Increasingly, genetic markers that are specific to particular tumor types are useful diagnostic tools. Chromosomal rearrangements are often found in hematologic cancers and in some solid tumors. For example, a chromosomal rearrangement called a translocation in the MYC oncogene is associated with Burkitt's lymphoma. A translocation involves the breakage and removal of a large segment of DNA from one chromosome, followed by attachment of the segment to a different chromosome. In Burkitt's lymphoma, the translocation occurs between chromosomes 8 and 14. The translocation causes MYC to be expressed at an inappropriately high level, thus contributing to Burkitt's lymphoma. Chromosomal rearrangements can also create novel chain fusion genes, resulting in fusion proteins that have abnormal biologic activity. This is the case with the BCR-ABL1 gene fusion that results from a translocation between chromosomes 9 and 22 in chronic myeloid leukemia.
An alteration in an individual gene, called a point mutation, is another cause of activation of proto-oncogenes through structural changes in their encoded proteins. These alterations can lead to the uncontrolled and continuous activity of the mutated protein. Point mutations, for example, identified in the family of proto-oncogenes (HRAS, KRAS, and NRAS) are present in a great variety of tumors and in the RET proto-oncogene in multiple endocrine neoplasia type 2A and 2B. These mutations can be detected and used to make the diagnosis.
Approaches to screening for and diagnosis of cancer may be based in part on genetic changes. As a result of genome-wide association and other cancer research studies, new biomarkers are expected to be identified in the next decade.
Research is ongoing to determine the genetic changes associated with cancer prognosis and disease progression. Waldman et al. found that an intestinal tumor-suppressing receptor in the lymph nodes called guanylyl cyclase C (GUCY2C) may be a better means of determining the risk for metastatic colorectal cancer. At present, prognosis of colorectal cancer is determined through biopsy of the lymph nodes. Even when no cancerous cells are detected in the lymph nodes, however, patients have a one-in-four risk of recurrence. The risk of recurrence increases to one in two when four or more lymph nodes are involved with cancer.
Research of individuals who had no cancerous cells in their lymph nodes found that analysis of GUCY2C looked like an independent marker for prognosis and risk of recurrence. GUCY2C testing suggested malignancy in 87%, in comparison to 13% identified using the conventional molecular staging techniques. The researchers conclude that improving molecular staging using genetic technology has the potential to increase the detection of malignancy, and they call for studies with larger numbers of patients for further assessment of the accuracy and reliability of this approach.
Financial Disclosure: The authors have no signifi cant fi nancial interest
or other relationship with the manufacturers of any products or
providers of any service mentioned in this article.
1. US Department of Health and Human Services, Personalized Medicine Coalition: Personalized Medicine 101. Available at: www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php. Accessed on December 22, 2009.
2. American Cancer Society: A Cancer Source Book for Nurses, 8th edition. Varricchio CG, Ades TB, Hinds PS, et al (eds). Sudbury, MA, Jones & Bartlett Publishers, 2004.
3. Consensus Panel on Genetic/Genomic Nursing Competencies: Essentials of Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators, 2nd edition. Silver Spring, MD, American Nurses Association, 2009. Available at: www.genome.gov/Pages/Careers/HealthProfessionalEducation/geneticscompetency.pdf. Accessed on December 22, 2009.
4. National Human Genome Research Institute: All about the Human Genome Project. Available at: www.genome.gov/10001772. Accessed on December 22, 2009.
5. National Human Genome Research Institute: Frequently Asked Questions About Genetic and Genomic Science. Available at:, 2009.
6. Guttmacher AE, Collins FS: Genomic medicine—a primer. N Engl J Med 347(19):1512–1520, 2002.
7. National Library of Medicine: What Are Genome-Wide Association Studies? Available at: http://ghr.nlm.nih.gov/handbook/genomicresearch/gwastudies. Accessed on December 22, 2009.
8. National Cancer Institute: The Cancer Genome Atlas. Available at: http://cancergenome.nih.gov/. Accessed on December 22, 2009.
9. US Department of Health and Human Services: Personalized Healthcare Initiative. Available at: www.hhs.gov/myhealthcare/. Accessed on December 22, 2009.
10. Ding L, Getz G, Wheeler DA, et al: Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216):1069–1075, 2008. .
11. Imperiale TF, Wagner DR, Lin CY, et al: Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal findings. N Engl J Med 20(343):169–174, 2002.
12. Traverso G, Shuber A, Olsson L, et al: Detection of proximal colorectal cancers through analysis of faecal DNA. Lancet 359(9304):403–404, 2002.
13. Agency for Healthcare Research and Quality: Guide to Clinical Preventive Services, 2008. Available at: www.ahrq.gov/Clinic/cps3dix.htm. Accessed on December 22, 2009.
14. Yoon PW, Scheuner MT, Khoury MJ: Research priorities for evaluating family history in the prevention of common chronic diseases. Am J Prev Med 24(2):128–135, 2003.
15. National Cancer Institute: What You Need to Know About Breast Cancer. Available at: www.cancer.gov/cancertopics/wyntk/breast. Accessed on December 22, 2009.
16. US Preventive Services Task Force: Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: Recommendation statement. Ann Intern Med 143(5):355–361, 2005.
17. US Surgeon General: My Family Health Portrait. Available at: https://familyhistory.hhs.gov/fhh-web/home.action. Accessed on July 14, 2009.
18. Korf B, Mikhail FM: Overview of genetic diagnosis in cancer. Curr Protoc Hum Genet 55:10.1.1–10.1.8, 2007.
19. National Human Genome Research Institute: Talking Glossary, 2009. Available at: www.genome.gov/Glossary/. Accessed on December 22, 2009.
20. Taub R, Kirsch I, Morton C, et al: Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A 79(24):7837–7841, 1982.
21. Baker SG: Improving the biomarker pipeline to develop and evaluate cancer screening tests. J Natl Cancer Inst 101(16):1116–1119, 2009.
22. Waldman SA, Hyslop T, Schulz S, et al: Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer. JAMA 301(7):745–752, 2009.
23. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33):5287–5312, 2007.
24. Budhu A, Jia HL, Forgues M, et al: Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 47(3):897–907, 2008. Available at http://www3.cancer.gov/intra/LHC/Budhu-Hep2008.pdf. Accessed on December 28, 2009.
25. National Human Genome Research Institute: Frequently Asked Questions About Pharmacogenomics. Available at: http://www.genome.gov/27530645. Accessed on December 22, 2009.
26. Allegra CJ, Jessup JM, Somerfield MR, et al: American Society of Clinical Oncology provisional clinical opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27(12):2091–2096, 2009.
27. HemOnc today: Cetuximab labeling revised for KRAS mutations. Available at www.hemonctoday.com/article.aspx?rid=41841. Accessed on December 22, 2009.
28. National Cancer Institute: Trastuzumab. Available at: http://www.cancer.gov/cancertopics/druginfo/trastuzumab. Accessed on December 22, 2009.
29. Yang JJ, Cheng C, Yang W, et al: Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301(4):393–403, 2009.
30. Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336(20):1401–1408, 1997.
31. Rubenstein WS: Hereditary breast cancer in Jews. Fam Cancer 3(3-4):249–257, 2004.
32. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian Version 1/2009. http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf. Accessed on January 26, 2010.
33. Cykert S, Phifer N, Hanson C: Tamoxifen for breast cancer prevention: A framework for clinical decisions. Obstet Gynecol 104(3):433–442, 2004.
34. King MC, Wieand S, Hale K, et al: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286(18):2251–2256, 2001.
35. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 356(9245):1876–1881, 2000.
36. Gronwald J, Tung N, Foulkes WD, et al: Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: An update. Int J Cancer 118(9):2281–2284, 2006.
37. Genetic and Rare Diseases Information Center (GARD), 2009. Available at http://rarediseases.info.nih.gov/GARD/. Accessed on January 25, 2010.