Journal of Surgical Oncology 2015;111:103–111
Hereditary Colorectal Cancer Syndromes and Genetic Testing CAROLE MACARON, MD,1 BRANDIE H. LEACH, MS, CGS,2 AND CAROL A. BURKE, 1
1 MD *
Department of Gastroenterology and Hepatology, The Cleveland Clinic, Cleveland, Ohio 2 Genomic Medicine Institute, The Cleveland Clinic, Cleveland, Ohio
Colorectal cancer (CRC) is a leading cause of cancer and cancer deaths in the Western world. Approximately 5–10% of CRC are hereditary, due to a defined genetic cause. Individuals and families affected with a hereditary CRC syndrome exhibit benign and malignant extra‐intestinal tumors, require aggressive cancer screening and benefit from management by a multi‐disciplinary team of professionals. The clinical manifestations, genetic causes and current management of patients with hereditary colon cancer syndrome is provided.
J. Surg. Oncol. 2015;111:103–111. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: colon cancer; hereditary syndromes; genetic testing Colorectal cancer (CRC) is one of the leading causes of cancer and cancer related deaths in the Western world. While over 90% of CRC is sporadic approximately 5–10% are due to a hereditary cause. The clinical presentation, lifetime risk of CRC and extra‐colonic cancers, and surgical and medical management of individuals with hereditary CRC syndromes (HCCS) requires a substantially altered approach compared to patients with sporadic CRC. The utilization of commercial genetic testing to identify the cause of the HCCS allows identification of patients and family members who will benefit from syndrome specific screening, alterations in surgical management, including prophylactic operations, and reassure family members who test negative to be returned to average risk CRC screening. The basis of cancer prevention in individuals with a HCCS is recognition of the phenotype, which may be subtle or overt and requires compilation of an accurate personal and three generation family health history, indicating age and cause of death, especially any diagnosis of cancer with age of onset, or history of polyps. Patients with red flags suspicious for a HCCS (Table I) should be referred for a risk assessment, preferably, with a genetic counselor. All HCCS are inherited in an autosomal dominant fashion with the exception of MYH associated polyposis (MAP), which is autosomal recessive. Generally the HCCS are divided into the polyposis syndromes, which are associated with numerous colorectal polyps, and the non‐polyposis syndromes with fewer colorectal polyps although there may be phenotypic overlap. The differentiation between polyposis syndromes may be facilitated by the histology of underlying polyps, adenomatous versus hamartomatous, or in the non polyposis syndromes by genetic alterations in the colorectal tumor, high levels of miscrosatellite instability (MSI‐H) versus microsatellite stable (MSS), for example.
THE ADENOMATOUS POLYPOSIS SYNDROMES The genetically defined adenomatous polyposis syndromes comprise familial adenomatous polyposis (FAP), MYH‐associated polyposis (MAP) and the recently described condition polymerase proofreading‐ associated polyposis (PPAP). Clinically, theses syndromes have significant phenotypic overlap and can be challenging to distinguish.
FAMILIAL ADENOMATOUS POLYPOSIS (FAP) Over 1,000 different germline mutations in the tumor suppressor gene Adenomatous Polyposis Coli (APC) located on chromosome 5q21‐ q22 have been shown to cause FAP. FAP occurs in 1 in 10,000
ß 2014 Wiley Periodicals, Inc.
individuals [1,2]. De novo mutation in APC have been described in approximately 25% of cases [3].
Clinical Presentation Certain APC mutations have been associated with a profuse or classic form of the disease in which hundreds to thousands of polyps are observed throughout the colon in the pre‐teen to mid‐teenage years. This phenotype is associated with a 100% risk of CRC by the age of 39 years in the absence of prophylactic colectomy. Often mutations in exon 9 or the 50 , or 30 region of the gene are associated with attenuated FAP (AFAP) which is characterized by a lower colorectal adenoma burden (20), size (1–4, 5–10, and >10 mm), histology and degree of dysplasia of adenoma in the duodenum to predict individuals at greatest risk of duodenal cancer. Patients with stage I–III have a 2.5%, 10 year cumulative risk of duodenal cancer while those with stage IV disease have a 36% risk. Adenomas can occur in the jejunum and ileum with an incidence of
*Correspondence to: Carol A. Burke, MD, The Cleveland Clinic, Desk A 31, 9500 Euclid Avenue, Cleveland, Ohio 44195. Fax: þ2164446305. E‐mail: [email protected] Received 8 March 2014; Accepted 24 May 2014 DOI 10.1002/jso.23706 Published online 29 June 2014 in Wiley Online Library (wileyonlinelibrary.com).
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Macaron et al.
TABLE I. Red Flags for the Presence of a Hereditary CRC Syndrome Early age of cancer onset CRC or endometrial cancer before age 50 CRC with high microsatellite instability (MSI‐H) MSI‐H histologic features present in a CRC Multiple first or second degree family members with synchronous or metachronous CRC and/or extra colonic cancers, especially younger than age 50 Multiple lifetime cumulative gastrointestinal polyps 10 adenomatous polyps 5 hamartomatous polyps >20 serrated polyps throughout the colon 5 serrated polyps proximal to sigmoid colon with at least 2 polyps 1 cm Individuals with a family history of hereditary CRC syndromes
Hereditary Colorectal Cancer Syndromes and Genetic Testing CAROLE MACARON, MD,1 BRANDIE H. LEACH, MS, CGS,2 AND CAROL A. BURKE, 1
1 MD *
Department of Gastroenterology and Hepatology, The Cleveland Clinic, Cleveland, Ohio 2 Genomic Medicine Institute, The Cleveland Clinic, Cleveland, Ohio
Colorectal cancer (CRC) is a leading cause of cancer and cancer deaths in the Western world. Approximately 5–10% of CRC are hereditary, due to a defined genetic cause. Individuals and families affected with a hereditary CRC syndrome exhibit benign and malignant extra‐intestinal tumors, require aggressive cancer screening and benefit from management by a multi‐disciplinary team of professionals. The clinical manifestations, genetic causes and current management of patients with hereditary colon cancer syndrome is provided.
J. Surg. Oncol. 2015;111:103–111. ß 2014 Wiley Periodicals, Inc.
KEY WORDS: colon cancer; hereditary syndromes; genetic testing Colorectal cancer (CRC) is one of the leading causes of cancer and cancer related deaths in the Western world. While over 90% of CRC is sporadic approximately 5–10% are due to a hereditary cause. The clinical presentation, lifetime risk of CRC and extra‐colonic cancers, and surgical and medical management of individuals with hereditary CRC syndromes (HCCS) requires a substantially altered approach compared to patients with sporadic CRC. The utilization of commercial genetic testing to identify the cause of the HCCS allows identification of patients and family members who will benefit from syndrome specific screening, alterations in surgical management, including prophylactic operations, and reassure family members who test negative to be returned to average risk CRC screening. The basis of cancer prevention in individuals with a HCCS is recognition of the phenotype, which may be subtle or overt and requires compilation of an accurate personal and three generation family health history, indicating age and cause of death, especially any diagnosis of cancer with age of onset, or history of polyps. Patients with red flags suspicious for a HCCS (Table I) should be referred for a risk assessment, preferably, with a genetic counselor. All HCCS are inherited in an autosomal dominant fashion with the exception of MYH associated polyposis (MAP), which is autosomal recessive. Generally the HCCS are divided into the polyposis syndromes, which are associated with numerous colorectal polyps, and the non‐polyposis syndromes with fewer colorectal polyps although there may be phenotypic overlap. The differentiation between polyposis syndromes may be facilitated by the histology of underlying polyps, adenomatous versus hamartomatous, or in the non polyposis syndromes by genetic alterations in the colorectal tumor, high levels of miscrosatellite instability (MSI‐H) versus microsatellite stable (MSS), for example.
THE ADENOMATOUS POLYPOSIS SYNDROMES The genetically defined adenomatous polyposis syndromes comprise familial adenomatous polyposis (FAP), MYH‐associated polyposis (MAP) and the recently described condition polymerase proofreading‐ associated polyposis (PPAP). Clinically, theses syndromes have significant phenotypic overlap and can be challenging to distinguish.
FAMILIAL ADENOMATOUS POLYPOSIS (FAP) Over 1,000 different germline mutations in the tumor suppressor gene Adenomatous Polyposis Coli (APC) located on chromosome 5q21‐ q22 have been shown to cause FAP. FAP occurs in 1 in 10,000
ß 2014 Wiley Periodicals, Inc.
individuals [1,2]. De novo mutation in APC have been described in approximately 25% of cases [3].
Clinical Presentation Certain APC mutations have been associated with a profuse or classic form of the disease in which hundreds to thousands of polyps are observed throughout the colon in the pre‐teen to mid‐teenage years. This phenotype is associated with a 100% risk of CRC by the age of 39 years in the absence of prophylactic colectomy. Often mutations in exon 9 or the 50 , or 30 region of the gene are associated with attenuated FAP (AFAP) which is characterized by a lower colorectal adenoma burden (20), size (1–4, 5–10, and >10 mm), histology and degree of dysplasia of adenoma in the duodenum to predict individuals at greatest risk of duodenal cancer. Patients with stage I–III have a 2.5%, 10 year cumulative risk of duodenal cancer while those with stage IV disease have a 36% risk. Adenomas can occur in the jejunum and ileum with an incidence of
*Correspondence to: Carol A. Burke, MD, The Cleveland Clinic, Desk A 31, 9500 Euclid Avenue, Cleveland, Ohio 44195. Fax: þ2164446305. E‐mail: [email protected] Received 8 March 2014; Accepted 24 May 2014 DOI 10.1002/jso.23706 Published online 29 June 2014 in Wiley Online Library (wileyonlinelibrary.com).
104
Macaron et al.
TABLE I. Red Flags for the Presence of a Hereditary CRC Syndrome Early age of cancer onset CRC or endometrial cancer before age 50 CRC with high microsatellite instability (MSI‐H) MSI‐H histologic features present in a CRC Multiple first or second degree family members with synchronous or metachronous CRC and/or extra colonic cancers, especially younger than age 50 Multiple lifetime cumulative gastrointestinal polyps 10 adenomatous polyps 5 hamartomatous polyps >20 serrated polyps throughout the colon 5 serrated polyps proximal to sigmoid colon with at least 2 polyps 1 cm Individuals with a family history of hereditary CRC syndromes
