Aside from HNPCC families there are few reported cases of clustering of the disease. A recent study identified a number of cases without faults in MMR genes 6 and a large Swedish study identified that daughters of women with endometrial cancer but without HNPCC syndrome had almost double the risk of endometrial cancer 7, although a major dominant gene for this disease is unlikely to exist 8. Instead, one or more low penetrance polymorphisms may account for the small number of familial cases observed.

Microarrays are being used to construct gene expression profiles for sporadic cases of both type I and type II cancers. In the future this will help to provide better prognostic information and more tailored treatments for this disease 9.

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References for uterine (womb) cancer molecular biology and genetics

  1.  Risinger, J.I., et al., PTEN/MMAC1 mutations in endometrial cancers. Cancer Res, 1997. 57(21): p. 4736-8.
  2.  Tashiro, H., et al., Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res, 1997. 57(18): p. 3935-40.
  3.  Mutter, G.L., et al., Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst, 2000. 92(11): p. 924-30.
  4.  Risinger, J.I., et al., Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling.Cancer Res, 2005. 65(12): p. 5031-7.
  5.  Umar, A., et al., Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer, 2004. 4(2): p. 153-8.
  6.  Ollikainen, M., et al., Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome? J Clin Oncol, 2005. 23(21): p. 4609-16.
  7.  Lorenzo Bermejo, J., F.L. Buchner, and K. Hemminki, Familial risk of endometrial cancer after exclusion of families that fulfilled Amsterdam, Japanese or Bethesda criteria for HNPCC. Ann Oncol, 2004. 15(4): p. 598-604.
  8.  Boyd, J., Genetic basis of familial endometrial cancer: is there more to learn? J Clin Oncol, 2005. 23(21): p. 4570-3.
  9.  Maxwell, G.L., et al., Microarray analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles associated with different histologic types of uterine cancer. Clin Cancer Res, 2005. 11(11): p. 4056-66.