Genetic Testing

The hunt is on for genetic fingerprints unique to cancer cells. "Very soon, we'll stop talking about 'breast cancer' or 'head-and-neck cancer' or 'gastrointestinal cancer,' and will instead call cancers by their genetic characteristics," predicts Dr. Larry Norton of Memorial Sloan-Kettering Cancer Center in New York. At UCLA, Dr. Stanley Nelson and colleagues are creating a catalog of brain cancers by determining which genes have been turned on and which have been silenced in these tumors. "Tumors that look exactly the same can respond dramatically differently to chemotherapy and radiation," says Nelson. "But we've had to treat them as if they were all the same." With a full genetic catalog of tumors, he says, "we ought to be able to attack them in a far more effective way."

The immediate importance of this for colon cancer patients is that there are certain tumor markers which will predict response to 5-FU. This could save patients the trouble of going through ineffective therapy, instead going straight to experimental alternatives such as those explored in this website.

Overview

6/13/01 Cancer: The Emerging Molecular Biology 1999 DENNIS W. ROSS University of North Carolina Discoveries at the molecular level have greatly increased our understanding of how a normal cell becomes a tumor cell, responsive only to growth signals. Cancer emerges as fundamentally genetic, representing mutations in protooncogenes and tumor suppressor genes arising from multiple "hits" over long spans of time. The knowledge portends abilities to interrupt the process at a precancerous stage.
6/20/01 Strategies to Lessen the Current Failure Rate in Colorectal Cancer Discusses genetic alterations leading to colon cancer
6/25/01 Genetic Health - Colon Cancer HNPCC, Microsatellite Instability, Genetic Testing
6/18/01 Staging Colon Cancer Treatment Depends on Where Disease Is Researchers currently know of about ten different proteins that can help predict the outcome of colorectal cancer and be used to decide how best to treat it. "There are commercially available antibodies that can detect these proteins, and there are some clinical laboratories that offer them as tests. But right now the only staging that is done routinely is a determination of the spread of the cancer, not an analysis of the molecular aspects of the tumor," One important protein, according to McLeod, is thymidylate synthase, which appears to be the best predictor of who should be treated with the drug 5-fluorouracil (5-FU). "Another one is dihydropyrimidine dehydrogenase, which is also a good predictor for 5-FU therapy,"
9/7/01 Thymidylate synthase activity linked with more aggressive bladder cancer Tuesday, Aug 28 2001 The activity of thymidylate synthase (TS), an enzyme inhibited by 5-fluorouracil (5-FU), correlates with progression and recurrence of bladder cancer, according to a report published in the August 1st issue of Cancer.
6/13/01 Discovery Health - Cancer Resource Center Cancer Profiler from the Discovery Channel - Uses some of the genetic test results to predict outcomes.
6/18/01 Made to Order Medicine By Sharon Begley NEWSWEEK June 25, 2001 A revolution in genetic research is targeting treatments to patients' unique characteristics. It can mean the difference between life and death
7/16/01 A TAILORED PLAN A genetics-based diagnostic technology allows oncologists to better determine which cancer treatment will work best against a patient's specific cancer. USC/Norris Comprehensive Cancer Center
6/20/01 NIH Soon to Release Plan for Disclosing Adverse Events in Gene Therapy Trials BETHESDA, Maryland (Reuters Health) Jun 14

Tests to See if 5-FU Will Work
6/10/01 Fighting the Odds: Advances in Colorectal Cancer Diagnosis and Treatment Medscape (registration required) May 14, 2001 ASCO Meeting. An educational session entitled "Integration of Molecular Biology in the Diagnosis and Treatment of Colorectal Cancer" was chaired by Dr. Cynthia Gail Leichman, from the Roswell Park Cancer Institute, Buffalo, New York.[4] Dr. Leichman reviewed the current role of the measurement of thymidylate synthase (TS) levels, thymidine phosphorylase (TP) levels, and dihydropyrimidine dehydrogenase (DPD) levels in tumors for assessment of the probability of tumor response to fluorinated pyrimidines. The bottom line here appears to be that if one can detect tumors low in TS, TP, and the 5-fluorouracil (5-FU)-catabolizing enzyme DPD, the likelihood of tumor response is well in excess of 50%. The frequency of such high-responding tumors is about 15% to 20%.
6/20/01 Genetic Test May Help Colorectal Cancer Patients NEW YORK, Jun 06 (Reuters Health) Researchers in California have discovered that colorectal cancer patients with a specific variation in a gene that codes for an enzyme essential for DNA production, called TS, are more likely to respond to the chemotherapy agent 5-fluorouracil (5-FU). The researchers report that those patients with the double-repeat version of the TS gene had the best response to 5-FU--their tumors shrank or the tumor disappeared completely for at least six weeks. These patients also lived approximately eight months longer than the patients with the other variations of the TS gene. Unfortunately, the researchers note that the patients who responded the best to 5-FU treatment were also the most sensitive and were more likely to rate their side effects to the drug as "severe".
7/11/01 Prognostic Value of Thymidylate Synthase (TS), Ki-67 and p53 in Patients (Pts) with Dukes' B & C Colon Cancer. 2001 ASCO Carmen Joseph Allegra, S. Paik, A. Parr, L. Colangelo, I. Kirsch, G. Kim, P. Klein, P. Johnston, L. Eaton, W. King, N. Wolmark, S. Wieand, National Cancer Institute, Bethesda, MD; NSABP, Pittsburgh, PA. In conclusion, high TS and low Ki-67 scores were found to be associated with a poor clinical outcome and may be useful for identifying pts at high risk for relapse and death
7/11/01 Thymidylate Synthase Expression in Colorectal Cancer-a Prognostic and Predictive Marker of Benefit from Adjuvant Fluorouracil Based Chemotherapy. David Edler, Bengt Glimelius, Marja Hallstrom, Anders Jakobsen, Patrick G Johnston, Inger Magnusson, Peter Ragnhammar, Henric Blomgren, Karolinska Institute, Inst. South Hospital, Stockholm, Sweden; Dept of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden; CONCLUSION: TS expression predicts for survival independent of Dukes´ stage in patients with CRC treated with surgery only. The study indicates that patients with high TS levels may benefit from adjuvant 5-FU based chemotherapy. However, patients with low TS levels appear to have a worse outcome when treated with adjuvant chemotherapy. Further studies are now necessary to understand the role of TS as a predictor of chemotherapeutic benefit in adjuvant 5-FU based chemotherapy.
7/11/01 Molecular Markers Affect Survival Following Adjuvant Treatment for Resected Hepatic Metastases from Colorectal Cancer (CRC). Amanda Hummer, Nancy Kemeny, Alice Zervoudakis, Carlos Cordon-Cardo, David Klimstra, Deidre Sullivan, Yuman Fong, Mithat Gonen, Memorial Sloan-Kettering Cancer Center, New York, NY. Conclusions: TS and combined EGF-R and p53 play an important role in survival for this patient population. Although TS predicts poor prognosis, treatment with HAI+SYS improves prognosis even for TS+ patients.
7/11/01 Revisited Role of Tumoral Thymidylate Synthase (TS) in Treatment Outcome Prediction for Colorectal Cancer Patients. a French Multicentric Study. Maurice Chazal, Marie-Christine Etienne, Nicolas Magné, Pierre Laurent-Puig, Emmanuel Chamorey, Christophe Rosty, Jean-Louis Formento, Patricia Formento, Nicole Renée, André Bourgeon, Jean-Robert Delpero, Christian TS was not significant in a bivariate analysis including tt response, suggesting that the impact of TS on specific survival was directly related to chemotherapy responsiveness and not to intrinsic tumor aggressiveness.
7/11/01 Vascular Endothelial Growth Factor (VEGF), p53 and BAX Expression in Node-Positive Rectal Cancer. Relationships with Tumor Recurrence After Adjuvant Chemoradiation. Stefano Cascinu, Francesco Graziano, Vincenzo Catalano, Sandro Barni, Anna Maria Baldelli, Maria Cristina Rossi, Simona Secondino, A Brenna, Paolo Giordani, These data suggest the potential role of innovative molecular markers in identifying categories of low and high-risk pts with rectal cancer. A favourable molecular profile of p53, BAX and VEGF characterized disease-free pts. A significant relationship was found between local relapses and p53 overexpression, and between distant metastases and VEGF up-regulation.

P53 Gene
6/7/01 P53 tumor mutations predict response to therapy The Lancet, Janet Fricker Vol 348 July 13, 1996 Ian Fentiman, deputy director of the Imperial Cancer Research Fund Clinical Oncology Unit at Guy's Hospital (London, UK), says that screening patients for the presence of p53 mutations could eventually be used in deciding appropriate treatments. "By identifying the presence of p53 mutations we may be able to spare people the unpleasant side-effects of a chemotherapy regime that won't benefit them", he says, adding that for people with p53 mutations there might be more justification for experimenting with new treatments.
6/7/01 Summary of P-53 Gene Gene therapy on the p53 gene may be an important way to treat cancer because there is documented synergy between p53 gene therapy and treatments like chemotherapy (Roth 1996). This demonstrates that p53 gene therapy could prove to be a powerful force in killing cancer coupled with current treatments. One possibility for treatment involving p53 is the use of the immune system to fight cancer. Generally p53 mutations result in the production of altered proteins so the immune system could be used to target the tumor cells producing the altered proteins. This type of immunotherapy provides a nontoxic, tumor-specific treatment for cancer. Experiments done on mice have shown that dendritic cells specific for p53 mutations slowed the growth of existing tumors (Gabrilovich 1996). So if nothing else, immunotherapy may provide a way to at least slow the growth of tumors, and it may even be further developed as a cure for cancer in the future.
6/7/01 TB45 Correlations Between P53 Gene Alterations And Protein Expression In Colorectal Carcinomas. O.P.F. Clausen3, G.I. Meling1, R.A. Lothe2, P. De Angelis3, Y. Chen3, T.O. Rognum1, 1Inst. of Forensic Medicine, 3Inst. of Pathology, The National Hospital, 2Dept. of Genetics, Inst. of Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.
6/7/01 SCHERING-PLOUGH PRESENTS FINDINGS OF p53 GENE THERAPY STUDIES AT AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL MEETING NEW ORLEANS, March 31, 1998 - Schering-Plough Research Institute presented findings here today from ongoing Phase I clinical studies of its recombinant adenovirus encoding human p53 (rAd/p53) gene therapy that confirm p53 transgene expression in patients with various types of cancer following intrahepatic, intraperitoneal and intratumoral administration. Expression of the normal p53 tumor-suppressor gene in human cancers lacking functional p53 genes is an important step in the clinical development of rAd/p53 as a cancer-fighting agent.
6/7/01 p53 Tumor Suppressor Gene: At the Crossroads of Molecular Carcinogenesis, Molecular Epidemiology, and Cancer Risk Assessment Curtis C. Harris Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland Because mutations in the p53 gene can occur in precancerous lesions in the lung, breast, esophagus, and colon, molecular analysis of the p53 gene in exfoliated cells found in either body þuids or tissue biopsies may identify individuals at increased cancer risk. p53 mutations in tumors generally indicate a poorer prognosis. In summary, the recent history of p53 investigations is a paradigm in cancer research, illustrating both the convergence of previously parallel lines of basic, clinical, and epidemiologic investigation and the rapid translation of research findings from the laboratory to the clinic
7/16/01 Rb, mcl-1 and p53 expression correlate with clinical outcome in patients with liver metastases from colorectal cancer Annals of Oncology 12 (6):779-785, June 2001. Conclusions: These results indicate that besides TS, also Rb, p53 and mcl-1 are correlated with clinical outcome in patients with liver metastases from colorectal cancer.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
6/5/02 Hereditary Colon Cancer Association (FAP and HNPCC)
6/19/01 What is Hereditary Colon Cancer? (MD Anderson) One type, Lynch syndrome I, begins at a young age, is more likely to be in the proximal (upper, or right) colon, and is often accompanied by other colon tumors. Lynch syndrome II has all of these features and is also often accompanied by cancers outside the colon, especially in the endometrium (the lining of the uterus) and the ovaries. HNPCC may also be associated with cancers of the stomach, small bowel, pancreas, urinary tract, or larynx in some families
6/19/01 HNPCC Brochure from John Hopkins University
6/19/01 HNPCC from Mayo Clinic
6/19/01 HNPCC Cleveland Clinic
6/19/01 CASE STUDY No. 2 Hereditary Nonpolyposis Colon Cancer
6/19/01 Definition of HNPCC They are not all the same!
6/19/01 Kimmel Cancer Center - HNPCC Screening Test
6/19/01 HNPCC Best Practice Meeting 24 NOV 1997 Screening Guidelines
6/19/01 Hereditary Nonpolyposis Colorectal Cancer (HNPCC): Molecular Genetics Easy to read intro
6/19/01 GENES LINKED TO EARLY ONSET, LOCATION OF HEREDITARY COLON CANCER 1/29/99 COLUMBUS, Ohio. Researchers have identified a mechanism that may explain where colorectal tumors arise and at what age the tumors develop in people with one form of colorectal cancer.
6/19/01 Lecture on HNPCC for Medical Professionals No known medical treatments for patients with HNPCC. Aspirin may play an important protective effect against the development of sporadic colorectal cancer, its impact on HNPCC is unknown. No other interventions other than diagnostic screening and prophylactic surgery have been demonstrated to have a beneficial effect in this disease.
A rare subset of HNPCC families has a constellation of findings termed the Muir-Torre Syndrome Muir-Torre Syndrome - all of the features of HNPCC + sebaceous gland tumors + keratoacanthomas a keratin-filled skin tumor that occurs in sun-exposed areas.
10/19/01 Study of Outcomes in Education and Counseling for Hereditary Nonpolyposis Colon Cancer Testing (Summary Last Modified 07/2001) Protocol IDs: NCI-95-HG-0165, NCI-NMOB-9501, NHGRI-95-HG-0165 Family history consistent with hereditary nonpolyposis colon cancer (HNPCC) At least 3 relatives with histologically proven colorectal cancer and 1 is a first degree relative of the other 2 At least 2 successive generations affected Colorectal cancer diagnosed under age 50 in 1 of the relativesORDiagnosis of colorectal cancer under age 41 ORHNPCC associated cancer/polyps under age 41 with a positive replication error(RER)/microsatellite instability (MSI) phenotypeORMultiple primary HNPCC associated cancers regardless of family history ORColorectal or other HNPCC associated tumor/polyp demonstrating a positiveRER/MSI phenotype and at least 1 second degree (or closer) and 1 third degree(or closer) relative with a HNPCC associated cancer 1 affected family member must have one of the following: Right sided colon cancer Multiple primary HNPCC associated cancers Diagnosis of cancer prior to age 51
10/17/01 Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis Am J Pathol 2001 Jul;159(1):297-304 Colorectal cancers with high-frequency microsatellite instability show peculiar clinicopathological features and a favorable clinical outcome. High-frequency microsatellite instability was found in 43% of stage II/III proximal colon cancers and was associated with significantly higher numbers of activated cytotoxic lymphocytes. The presence of local cytotoxic immune responses is probably the major determinant of the good clinical course of patients with microsatellite unstable colon cancer. Furthermore, high-frequency microsatellite instability coupled with a high content of intratumoral cytotoxic lymphocytes may identify a subset of colon cancer patients with a favorable clinical outcome, particularly in stage III disease
10/17/01 Microsatellite Instability in Sporadic Colon Cancer Is Associated with an Improved Prognosis at the Population Level. Cancer Epidemiol Biomarkers Prev 2001 Sep;10(9):917-23 There was a significant relationship between microsatellite instability and improved prognosis, even after adjusting for stage, with a reduction in the risk of death attributable to colon cancer of approximately 60%. Most of this risk reduction occurred in individuals with American Joint Committee on Cancer stage III tumors
10/17/01 Dietary intake and microsatellite instability in colon tumors. Int J Cancer 2001 Aug 15;93(4):601-7 Microsatellite instability (MSI) occurs in approximately 15% of colon tumors. Other than relatively rare mutations in mismatch repair genes, the causes of MSI are not generally known The likelihood of having MSI in the tumor from the combined effects of high alcohol consumption and smoking cigarettes showed a 70% excess in risk from the additive model. There were some suggestions that high intakes of refined grain might also be associated with MSI+ tumors, although associations were less consistent. Risk estimates for most other dietary factors did not differ substantially by MSI status

Microsatellite Instability
9/7/01 Benign lesions may give rise to colorectal cancers with microsatellite instability Wednesday, Sep 5 2001 Benign proliferative lesions, such as hyperplastic polyps or serrated adenomas, collectively termed serrated polyps, may give rise to sporadic colorectal cancers with microsatellite instability (MSI), according to a report published in the September 5th issue of the Journal of the National Cancer Institute.
4/20/01 Article: Genetic Markers Predict Colon Cancer Survival Reuters, April 18, 2001. Dr. Stanley R. Hamilton of University of Texas MD Anderson Cancer Center "Among patients with microsatellite instability, the 5-year survival rate was 74% when there was a mutated gene for the type II receptor for TGF-ß1; without this mutation, the rate was 46%."
6/10/01 Fighting the Odds: Advances in Colorectal Cancer Diagnosis and Treatment Medscape (registration required) May 14, 2001 ASCO Meeting. Summary of latest Advances. Importance of Microsatellite Instability The Benefits of Cyclo-oxygenase (COX)-2 Inhibition, Controversial Issues in Chemotherapy Treatment, The Value of "Drug Holidays"
4/17/01 John Hopkins Hereditary Colon Cancer Microsatellite instability (MSI) testing is used as a screening test to see how likely it is that a person's cancer was caused by one of the genes associated with HNPCC. It is usually done on colon tumor tissue that is removed and stored as part of the normal process when a person has surgery for colon cancer. If the tumor tissue tests MSI positive, it is considered more likely that the cancer is due to one of the HNPCC gene mutations. People who have a positive MSI test have the option to pursue the genetic blood test. If the tumor tissue tests MSI negative, however, it is highly unlikely that current genetic testing will be helpful for the affected person's family. An MSI negative test result does not rule out the diagnosis of HNPCC.
6/19/01 HNPCC Microsatellite Instability Test from Roche Pharmaceuticals
7/12/01 TITLE: Implications of low COX-2 expression in colorectal neoplasms with defective DNA mismatch repair. AUTHOR: Karnes WE SOURCE: J Cell Biochem Suppl; 34:23-7 2000 UI: 20222648 Summary: Although the clinical implications of these observations are unknown, the presence of MSI should be considered an important variable when assessing the efficacy of COX-2 inhibitors in chemoprevention trials.
7/12/01 Overexpression of cyclooxygenase-2 protein is less frequent in gastric cancers with microsatellite instability. AUTHOR: Yamamoto H, Itoh F, Fukushima H, Hinoda Y, Imai K SOURCE: Int J Cancer; 84(4):400-3 1999 UI: 99359455 Summary: Overexpression of COX-2 in cancer tissues compared with matched non-cancerous tissues was found in 70% of cases and was significantly associated with lymphatic involvement, lymph node metastasis and advanced tumor stage. Interestingly, overexpression of COX-2 was less frequent in gastric cancers with microsatellite instability (MSI) than in those without MSI (8/20 vs. 62/80, p < 0.01).
7/12/01 Reduced COX-2 protein in colorectal cancer with defective mismatch repair. AUTHOR: Karnes WE, Shattuck-Brandt R, Burgart LJ, DuBois RN, Tester DJ, Cunningham JM, Kim CY, McDonnell SK, Schaid DJ, Thibodeau SN SOURCE: Cancer Res; 58(23):5473-7 1998 UI: 99065333 Summary: Overall, our results showed that low or absent COX-2 staining was significantly more common among tumors with defective mismatch repair (P = 0.001). Other features predictive of low COX-2 staining included marked tumor infiltrating lymphocytosis, and solid/cribiform or signet ring histological patterns

Home