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Stephen B. Gruber and Wendy Kohlmann

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 3% to 5% of all colorectal cancer. HNPCC is caused by germline mutations in the mismatch repair system and is recognized by a characteristic clinical phenotype as well as a hallmark of the tumors termed “microsatellite instability.” Microsatellite instability serves as a molecular fingerprint for defective mismatch repair and has proven to be useful in the molecular diagnostic workup for HNPCC. The crystal structure of the DNA mismatch repair protein MutS has been solved, providing insight into the molecular basis of defective mismatch repair. Genetic testing has become a key component of the treatment of patients and families with HNPCC, and enhanced surveillance for HNPCC has been shown to reduce the rate of colorectal cancer by more than half and improve 10-year survival from 68% to 93%.

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Mary B. Daly, Jennifer E. Axilbund, Saundra Buys, Beth Crawford, Carolyn D. Farrell, Susan Friedman, Judy E. Garber, Salil Goorha, Stephen B. Gruber, Heather Hampel, Virginia Kaklamani, Wendy Kohlmann, Allison Kurian, Jennifer Litton, P. Kelly Marcom, Robert Nussbaum, Kenneth Offit, Tuya Pal, Boris Pasche, Robert Pilarski, Gwen Reiser, Kristen Mahoney Shannon, Jeffrey R. Smith, Elizabeth Swisher and Jeffrey N. Weitzel

OverviewAll cancers develop as a result of mutations in certain genes, such as those involved in the regulation of cell growth and/or DNA repair,1,2 but not all of these mutations are inherited from a parent. For example, sporadic mutations can occur in somatic/tumor cells only, and de novo mutations can occur for the first time in a germ cell (i.e., egg or sperm) or in the fertilized egg itself during early embryogenesis. However, family studies have long documented an increased risk for several forms of cancer among first-degree (i.e., parents, siblings, and children) and second-degree relatives (i.e., grandparents, aunts or uncles, grandchildren, and nieces or nephews) of affected individuals. These individuals may have an increased susceptibility to cancer as the result of 1 or more gene mutations present in parental germline cells; cancers developing in these individuals may be classified as hereditary or familial cancers.Hereditary cancers are often characterized by mutations associated with a high probability of cancer development (i.e., a high penetrance genotype), vertical transmission through either mother or father, and an association with other types of tumors.3,4 They often have an early age of onset and exhibit an autosomal dominant inheritance pattern (i.e., occur when the individual has a mutation in only 1 copy of a gene).Familial cancers share only some features of hereditary cancers. For example, although familial breast cancers occur in a given family more frequently than in the general population, they generally do not exhibit the inheritance patterns or onset age consistent...
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Randall W. Burt, James S. Barthel, Kelli Bullard Dunn, Donald S. David, Ernesto Drelichman, James M. Ford, Francis M. Giardiello, Stephen B. Gruber, Amy L. Halverson, Stanley R. Hamilton, Mohammad K. Ismail, Kory Jasperson, Audrey J. Lazenby, Patrick M. Lynch, Edward W. Martin Jr., Robert J. Mayer, Reid M. Ness, Dawn Provenzale, M. Sambasiva Rao, Moshe Shike, Gideon Steinbach, Jonathan P. Terdiman and David Weinberg

Overview Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and women in the United States. In 2009, an estimated 106,100 new cases of colon cancer and 40,870 new cases of rectal cancer will occur in the United States, and 49,920 people will die of colon and rectal cancers. Patients with lo-calized colon cancer have a 90% 5-year survival rate. CRC mortality can be reduced through early diagnosis and cancer prevention with polypectomy. Therefore, the goal of CRC screening is to detect cancer at an early, curable stage and to detect and remove clinically significant adenomas. Screening tests that can detect both early cancer and adenomatous polyps are encouraged, although the panel recognizes that patient preference and resource accessibility play a large role in test selection. Curent technology falls into 2 broad categories: structural and stool/fecal-based tests. Although some techniques are better established than others, panelists agreed that any screening is better than none. Structural Screening Tests Structural tests are able to detect both early cancer and adenomatous polyps using endoscopic or radiologic imaging. These have several limitations, including their relative invasiveness, the need for dietary preparation and bowel cleansing, and the time dedicated to the examination (typically a day). Endoscopic examinations require informed consent and sedation, and have related risks, including perforation and bleeding. Recently, a large cohort study of 53,220 Medicare patients between ages 66 and 95 years showed that risk for adverse events after colonoscopy increases with age. Colonoscopy Colonoscopy is the most complete...