Recognition and management of hereditary colorectal cancer syndromes

Abstract

Over 1.900 colorectal tumors will arise in association with a hereditary colorectal cancer syndrome in Spain in 2009.The genetic defects responsible for the most common syndromes have been discovered in recent years.Genetic testing helps diagnose affected individuals and allows identification of individuals at-risk.Colonoscopy and prophylactic colectomy decrease colorectal cancer incidence and overall mortality in patients with hereditary colon cancer.Extracolonic tumors are frequent in these syndromes, so specific surveillance strategies should be offered.Key words: Familial adenomatous polyposis. Lynch syndrome. MYH-associated polyposis. Hereditary colon cancer. INTRODUCTIONIn 2009, it is estimated that around 38,000 people (1) in Spain will be diagnosed with colorectal cancer (CRC). Among these cases, more than 15% will exhibit familial clustering, and over 1,900 tumors (5%) will arise in association with a hereditary colorectal cancer syndrome. The most common hereditary colon cancer syndromes are: Familial Adenomatous Polyposis (FAP), attenuated FAP (AFAP), MYH associated polyposis (MAP), and Lynch syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) (2).During the last two decades, the most important advancement has been the identification of the genes that underlie these syndromes. This has permitted more accurate classifications of the various syndromes based upon genetic criteria, and consequently this has resulted in more tailored management strategies based on these criteria (3). The management of individuals with hereditary colon cancer or at-risk for hereditary colon cancer is dramatically different, so recognizing these syndromes is critical. Specifically, surveillance strategies for colon and extra-colonic tumors as well as surgical approaches (4) for the prevention and treatment of cancer reflect the heightened risks.This review is focused on current treatment strategies in hereditary colon cancer. It is important to recognize that "treatment" includes not only management of already diagnosed cancers but also to prevention of cancer in these high-risk populations. We first briefly summarize the major clinical features of each syndrome, including pattern of inheritance and penetrance, age at diagnosis and associated extra-colonic tumors. Familial adenomatous polyposis and attenuated FAPFAP is the most common adenomatous polyposis syndrome. Its prevalence is 1:5.000-10.000, with a uniform worldwide distribution, affecting both genders equally (5). Inherited in an autosomal dominant manner with a virtually penetrance of 100%, it is caused by a germline mutation in the Adenomatous Polyposis Coli (APC) tu- POINT OF VIEWmor suppressor gene on chromosome 5q21 (6). In 15-20%, the cases are "de novo" without clinical or genetic evidence of FAP in the parents (7). Recent studies indicate the presence of mosaicism in approximately 15% of such cases (8,9).Classic FAP is characterized by the development of hundreds to thousands of colorectal adenomas starting during the...

Endoscopic and Surgical Management of Hereditary Nonpolyposis Colorectal Cancer

“…To prevent or delay the development of neoplasia in the colon and rectum in the setting of HNPCC or Lynch syndrome, and hopefully avoid the need for surgical intervention, there has been an attempt to use medical therapy as chemopreventative agents, much as they have been used in the setting of FAP (see article on FAP in this issue of Clinics). 7 Unlike FAP, however, fewer human trials have been conducted because of the relative infrequency of developing adenomas in HNPCC, the numbers of patients that are required for such trials, and the lack of understanding of the impact of genotypephenotype correlations on the development of neoplasia based on each patient's MMR gene mutation (assuming they have been gene tested or they are positive for a mutation). 13 Much like in FAP, however, attempts at developing or identifying chemoprevention agents seem appropriate given the high risk circumstances for HNPCC patients.…”

“…34 Nitric oxide (NO)-donating NSAIDs for Lynch syndrome have shown promise based on their inhibition of MSI with apparently low toxicity, whereas more selective COX-2 inhibitors (such as celecoxib) have unclear promise as chemoprevention in HNPCC based on mixed expression of COX-2 in Lynch syndrome tumors (as opposed to high expression in some sporadic adenomas). 7,31,35 Human studies with COX-2 inhibitors in HNPCC are ongoing. Calcium has been considered as a chemopreventative agent as it is thought to bind fatty acids and bile salts thus decreasing colonic irritation and cell proliferation.…”

“…This leads to a younger age at diagnosis of CRC in HNPCC (mean of 45 years old) and a need for a shortened screening interval. 7 These CRCs are also more likely to be right-sided (60-70%), and are associated with high risk of synchronous (18%) and metachronous (11-45%) tumors. 1,2,8,9 Therefore, it is imperative that the entire wellprepped colon is evaluated during screening and that screening colonoscopy begin earlier than in individuals with average CRC risk (i.e., earlier than age 50).…”

“…6 Alterations in screening intervals between Lynch syndrome patients versus those with HNPCC have not been studied in a prospective fashion, however; therefore, most authors recommend colonoscopy every 1 to 2 years beginning at age 20 to 25, or 10 years younger than the first diagnosis in the family (whichever is first), then yearly after age 40 for patients with either HNPCC or Lynch syndrome. 2,7,12 Adjunctive technologies beyond standard colonoscopy may increase the identification of neoplasia during screening of HNPCC patients and may impact CRC mortality rates in these patients. Technologies such as dye-spray or chromoendoscopy, 13 as well as narrow band imaging have shown promise in better-identifying adenomas when used for screening HNPCC patients.…”

Multiple desmoid tumors in a patient with familial adenomatous polyposis caused by the novel W421X mutation

“…The syndrome is also characterized by extra-colorectal features including upper gastrointestinal tract polyps, especially of the duodenum, desmoid tumors (fibromatosis), osteomas, epidermoid cysts, congenital hypertrophy of the retinal pigment epithelium, dental anomalies and increased risk for peri-ampullary carcinoma, meduloblastoma, papillary carcinoma of the thyroid and hepatoblastoma (1,2,5). The syndrome is inherited by an autosomal dominant gene, the adenomatous polyposis coli (APC) gene, although new mutations account for 15-30% of cases and results from a germline mutation (1,2,6,7). We present the physical history, clinical presentation, diagnosis and treatment of a patient with a novel germline APC mutation, the W421X mutation, which resulted in FAP presenting with about a hundred colorectal polyps, gastric hyperplastic polyps and multiple aggressive intra-abdominal and extra-abdominal desmoid tumors.…”