Genetic Testing for Hereditary Colorectal Cancer Syndromes

Laura Witrak Belcastro, M.S. C.G.C
Certified Genetic Counselor
SMDC

VHJOE Editor:

John Deutsch, MD
St. Mary's Duluth Clinic

International Editor:

Manoop S. Bhutani, MD
MD Anderson Cancer Center
Houston, TX

Editorial Board:

William R. Brugge, MD
Massachusetts General Hospital

Peter R. McNally, DO
Denver, CO

Thomas J. Savides, MD
University of California,
San Diego

C. Mel Wilcox, MD
University of Alabama, Birmingham
Introduction

In 2008, approximately 140,000 people will have been diagnosed with colorectal cancer (CRC) and an estimated 49,000 will die from it3. Of these cases, 5% of them will be associated with a hereditary predisposition to not only colorectal cancer but extracolonic malignancies, polyposis and benign but problematic features1,4. Currently, of the eight recognized hereditary colorectal cancer syndromes, all have clinically available molecular genetic testing algorithms as well as clinical practice guidelines, prevention methods, therapies and treatment for patients positive for a genetic mutation.

It is important for clinicians to recognize hereditary cancer syndromes in patients and families. Due to the complex nature of differing types of gene classes involved in the hereditary colorectal cancer syndromes and the testing algorithms themselves, it is also important to try to determine which syndrome a patient or family may have. Genetic counselors can greatly aid physicians in this realm using the family pedigree, pathology/histology reports, and expertise in the syndromes themselves and genetic testing. Genetic testing can be costly and time consuming; therefore it is critical to test the correct person with the correct test to minimize insurance or personal burden and maximize the amount of helpful clinical information for the patient, their family and the physician. Genetic testing for hereditary cancer syndromes can be as high as $3000. Typically insurance companies will cover the cost of the test especially if the genetic testing can help guide clinical management. There are currently federal laws written to protect individuals who are carriers for genetic mutations that predispose them to certain diseases/disorders from discrimination: the Americans with Disabilities Act (ADA) & the Genetic Information Nondiscrimination Act (GINA).

The CRC syndromes can be divided into two categories: nonpolypsis and polyposis syndromes2,4. Of the polyposis syndromes, these can be further divided into two other groups: adenomatous polyposis and hamartomatous polyposis syndromes2,3,4. Following is a listing of the syndromes along with associated genes, polyp number, the most common malignancy risks, syndromic variants and molecular laboratories offering clinical testing in the United States. Malignancy risks are related to untreated patients (i.e. no preventative surgeries/treatment). All of the syndromes exhibit an autosomal dominant inheritance pattern save for the MYH-associated polyposis (MAP) which in most families shows an autosomal recessive pattern.

Nonpolyposis Syndromes:

These syndromes are responsible for approximately 2-3% of all CRC cases and are associated with the mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2, PMS1 and MSH33,4,5.

  • Hereditary Nonpolyposis Colon Cancer (HNPCC) or Lynch Syndrome
    • Colon polyps: 2-3 times the sporadic rate
    • Malignancy risks & mean age of onset: Colon 80% by 44 years; Uterine 20-60% by 46 years; Stomach 11-19% by 56 years; Ovary 9-12% by 42.5 years; Urinary, biliary, renal, central nervous system & small bowel – rare3,4.
    • Testing algorithm: Microsatellite Instability (MSI) and Immunohistochemistry (IHC) tumor tissue testing followed by molecular gene sequencing if appropriate based on MSI (high instability) and IHC (absent proteins) results and/or personal/family history. Note: approximately 5-10% of tumors exhibiting normal MSI/IHC will actually be related to genetic mutations in the MMR genes (3).
      • Up to 95% sensitivity rate for molecular gene sequencing.
    • Muir-Torre Syndrome – variant of HNPCC
      • Similar presentation to HNPCC patients/families with one or more internal malignancies and skin neoplasias3,4.
      • Sebaceous skin neoplasias: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas.
    • Turcot Syndrome – variant of both HNPCC & FAP syndromes
      • Similar presentation to HNPCC patients/families with either colon cancer or colonic adenomas and central nervous system tumors3,4.
      • Central Nervous System malignancies: glioblastoma multiforme.
    • Laboratories offering both tumor tissue and DNA tests: ARUP, Baylor College of Medicine, LINK , City of Hope's Molecular Diagnostic Laboratory, Huntington Medical Research Institute, Mayo Clinic – Minnesota, Myriad Genetic Laboratories, Inc., & Quest Diagnostics – Nichols Institute.

Polyposis Syndromes:

The following five syndromes are divided into two groups based on histopathology of the polyps. Each syndrome is associated with a unique gene(s) and they are responsible for approximately 1% of all CRC cases7.

Adenomatous polyposis syndromes:

  • Familial Adenomatous Polyposis (FAP)
    • Gene: APC
    • Polyposis: 100s-1000s of polyps in colon; polyposis also in stomach, duodenum, jejunum & ileum3,4,7.
      • Fundic gland polyps are the most common type of polyps in the stomach. There have been reports of gastric cancer arising from fundic gland polyps, mainly in Japanese and Korean populations where the risk for gastric cancer is 2-4%.
      • Polyposis can begin as early as the first decade of life (average is 16 years).
    • Malignancy risks & mean age of onset: Colon 100% by 39 years; Small bowel 4-12%; Pancreatic adenocarcinoma, Papillary thyroid carcinoma, CNS medulloblastoma, Hepatoblastoma & Bile duct adenocarcinoma – all under 2%3,4,7.
    • Benign extracolonic features: Osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, & desmoid tumors.
    • Gardner Syndrome – variant of FAP
      • Similar presentation to colonic polyposis of typical FAP with osteomas & soft tissue tumors: epidermoid cysts, fibromas & desmoid tumors4,7.
    • Turcot Syndrome – variant of both HNPPC & FAP
      • Similar presentation of colonic polyposis of typical FAP with CNS tumors; primarily medulloblastomas4,7.
    • Attenuated FAP (AFAP)
      • Fewer polyps (average 30) and polyps more proximally located than they are in classic FAP; later age of onset for colon cancer (50-55 years) and a lifetime risk of 70% for CRC by age 80.
      • Fundic gland polyps are also found in patients with AFAP and carry a similar malignancy risk as they do in FAP4,7.
    • Testing algorithm: Sequence analysis of the APC gene; deletion/duplication analysis also offered.
      • Up to 90% sensitivity for molecular gene sequencing.
    • Laboratories for FAP: Baylor College of Medicine, Boston University School of Medicine, Harvard Medical School, Huntington Medical Research Institute, Mayo Clinic – Minnesota, Myriad Genetic Laboratories, Inc., & University of Pennsylvania School of Medicine

  • MYH-associated polyposis (MAP)
    • Gene: MYH or MutYH
    • Polyposis: Few to 100’s of polyps in colon, rectum and stomach.
    • Malignancy risks & mean age of onset: Due to autosomal recessive inheritance; heterozygote (or monoallelic) carriers present a lower risk for CRC while homozygotes (or biallelic) may have up to a 20% risk for CRC and up to 15% for upper gastrointestinal malignancies. Mean age of onset in mid-late 50’s6,7.
    • Testing algorithm: Sequence and targeted mutation analysis of MYH gene.
    • Laboratories for MAP: Baylor College of Medicine, Boston University School of Medicine, Harvard Medical School, Huntington Medical Research Institute, Mayo Clinic – Minnesota, Myriad Genetic Laboratories, Inc., & University of Pennsylvania School of Medicine

Hamartomatous Polyposis Syndromes:


  • Peutz-Jeghers Syndrome (PJS):
    • Gene: STK11 (also called LKB1)
    • Polyposis: Peutz-Jeghers type polyps found mainly in jejunum, ileum & duodenum. Polyps can be found in stomach as well. Median age of polyposis can be as early as 10 years1,4.
      • Peutz-Jeghers polyps are hamartomas that differ significantly from Juvenile polyps in that the muscularis mucosa branches into different epithelial layers such as the lamina propria. PJS polyps in the colon can contain an adenomatous appearance and are thought to be more malignant than the PJS polyps found in the stomach1.
    • Malignancy risks & mean age of onset: Colon 39% by 46 years; Breast, pancreatic, gastric, ovarian, lung, uterine & small bowel – risks range from 10-40%1.
    • Benign extracolonic features: Ocular, nasal and perianal mucocutaneous pigmented spots.
    • Testing algorithm: Sequence analysis of STK11
      • 50% of patients with PJS have a de novo mutation (i.e. negative family history).
      • Over 90% sensitivity for molecular gene sequencing.
    • Laboratories: GeneDx & Ohio State University Molecular Pathology Laboratory.

  • Juvenile Polyposis Syndrome:
    • Gene: SMAD4 & BMPR1A
    • Polyposis: Few to 100 Juvenile type polyps in stomach, small bowel & colon1,4.
      • Juvenile polyps are hamartomas showing dense stroma, inflammatory infiltrate and mucus-filled cystic glands. They usually have normal epithelium and a smooth looking appearance. No muscle fibers or adenomatous changes are seen in Juvenile polyps1.
      • Median age of polyposis is 18 years.
    • Malignancy risks & mean age of onset: GI cancers 9-50% by 34 years; Pancreatic – rare1.
    • Benign extracolonic features: Hereditary Hemorrhagic Telangiectasia (HHT) can be caused by mutations in the SMAD4 gene; therefore a family history of recurrent and chronic nosebleeds, AVMs and juvenile polyposis should be followed up with genetic testing and appropriate screening. Testing for this combined syndrome is offered through ARUP Laboratories and AMBRY Genetics1.
    • Testing algorithm: Sequence analysis of both SMAD4 & BMPR1A
      • Approximately 20% sensitivity for both genes for molecular gene sequencing.
    • Laboratories: Ohio State University Molecular Pathology Laboratory.

  • PTEN Hamartoma Tumor Syndrome (PHTS):This syndrome is associated with Cowden Syndrome (CS), Bannayan-Ruvalcaba-Riley Syndrome (BRRS), Proteus Syndrome (PS) and Proteus-like Syndrome. CS is the most common1,4.
    • Gene: PTEN
    • Polyposis: Juvenile type polyposis in stomach, colon, esophagus and duodenum. CS & BRRS polyps are not thought to increase the risk of CRC.
    • Malignancy risks & mean age of onset: For patients with CS: breast 25-50% by age 50; Follicular thyroid cancer up to 10%; Endometrial cancer 5-10%. Similar risks for patients with BRRS but the data is not as strong1,4.
    • Benign extracolonic features: Macrocephaly, hypertelorism, cognitive deficits, facial trichelemmomas, oral papillomas, acral keratoses, mucosal lesions, goiter & fibrocystic breast disease.
    • Testing algorithm: Sequence, deletion and promoter analysis for the PTEN gene.
      • Up to 80% sensitivity for molecular gene sequencing for patients with CS.
    • Laboratories: Boston University School of Medicine, GeneDx, Greenwood Genetic Center, Johns Hopkins Hospital, Signature Genomic Laboratories, and the Ohio State University Molecular Pathology Laboratory.

References

1. Calva D, Howe JR. Hamartomatous Polyposis Syndromes. Surg Clin N Am. 2008; 88:779-817. <Related link>

2. Hagop, M. Kantarjian, Robert A. Wolff and Charles A. Koller. MD Anderson Manual of Medical Oncology. New York: McGraw Hill, 2006. <Related link>

3. Kwak EL, ChungDC. Hereditary colorectal cancer syndromes: an overview. Clin Colorectal Cancer. 2007 Jan;6(5):340-4.
<Related link>

4. Lindor NM et al. The Concise Handbook of Family Cancer Syndromes. J Natl Cancer INst. 1998 Jul 15;90(14):1039-71. <Related link>

5. Lipkin SM, Afrasiabi K. Familial colorectal cancer syndrome X. Semin Oncol. 2007 Oct;34(5):425-7.<Related link>

6. Lipton L, Tomlinson I. The multiple colorectal adenoma phenotype and MYH, a based excision repair gene. Clin Gastroenterol Hepatol. 2004 Aug;2(8):633-8. <Related link>

7. Schulmann K, Pox C, Tannapfel A, Schmiegel W. The patient with multiple intestinal polyps. Best Pract Res Clin Gastroenterol. 2007;21(3):409-26. <Related link>

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