The Hereditary Colorectal Cancer Family Registry and Research Program at Memorial Sloan-Kettering Cancer Center

Submitted by José G. Guillem, M.D., M.P.H.

Colorectal cancer is a major public health problem in the United States, with an estimated 148,000 new cases and 50,000 deaths
due to disease in 2008. Up to 15% of colorectal cancer cases are believed to be inherited or “passed-on” through families.  Since patients with hereditary forms of colorectal cancer may also be at higher risk of developing cancers in other organs, close surveillance of affected individuals as well as at-risk family members is important.

Dr. Guillem’s interest in hereditary colorectal cancer dates back to his time as a general surgery resident at Columbia Presbyterian Medical Center. In the first publication of its kind, he described the rate of colonic neoplasms in first-degree relatives of patients with colorectal cancer.  The findings of this study lead to heightened awareness of the risk of neoplasia in patients with family
histories of colorectal cancer.  Dr. Guillem’s interest in hereditary colorectal cancer was further encouraged during his fellowship in
Colon and Rectal Surgery at the Lahey Clinic in Burlington, Massachussettes.

Upon completion of fellowship training, Dr. Guillem joined the faculty at Memorial Sloan-Kettering Cancer Center in New York.
In collaboration with members of the Gastroenterology Service and the Clinical Genetics Service, Dr. Guillem established the first Hereditary Colorectal Cancer Family Registry at this institution in 1991. This was later formalized into an institutional protocol in 2001. The scientific aims of the registry are three-fold:

  • To identify and prospectively track families with possible hereditary forms of colorectal cancer.
  • To act as an educational resource for those identified as having a known cancer syndrome or presumed to be at increased risk of developing colorectal cancer.
  • To provide patients for existing research protocols.

Numerous research projects have been supported by the Hereditary Colorectal Cancer Family Registry. Notable is the MSH2A636P gene mutation study in Ashkenazi Jewish patients with early age-of-onset colorectal cancer. This study demonstrated that this mutation is found in colorectal cancer patients of Ashkenazi descent, and in particular those with early age-of-onset colorectal cancer or a strong family history of colorectal cancer. The identification and characterization of this novel mutation has been greatly facilitated by the study of patients with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) and early age-of-onset CRC participating in the Registry.

The reputation of the Hereditary Colorectal Cancer Family Registry has prompted Pfizer, Inc. to invite MSKCC to participate in a new clinical trial entitled “A Phase III Placebo-Controlled Trial of Celecoxib in Genotype Subjects with FAP.”  Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome characterized by polyposis of the colon and rectum and a near 100% progression to colorectal cancer at a very early age. The overall goal of this study is to attempt to delay prophylactic surgical removal of the colon and rectum by reducing the number of polyps. This study may provide an important option for delaying surgery until patients are older and able to cope with the complexities of major surgery. The Registry will serve as a valuable resource for identifying eligible patients.

We have recently completed a study titled “The Prospective Immunohistochemical Analysis of Primary Colorectal Cancers for Loss of Mismatch Repair Protein Expression”, which was presented during the 2008 annual meeting of the American Society of Colon and Rectal Surgeons.  This study, addressing the diagnosis of HNPCC in early age-of-onset colorectal cancer patients, investigates the utility of routine testing of colorectal cancer specimens for proteins involved in DNA repair.  We have shown that assessment of family cancer history alone may be inadequate for identifying this genetic syndrome in young patients with colorectal cancer. We believe that this technique may improve identification of patients with HNPCC.

Some of our studies are multi-centered and are supported, in part, by the National Cancer Institute (NCI).  One study aims to prospectively determine the diagnostic accuracy of careful pathologic review to predict HNPCC.  This study has the potential to change the standard of care for patients with early age-of-onset CRC.  Similarly, a second study involves the genome-wide DNA analysis by single nucleotide polymorphism arrays, which provides very high-resolution analysis of both DNA copy number alterations and loss of heterozygosity events in cancer cells. This technique can accurately map genetic changes present across the entire genome, allowing for focused evaluation of novel candidate genes in patients with colorectal cancer.

We are also interested in patients with Hyperplastic Polyposis Syndrome (HPS).  This rare and poorly understood condition is characterized by the development of numerous small hyperplastic polyps throughout the colon and rectum.  Some patients also develop polyps in other parts of the gastrointestinal tract, and there are reports of an association with colorectal cancer.  Recent studies have identified potential genetic mutations responsible for this syndrome. However, given the rarity of this disease, it is difficult for any single institution to assemble enough patients to perform large-scale investigations. This has led us to begin collaborations with other academic institutions.  Our hope is to initiate multi-center studies to better define the natural history of this disease, as well as to investigate the potential role of medications that may delay the onset of or prevent polyp formation.

Information on the natural history of hereditary forms of colorectal cancer, gleaned from maintaining the Registry, has facilitated the development of recommendations for screening and surveillance.  Recently, Dr. Guillem assembled a panel of experts to author a standard of care document on Risk-Reducing Surgery for Hereditary Cancers, for the widely read 8th edition of Cancer: Principles & Practice of Oncology, by DeVita, Hellman and Rosenberg.

Dr. Guillem is a founding member and Past-President of the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA-ICC).  This organization was established in 1995 to improve understanding of the causes and natural history of inherited colorectal cancer as well as the clinical management of affected families. This organization provides opportunities for participation in multi-institutional collaborative studies, locates resources and provides support to patients and their families.

The high level of clinical research and patient care that The Hereditary Colorectal Cancer Family Registry is able to provide is made possible by the support of a diverse research team.  Below is a brief list of our current members:

Jose G. Guillem, M.D., M.P.H., Attending Physician
Arnold Markowitz, M.D., Attending Physician
Udo Rudloff, M.D., Ph.D., Clinical Research Fellow
Steven Lee-Kong, M.D., Clinical Research Fellow
Stephanie Hauck, R.N., Clinical Nurse
Zana Correa, N.P., Nurse Practicioner
Christopher Papadopoulos, B.A., Registrar

References

  • Lee-Kong S, Shia J, Markowitz A, Papadopoulos C, Glogowski E, Zheng J, Weiser M, Temple L, Paty P, Offit K, Wong WD, Guillem J. Prospective Immunohistochemical Analysis of Primary Colorectal Cancers for Loss of Mismatch Repair Protein Expression. Abstract. American Society of Colon and Rectal Surgeons, Annual Meeting, June 2008. Boston, MA.
  • Guillem JG, Berchuck A, et al. Cancer: Principles & Practice.8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:637-650.
  • Guillem JG, Moore HG, Nata, Markowitz A, Palmer, Glogowski, Finch R, Shia J, Offit K, Ellis N.  Single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish individuals satisfying criteria for HNPCC syndrome; Annals of Surgery 2007 April; 245(4):560-565
  • Chessin DB, Guillem JG.  Colorectal polyps, polyposis, and hereditary nonpolyposis colorectal cancer.  In Pemberton J, ed.
    Shackleford’s Surgery of the Alimentary Tract, 6th Edition, Volume IV-Colon. Philadelphia, PA: WB Saunders, 2007: 2152-2181
  • Quah HM, Joseph R. Schrag D, Shia J, Guillem JG, Paty PB, Temple LK, Wong WD, Weiser MR.  Young age influences treatment but not outcome of colon cancer. Ann Surg Oncol 2007;14(10):2759-2765
  • Guillem JG, Moore H.G. Hereditary Colorectal Cancer and Polyposis Syndromes. ACS Surgery, Web MD, 2006; 562-571
  • Jeong SY, Chessin DB, Guillem JG.  What is the best strategy for the treatment of hereditary colorectal cancer.  In Scholefield JH, Abcarian H, Grothey A, Maughan T, eds.  Challenges in Colorectal Cancer, 2nd Edition Oxford, UK: Blackwell Publishing, 2006:89-111
  • Guillem JG, Wood WC, Moley JF, Berchuck A, Karlan BY, Mutch DG, Gagel RF, Weitzel J, Morrow M, Weber BL,
    Giardiello F, Rodriguez-Bigas M, Church J, Gruber S, Offit K.  ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes; Journal of Clinical Oncology 2006 Oct 1; 24(28):4642-60. Review
  • Guillem JG, Wood WC, Moley JF, Berchuck A, Karlan BY, Mutch DG, Gagel RF, Weitzel J, Morrow M, Weber BL,
    Giardiello F, Rodriguez-Bigas M, Church J, Gruber S, Offit K.  ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes; Annals of surgical oncology. 2006 Oct; 13(10):1296-321. Review
  • Finch R, Moore HG, Lindor N, Jalal SM, Markowitz A, Jhanwar S, Offit K, Guillem JG.  Familial adenomatous polyposis and mental retardation due to a de novo chromosomal deletion at 5q15-q22.  Dis Colon Rectum 2005;48(11):2148-2152
  • Chessin DB, Markowitz AJ, Guillem JG. Peutz-Jeghers Syndrome.  In:  Cancer of the colon, rectum, and anus, Mauro Rossi et al.  (Ed); 2004
  • Guillem JG, Moore HG, Palmer C, Glogowski E, FinchR, Nafa K, Markowitz A, Offit K, Ellis N.  A636P testing in Ashkenazi Jews.  Familial Cancer 2004; 3; 223-227
  • Manne S, Markowitz A, Winawer S, Guillem JG, Meropol NJ, Haller D, Jandorf L, Rakowski W, Babb J, Duncan T.  Understanding intention to undergo colonoscopy among intermediate-risk siblings of colorectal cancer patients:  a test of a mediational model.  Preventive Med 2003;36(1):71-84
  • Guillem J, Rapaport B, Kolachana P, Kirchhoff T, Nafa K, Glogowski E, Finch R, Huang H, Markowitz A, Ellis N, Offit K.  A636P is associated with early onset colon cancer in Ashkenazi Jews.  Journal of the American College of Surgeons 2003; 196(2):222-225
  • Shia J, Ellis NA, Paty PB, Nash GM, Qin J, Offit K, Zhang XM, Markowitz AJ, Nafa K, Guillem JG, Wong WD, Gerald WL, Klimstra DS. Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer. Am J Surg Pathol 2003; 27: 1407-17
  • Peterlongo P, Nafa K, Lerman GS, Glogowski E, Shia J, Ye TZ, Markowitz AJ, Guillem JG, Kolachana P, Boyd JA, Offit K, Ellis NA.
    MSH6 germline mutations are rare in colorectal cancer families.  Int J Cancer 2003; 107: 571-9
  • Ruo L, Coit DG, Brennan MF, Guillem JG.  Long-term follow-up of patients with familial adenomatous polyposis undergoing
    pancreaticoduodenal surgery.  J Gastrointest Surg 2002;6(5):671-675
  • Hernegger GS, Moore HG, Guillem JG.  Attenuated familial adenomatous polyposis: an evolving and poorly understood entity.  Dis Colon Rectum 2002;45(1):127-134
  • Ruo L, Guillem JG.  Screening and surveillance in FAP and HNPCC.  Semin Colon Rectal Surg 2000;11:21-33.
  • Guillem JG, Puig-La Calle J Jr, Cellini C, Murray M, Ng J, Fazzari M, Paty PB, Quan SH, Wong WD, Cohen AM.  Varying features of early age-of-onset “sporadic” and hereditary nonpolyposis colorectal cancer patients.  Dis Colon Rectum 1999;42(1):36-42.
  • Guillem JG.  Letter: Molecular diagnosis of hereditary nonpolyposis colon cancer.  N Engl J Med 1998;339(13):924-925
    Guillem JG.  Need for screening colonoscopy in first-degree relatives.  Gastroenterology 1997;112(6):2161-2162
  • Howe JR, Guillem JG.  The genetics of colorectal cancer.  Surg Clin North Am 1997;77(1):175-195
  • Guillem JG, Bastar AL, Ng J, Huhn JL, Cohen AM.  Clustering of colorectal cancer in families of probands under 40 years of age.  Dis Colon Rectum 1996;39(9):1004-1007
  • Guillem JG, Forde KA, Treat MR, Neugut AI, O’Toole KM, Diamond BE.  Colonoscopic screening for neoplasms in asymptomatic first-degree
    relatives of colon cancer patients. A controlled, prospective study.  Dis Colon Rectum 1992;35(6):523-529
  • Guillem JG, Neugut AI, Forde KA, Waye JD, Treat MR.  Colonic neoplasms in asymptomatic first-degree relatives of colon cancer patients.  Am J Gastroenterol 1988;83(3):271-273