Commentary (Offit): Genetics of Colorectal Cancer

March 1, 2006

Approximately 6% of colorectal cancers can be attributed to recognizable heritable germline mutations. Familial adenomatous polyposis is an autosomal dominant syndrome classically presenting with hundreds to thousands of adenomatous colorectal polyps that are caused by mutations in the APC gene.

On first reading, the concise review of colon cancer genetic syndromes by Jeter et al seems to parallel a recent description in this journal of breast and ovarian cancer syndromes by Peshkin and Isaacs.[1,2] There are, however, striking biologic and clinical differences between these syndromes that make counseling for hereditary colon cancer a special challenge for the practitioner. These biologic and genetic complexities are in contrast to the relative simplicity of the clinical interventions (colonoscopy and preventive surgery) that remain the gold standard for early detection and prevention of this disease. The special challenges that confront the oncologist include the increasingly complex genetics of colon cancer syndromes, the multiple means of diagnosing colon cancer syndromes using a variety of phenotypic markers, and finally, remaining barriers to colon cancer genetic testing stemming from ethical concerns regarding timing of informed consent and the potential for genetic discrimination.

Distinctive Susceptibility Patterns

In contrast to breast cancer and most other “adult cancer predispositions,” colon cancer susceptibility demonstrates heterogeneity not only of genes but also modes of inheritance. Perhaps most distinctive is the existence of a recessive mode of inheritance for MYH-mediated colon cancer susceptibility. While recessive modes of inheritance are observed for other human cancers (for example, leukemias and lymphomas in Bloom and Fanconi syndromes), such a pattern poses a challenge for the oncologist treating common adult neoplasias. And MYH is not the only example of recessive modes of susceptibility to this disease. As briefly mentioned by Jeter et al, a significantly increased risk of colon cancer is associated when TGFβR1 mutations occur in the homozygous or compound heterozygous state.[3]

Because of the molecular pathogenesis of hereditary nonpolyposis colorectal cancer (HNPCC) syndromes, whereby a defect in DNA mismatch repair results in a characteristic pattern of microsatellite instability (MSI) in the colon tumors themselves, there exists a “phenotypic marker” for the most common hereditary colon cancer syndrome. This is not the case, for example, in hereditary breast cancer, where immuno-phenotypic differences, while they exist, are much more subtle.

Screening Strategy

As documented by Jeter et al, both genetic testing for MSI and immunohistochemical testing for expression of MSH2, MLH1, MSH6, and PMS2 provide a strategy for HNPCC screening. Such a strategy is cost-efficient as well because it specifies the particular HNPCC gene to be sequenced. This approach is appropriate in most populations, with the possible exception of early-onset colon cancer in Ashkenazi Jews, where we believe that DNA testing for the MSH2 “founder” mutation A636P should be included in the initial screen.[4] The existence of A636P and other founder mutations in MSH2 and MYH offers one means of targeting genetic screening in selected populations. Another aspect of genetic evaluation not included in the excellent discussion by Jeter et al is the increasing evidence that documentation of BRAF mutation hot spots can provide strong evidence against classic HNPCC, defining yet another subset of hereditary colorectal cancer.[5]

The existence of “phenotypic markers” also poses special challenges, and offers special opportunities, in the evaluation of hereditary colorectal neoplasia. A recent study of 131 unselected cases of colorectal cancer diagnosed before the age of 45 found germline HNPCC mutations in a striking (14%) of cases. In each of the 18 cases with HNPCC germline mutations, the tumors demonstrated loss of mismatch repair gene expression by immunohistochemistry (IHC).[6] Thus, IHC was far more sensitive in predicting mismatch repair gene mutation status than clinical or family history. These, and the findings of both large population-based studies[7] and clinic-based series,[8] support the rationale for large cancer centers to implement routine IHC screening for early-onset colorectal cancer. In addition, we have described a histologic pattern in HNPCC tumors, which also may be useful in identifying cases that should undergo genetic counseling and molecular evaluation.[8]

Counseling Considerations

The existence of these “phenotypic markers” for the largest subset of hereditary colon cancer leads to the issue of whether genetic counseling is required before IHC or MSI testing. This question is not a new one,[9] but recently has reemerged as a challenge to clinicians to consider whether formal genetic counseling needs to precede mismatch repair and/or MSI testing.[10] One potential approach would be to utilize IHC screening of colorectal cancers in defined groups (based on age at onset, histology, family history) and then to refer all suspicious cases for counseling and further DNA testing.

In addition to these biologic and clinical complexities, the clinician is faced with the persistent concern regarding possible genetic discrim­ination. While such concerns have proven to be unfounded for BRCA testing,[2] studies have continued to document a very high proportion-up to half of individuals in one recent report-concerned about genetic discrimination in the specific setting of genetic testing for the risk of colorectal cancer.[11]

Nevertheless, there has been a heartening simplification of one important aspect of hereditary colon cancer counseling. That shift was the rebirth of the eponymous “Lynch syndrome” designation to describe what Jeter et al (and most practitioners) still refer to as hereditary nonpolyposis colon cancer.[12] In addition to being simpler to pronounce, this designation provides a fitting tribute to Henry, Jane, and Patrick Lynch, who have done so much to increase public awareness of the potential for genetics as a tool for colorectal cancer prevention.


The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Peshkin BN, Isaacs C: Evaluation and management of women with BRCA1/2 mutations. Oncology 19:1451-1459, 2005.

2. Offit K: The Peshkin/Isaacs article reviewed. Oncology 19:1459-1474, 2005.

3. Kaklamani VG, Hou N, Bian Y, et al: TGFBR1*6A and cancer risk: A meta-analysis of seven case-control studies. J Clin Oncol 21:3236-3243, 2003.

4. Guillem JG, Moore HG, Palmer C, et al: A636P testing in Ashkenazi Jews. Fam Cancer 3:223-227, 2004.

5. Sinicrope FA: Insights into familial colon cancer: The plot thickens. Clin Gastroenterol Hepatol 3:216-217, 2005.

6. Southey MC, Jenkins MA, Mead L, et al: Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol 23:6524-6532, 2005.

7. Hampel H, Frankel WL, Martin E, et al: Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352:1851-1860, 2005.

8. Shia J, Klimstra DS, Nafa K, et al: Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol 29:96-104, 2005.

9. Offit K: Genetic prognostic markers for colorectal cancer. N Engl J Med 342:124-125, 2000.

10. Lenz HJ: First Amsterdam, then Bethesda, now Melbourne? J Clin Oncol 23:6445-6449, 2005.

11. Apse KA, Biesecker BB, Giardiello FM, et al: Perceptions of genetic discrimination among at-risk relatives of colorectal cancer patients. Genet Med 6:510-516, 2004.

12. Offit K, Kauff ND: Reducing the risk of gynecologic cancer in the Lynch syndrome. N Engl J Med 354:293-295, 2006.