Hereditary colorectal cancer registries in Canada: report from the Colorectal Cancer Association of Canada consensus meeting; Montreal, Quebec; October 28, 2011.

At a consensus meeting held in Montreal, October 28, 2011, a multidisciplinary group of Canadian experts in the fields of genetics, gastroenterology, surgery, oncology, pathology, and health care services participated in presentation and discussion sessions for the purpose of developing consensus statements pertaining to the development and maintenance of hereditary colorectal cancer registries in Canada. Five statements were approved by all participants.

Long-term outcome of colectomy and ileorectal anastomosis for Crohn's colitis.

BACKGROUND: Ileorectal anastomosis is an important surgical option for patients with Crohn's colitis with relative rectal sparing. OBJECTIVE: This study aimed to audit outcomes of ileorectal anastomosis for Crohn's and factors associated with proctectomy and reoperation. DESIGN: This retrospective study involved a chart review and contacting patients. SETTINGS: Patients with Crohn's colitis who had an ileorectal anastomosis were identified from the Mount Sinai Hospital Inflammatory Bowel Disease Database. PATIENTS: Demographics, operative and perioperative outcomes, and reoperative data were collected. MAIN OUTCOME MEASURES: Five- and 10-year Kaplan-Meier survival estimates and 95% confidence intervals were calculated for survival from proctectomy and Crohn's-related revisional surgery. Cox proportional hazards models were used to model the hazards of proctectomy and Crohn's-related revision on the clinical characteristics of patients. RESULTS: Eighty-one patients had an ileorectal anastomosis for Crohn's disease from 1982 to 2010. The most common indications for surgery were failed medical management (60/81, 74.1%) and a stricture causing obstruction (14/81, 17.3%). Seventy-seven percent (n = 62) had a 1-stage procedure, whereas 23% (n = 19) had a 2-stage procedure (colectomy followed by ileorectal anastomosis). The overall anastomotic leak rate was 7.4% (n = 6). Fifty-six patients had a functioning ileorectal anastomosis at the time of follow-up. At 5 and 10 years, 87% (95% CI: 75.5-93.3) and 72.2% (95% CI: 55.8-83.4) of individuals had a functioning ileorectal anastomosis. Eighteen patients required proctectomy for poor symptom control, whereas 11 patients required a small-bowel resection plus redo-ileorectal anastomosis. The mean time to proctectomy from the original ileorectal anastomosis was 88.3 months (SD = 62.1). Smoking was associated with both proctectomy (HR 3.93 (95% CI: 1.46-10.55)) and reoperative surgery (HR 2.12 (95% CI: 0.96-4.72)). LIMITATIONS: : This study was retrospective. CONCLUSIONS: Ileorectal anastomosis is an appropriate operation for selected patients with Crohn's colitis with sparing of the rectum. However, patients must be counseled that the reoperation rate and/or proctectomy rate is approximately 30%.

Familial colorectal cancer: Patient assessment, surveillance and surgical management.

Germline mutations account for 5-10% of colorectal cancer. Most mutations are autosomal dominant with high penetrance and affected patients benefit greatly from appropriate treatment. This review presents the current knowledge regarding familial colorectal cancer and provides practical information based on international guidelines and the best available evidence regarding patient assessment, surveillance and surgical management. Surgeons are often the first point of contact and frequently, the main provider of care for families with cancer syndromes or patients with familial cancer. Patients with a polyposis phenotype should undergo appropriate genetic testing. In non-polyposis patients with a cancer diagnosis, tumor testing for Lynch syndrome can guide the use of genetic testing. In patients without a personal history of cancer or polyposis, a carefully obtained family history with testing of available tumor tissue or of a living relative affected by colorectal cancer informs the need for genetic testing. Surveillance and surgical management should be planned following thorough assessment of familial cancer risk. Evidence exists to provide guidance as to the surveillance strategies required, the specific indications of genetic testing and the appropriate timing of operative intervention. A carefully obtained family history with selective genetic testing should inform surveillance and surgical management in patients who have a genetic predisposition for the development of colorectal cancer.

Somatic instability of the APC I1307K allele in colorectal neoplasia.

The adenomatous polyposis coli (APC) gene is proposed to function as a gatekeeper of colorectal neoplasia. A germ-line variant of this gene, the APC I1307K allele, is present in approximately 6% of the Ashkenazi Jewish population. To assess the role in tumorigenesis of the variant (A)8 tract produced by this allele, we undertook a somatic mutation analysis of the region surrounding codon 1307 in colorectal tumors from APC I1307K carriers. Somatic mutations involving the variant (A)8 tract were identified in 53 of 127 (42%) tumors from APC I1307K carriers compared with 5 of 127 (4%) mutations involving the wild-type allele of these tumors (P < 0.0001). Loss of heterozygosity of the wild-type allele was significantly more common in tumors with APC I1307K allele mutations (25 of 41, 61%) compared with APC I1307K carrier tumors without mutation of the variant (A)8 tract (12 of 53, 23%; P < 0.0005). This somatic biallelic APC inactivation further confirms the biological importance of the I1307K germ-line variant. The vast majority of APC I1307K somatic mutations consisted of a single adenine insertion (insA) involving the variant (A)8 tract. This insA mutation was mutually exclusive of the presence of microsatellite instability with 0 of 49 tumors with insA displaying BAT-26 instability compared with 9 of 78 tumors without insA (P=0.01). These findings support a model where somatic instability of the (A)8 tract produced by the APC I1307K allele leads to increased APC gene inactivation and directly accounts for 42% of the colorectal neoplasms occurring in APC I1307K carriers.

Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway.

Some colorectal tumors with wild-type adenomatous polyposis coli gene have activating mutations in beta-catenin (encoded by CTNNB1) that result in decreased phosphorylation by GSK-3beta and increased signaling through the Tcf/Lef transcription factors. To investigate the relationship between CTNNB1 mutations and underlying pathways of genomic instability, we examined 80 colorectal cancers stratified by the presence or absence of microsatellite instability (MSI). CTNNB1 mutations were identified in 13 (25%) of 53 cancers with high frequency MSI (MSI-H), including 12 point mutations at exon 3 phosphorylation sites (codons 41 and 45) and one deletion of the entire exon 3 degradation box. No CTNNB1 mutations were identified in 27 microsatellite stable or low frequency MSI (MSI-L) colorectal cancers (P < 0.01). In contrast, CTNNB1 mutations were identified in 3 of 9 (33%) MSI-H and 10 of 20 (50%) MSS/MSI-L endometrial carcinomas, suggesting a more generalized involvement in these tumors. Only six (46%) of the endometrial carcinoma CTNNB1 mutations occurred at residues directly phosphorylated by GSK-3beta, and only one of these was at either codon 41 or 45. All point mutations in MSI-H cancers were transitions, whereas 64% of those in MSS/MSI-L cancers were transversions (P < 0.01). The differences in the mutation profiles suggest that there may be molecular fingerprints of CTNNB1 mutations, determined by biological factors related to both tumor type and underlying pathways of genomic instability.

Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors.

Inactivation of deoxyribonucleic acid (DNA) mismatch repair genes, most commonly human mutL homologue 1 (hMLH1) or human mutS homologue 2 (hMSH2), is a recently described alternate pathway in cancer development and progression. The resulting genetic instability is characterized by widespread somatic mutations in tumor DNA, and is termed high-frequency microsatellite instability (MSI-H). Although described in a variety of tumors, mismatch repair deficiency has been studied predominantly in colorectal carcinoma. Most MSI-H colorectal carcinomas are sporadic, but some occur in patients with hereditary nonpolyposis colorectal cancer (HNPCC), and are associated with germline mutations in mismatch repair genes. Until now, the identification of MSI-H cancers has required molecular testing. To evaluate the role of immunohistochemistry as a new screening tool for mismatch repair-deficient neoplasms, the authors studied the expression of hMLH1 and hMSH2, using commercially available monoclonal antibodies, in 72 formalin-fixed, paraffin-embedded tumors that had been tested previously for microsatellite instability. They compared immunohistochemical patterns of 38 MSI-H neoplasms, including 16 cases from HNPCC patients with known germline mutations in hMLH1 or hMSH2, with 34 neoplasms that did not show microsatellite instability. Thirty-seven of 38 MSI-H neoplasms were predicted to have a mismatch repair gene defect, as demonstrated by the absence of hMLH1 and/or hMSH2 expression. This included correspondence with all 16 cases with germline mutations. All 34 microsatellite-stable cancers had intact staining with both antibodies. These findings clearly demonstrate that immunohistochemistry can discriminate accurately between MSI-H and microsatellite-stable tumors, providing a practical new technique with important clinical and research applications.

Molecular biology of colorectal cancer.

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a proliferative advantage to cells and contribute to development of the malignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene--a tumor-suppressor gene on chromosome 5q--mark one of the earliest events in colorectal carcinogenesis. Germline mutation of the APC gene and subsequent somatic mutation of the second APC allele cause the inherited familial adenomatous polyposis syndrome. This syndrome is characterized by the presence of hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to dysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity on the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict poor prognosis. Loss of the 18q region is thought to contribute to inactivation of the DCC tumor-suppressor gene. More recent evidence suggests that other tumor-suppressor genes--DPC4 and MADR2 of the transforming growth factor beta (TGF-beta) pathway--also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apoptosis. Neoplastic progression is probably accompanied by additional, undiscovered genetic events, which are indicated by allelic loss on chromosomes 1q, 4p, 6p, 8p, 9q, and 22q in 25% to 50% of colorectal cancers. Recently, a third class of genes, DNA repair genes, has been implicated in tumorigenesis of colorectal cancer. Study findings suggest that DNA mismatch repair deficiency, due to germline mutation of the hMSH2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of hereditary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display microsatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficiency may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulin-like growth-factor II receptor. Individuals from families at high risk for colorectal cancer (hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent studies have examined colorectal carcinogenesis in the light of other genetic processes. Telomerase activity is present in almost all cancers, including colorectal cancer, but rarely in benign lesions such as adenomatous polyps or normal tissues. Furthermore, genetic alterations that allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In addition, hypomethylation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.

Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism.

Germ-line and somatic truncating mutations of the APC gene are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis, respectively. Recently, an isoleucine-->lysine polymorphism at codon 1307 (I1307K) of the APC gene has been identified in 6%-7% of the Ashkenazi Jewish population. To assess the risk of this common APC allelic variant in colorectal carcinogenesis, we have analyzed a large cohort of unselected Ashkenazi Jewish subjects with adenomatous polyps and.or colorectal cancer, for the APC I1307K polymorphism. The APC I1307K allele was identified in 48 (10.1%) of 476 patients. Compared with the frequency in two separate population control groups, the APC I1307K allele is associated with an estimated relative risk of 1.5-1.7 for colorectal neoplasia (both P=.01). Furthermore, compared with noncarriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient (P=.03), as well as a younger age at diagnosis. We conclude that the APC I1307K variant leads to increased adenoma formation and directly contributes to 3%-4% of all Ashkenazi Jewish colorectal cancer. The estimated relative risk for carriers may justify specific clinical screening for the 360,000 Americans expected to harbor this allele, and genetic testing in the setting of long-term-outcome studies may impact significantly on colorectal cancer prevention in this population.

Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.

BACKGROUND: Colorectal cancer can arise through two distinct mutational pathways: microsatellite instability or chromosomal instability. We tested the hypothesis that colorectal cancers arising from the microsatellite-instability pathway have distinctive clinical attributes that affect clinical outcome. METHODS: We tested specimens of colorectal cancer from a population-based series of 607 patients (50 years of age or younger at diagnosis) for microsatellite instability. We compared the clinical features and survival of patients who had colorectal cancer characterized by high-frequency microsatellite instability with these characteristics in patients who had colorectal cancers with microsatellite stability. RESULT: We found high-frequency microsatellite instability in 17 percent of the colorectal cancers in 607 patients, and in a multivariate analysis, microsatellite instability was associated with a significant survival advantage independently of all standard prognostic factors, including tumor stage (hazard ratio, 0.42; 95 percent confidence interval, 0.27 to 0.67; P< 0.001). Furthermore, regardless of the depth of tumor invasion, colorectal cancers with high-frequency microsatellite instability had a decreased likelihood of metastasizing to regional lymph nodes (odds ratio, 0.33; 95 percent confidence interval, 0.21 to 0.53; P< 0.001) or distant organs (odds ratio, 0.49; 95 percent confidence interval, 0.27 to 0.89; P=0.02). CONCLUSION: High-frequency microsatellite instability in colorectal cancer is independently predictive of a relatively favorable outcome and, in addition, reduces the likelihood of metastases.

Family history characteristics, tumor microsatellite instability and germline MSH2 and MLH1 mutations in hereditary colorectal cancer.

Recent characterization of the molecular genetic basis of hereditary nonpolyposis colorectal cancer provides an important opportunity for identification of individuals and their families with germline mutations in mismatch repair genes. Cancer family history criteria that accurately define hereditary colorectal cancer are necessary for cost-effective testing for germline mutations in mismatch repair genes. The present report describes the results of analysis of 33 colorectal cancer cases/families that satisfy our modified family history criteria (Mount Sinai criteria) for colorectal cancer. Fourteen of these families met the more stringent Amsterdam criteria. Germline MSH2 and MLH1 mutations were identified by the reverse transcription-polymerase chain reaction and the protein truncation test, and confirmed by sequencing. Microsatellite instability analysis was performed on available tumors from affected patients. MSH2 or MLH1 mutations were detected in 8 of 14 Amsterdam criteria families and in 5 of the remaining 19 cases/families that only satisfied the Mount Sinai criteria. Three of the latter families had features of the Muir-Torre syndrome. A high level of microsatellite instability (MSI-H) was detected in almost all (16/18) colorectal cancers from individuals with MSH2 and MLH1 mutations, and infrequently (1/21) in colorectal cancer specimens from cases without detectable mutations. Families with germline MSH2 and MLH1 mutations tended to have individuals affected at younger ages and with multiple tumors. The Amsterdam criteria are useful, but not sufficient, for detecting hereditary colorectal cancer families with germline MSH2 and MLH1 mutations, since a proportion of cases and families with mutations in mismatch repair genes will be missed. Further development of cancer family history criteria are needed, using unbiased prospectively collected cases, to define more accurately those who will benefit from MSH2 and MLH1 mutation analysis.