Surveillance for Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer is caused by germline mutations in DNA mismatch repair genes. Mutation carriers have a 60 to 85 percent risk of developing colorectal cancer. In the Netherlands hereditary nonpolyposis colorectal cancer families are monitored in an intensive surveillance program. The aim of this study was to examine the stage of the screening-detected tumors in relation to the surveillance interval and to assess the risk of developing colorectal cancer while on the program. METHODS: The Dutch hereditary nonpolyposis colorectal cancer family registry was used. A total of 114 families had a mismatch repair gene defect and/or met the clinical criteria for hereditary nonpolyposis colorectal cancer. The interval between surveillance and colorectal cancer was investigated in initially healthy family members who underwent at least one surveillance examination without showing evidence for colorectal cancer (surveillance group) and in family members who previously underwent partial or subtotal colectomy for colorectal cancer. The risk of colorectal cancer was calculated for proven mutation carriers (surveillance group) and for putative carriers after partial or subtotal colectomy. RESULTS: A total of 35 cancers were detected while on the program. With intervals between colorectal cancer and the preceding surveillance examination of two years or less, tumors were at Dukes Stage A (n = 4), B (n = 11), and C (1). With intervals of more than two years, tumors were at Dukes Stage A (n = 3), B (n = 10), and C (n = 6). The 10-year cumulative risk of developing colorectal cancer was 10.5 (95 percent confidence interval, 3.8–17.2) percent in proven mutation carriers, 15.7 (95 percent confidence interval, 4.1–27.3) percent after partial colectomy, and 3.4 percent after subtotal colectomy. CONCLUSION: There is a substantial risk of developing colorectal cancer while on the program. However, all tumors but one of subjects who underwent a surveillance examination two years or less before detection were at a local stage. We recommend surveillance for hereditary nonpolyposis colorectal cancer with an interval of two years or less.     

Varying features of early age-of-onset “Sporadic” and hereditary nonpolyposis colorectal cancer patients

PURPOSE: Although the criteria for clinical diagnosis of hereditary nonpolyposis colorectal cancer are not fully agreed on, young age seems to be a common trait. The purpose of this study is to identify clinicopathologic features of hereditary nonpolyposis colorectal cancer in early age-of-onset colorectal cancer patients stratified as a function of family cancer history. METHODS: Two hundred thirty consecutive colorectal cancer patients 40 years or older at time of diagnosis were registered into an ongoing database during a ten-year period. Accurate family history was obtained via medical records, telephone calls, and questionnaires on 146 patients. According to extent of family history of cancer, patients were stratified into seven groups: 1) fulfilling Amsterdam criteria, 2) fulfilling less strict criteria, 3) having at least one first-degree relative with colorectal cancer, 4) having at least one distant relative with colorectal cancer, 5) having at least one first-degree relative with any cancer, 6) having at least one distant relative with any cancer, 7) having no family history of cancer. RESULTS: Twenty-two of 146 patients fulfilled Amsterdam and less strict hereditary nonpolyposis colorectal cancer criteria (15 percent). These hereditary nonpolyposis colorectal cancer patients were significantly younger (31 vs. 35 years; P = 0.0003) and had more metachronous colorectal cancer (27 percent vs. 2 percent; P = 0.007) and less colorectal cancer with nodal or metastatic spread than the non-hereditary nonpolyposis colorectal cancer patients (35 percent vs. 65 percent; P = 0.01). CONCLUSION: Precise familial cancer assessment in early age-of-onset colorectal cancer increases the yield of hereditary nonpolyposis colorectal cancer diagnosis. Because of the frequent development of metachronous colorectal cancer and favorable prognosis, extensive rather than segmental surgery should be considered in early age-of-onset colorectal cancer patients belonging to hereditary nonpolyposis colorectal cancer families.     

Early-Age-at-Onset Colorectal Cancer and Microsatellite Instability as Markers of Hereditary Nonpolyposis Colorectal Cancer

PURPOSE: Early-age-at-onset colorectal cancer and microsatellite instability are characteristic features of hereditary nonpolyposis colorectal cancer. Our aim was therefore to investigate whether these features might be useful markers in screening for hereditary nonpolyposis colorectal cancer and mismatch repair gene mutations. METHODS: From 1,132 consecutive patients who underwent surgery for colorectal cancer at our department between 1980 and 1999, we selected all patients 40 years of age or younger (study group, n = 59) and a subset of patients 40 years of age or older (control group, n = 60) who were matched for gender and pathologic TNM stage. Patients for whom a complete family cancer history or microsatellite status was unavailable were excluded from the study. Family cancer histories, retrieved from archival charts, were reassessed. Microsatellite status was investigated with the five microsatellites from the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, and D17S250). On the basis of the number of altered microsatellites ( 2, 1, or 0), tumors were considered as having high or low instability or microsatellite stability, respectively. Mutation analysis for MLH1 and MSH2 genes was performed only in cases of high instability. DNA was investigated for mutations by single-strand conformational polymorphism and sequencing analysis. RESULTS: Data from 95 patients (study group: n = 37, 18 males, mean age 35 years; control group: n = 58, 29 males, mean age 62 years) were available for analysis. Four patients (study group, n = 3; control group, n = 1) fulfilled the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. Of the 37 study group tumors, 12 (32.4 percent) showed high-frequency microsatellite instability, and 25 had microsatellite stability, whereas among the 58 control group tumors, 4 (7 percent) showed high-frequency microsatellite instability, and 54 had microsatellite stability (P < 0.002). Mismatch repair gene mutation analysis was performed in 12 cases (study group, n = 7; control group, n = 5). We found four mutations (MSH2 119delG, MLH1 ex9 684insT, MSH2 Gln239Stop, and MLH1 del0.8 Kb) in the study group patients and none in the control group. Of four hereditary nonpolyposis colorectal cancer patients who underwent mismatch repair gene mutation analysis, one had a mutation. CONCLUSIONS: Early-age-at-onset colorectal cancer is significantly correlated with high-frequency microsatellite instability tumor status and is a useful criterion to identify hereditary nonpolyposis colorectal cancer patients. Moreover, when used in association with high-frequency microsatellite instability status, it is effective in selecting patients for mismatch repair gene mutation analysis.     

Evaluation of Bethesda guidelines in relation to microsatellite instability

PURPOSE: The Bethesda guidelines were developed for selection of patients whose tumors should be tested for high microsatellite instability. This study examined the validity of the different Bethesda criteria in relation to microsatellite instability status to simplify their use in clinical practice. METHODS: A total of 164 patients with colorectal or hereditary nonpolyposis colorectal cancer-associated cancers were registered on the basis of the Amsterdam criteria without age limitations (11 cases), multiple tumors (2 cases), the accumulation of colorectal cancer in the family (no first-degree relatives affected or the index patient's age up to 50 years; 45 cases), an early age at onset up to 50 years (13 cases), morphologic and histopathologic manifestations (right-sided colorectal cancer, mucinous undifferentiated histology; 1 case), and the Bethesda criteria (92 cases). The microsatellite instability status of tumors was determined using the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer marker reference panel. RESULTS: When applying all Bethesda criteria, high microsatellite instability tumors were identified in our hereditary nonpolyposis colorectal cancer registry with a sensitivity of 87 percent. Twenty-nine percent (27/92) of the Bethesda-positive patients displayed high microsatellite instability compared with 6 percent of patients (4/72) not meeting these criteria (P<0.001). Only Bethesda Criteria 1, 3, and 4 showed a significantly different distribution of the microsatellite instability status when compared with those of the remaining patients registered (P0.001). These three criteria detected high microsatellite instability tumors in 48 percent (10/21), 50 percent (18/36), and 31 percent (21/67) of patients, respectively. When applying these criteria only, a cumulative detection rate of 77 percent of all (24/31) high microsatellite instability cases was found, thereby identifying 89 percent of high microsatellite instability tumors among the Bethesda-positive patients. Patients matching Criteria 1, 3, and 4 frequently showed hMSH2 or hMLH1 germline mutations and tumor-specific loss of protein expression. CONCLUSION: In our hereditary nonpolyposis colorectal cancer registry the complete Bethesda criteria showed the highest sensitivity to identify patients with high microsatellite instability tumors. However, for general medical practice outside academic centers, three criteria are reasonably accurate for adequate high microsatellite instability tumor selection.Supported by the Deutsche Krebshilfe, Grant 70-1940-GF I.     

Suspected hereditary nonpolyposis colorectal cancer

PURPOSE: The aim of this study was to determine the frequency of mutations in the mismatch repair genes in families suspected of having hereditary nonpolyposis colorectal cancer. METHODS: We devised two criteria for families suspected of having hereditary nonpolyposis colorectal cancer (Criteria I and II). Criteria I consist of at least two first-degree relatives affected with colorectal cancer with at least one of the following: development of multiple colorectal tumors including adenomatous polyp, at least one colorectal cancer case diagnosed before the age of 50, and occurrence of a hereditary nonpolyposis colorectal cancer extracolonic cancer (endometrium, urinary tract, small intestine, stomach, hepatobiliary system, or ovary) in family members. Criteria II consist of one colorectal cancer patient with at least one of the following: early age of onset (<40 years); endometrial, urinary tract, or small intestine cancer in the index patient or a sibling (one aged <50 years); and two siblings with other integral hereditary nonpolyposis colorectal cancer extracolonic cancers (one aged <50 years). A questionnaire was mailed to members of the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer to determine the mutation detection rate in mismatch repair genes from the families fulfilling these criteria. For comparison the mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria in each institution was also obtained. RESULTS: Data were obtained from eight different institutions (in 7 different countries). In a total of 123 patients from 123 families (67 families fulfilling Criteria I and 56 families fulfilling Criteria II), genetic testing for germline mismatch repair gene variants was performed. Germline mutations of the hMLH1 or hMSH2 genes were identified in 24 families (20 percent). Of these, the mutation detection rate for families fulfilling Criteria I was 28 percent (19/67). The mutation detection rate for families fulfilling Criteria II was 9 percent (5/56). In these eight institutions, the overall mutation detection rate for families fulfilling the Amsterdam hereditary nonpolyposis colorectal cancer criteria was 50 percent (77/154). CONCLUSION: The Criteria I for suspected hereditary nonpolyposis colorectal cancer have the advantages that they can be applied to nuclear families and they can include extracolonic cancers. The results of this study suggest that families fulfilling Criteria I should be offered genetic testing. The relatively low mutation detection rate in those families fulfilling Criteria II suggests that, using current techniques, genetic testing in these families is not practical.     

Frequency of hereditary nonpolyposis colorectal cancer in southern Alberta

The frequency of hereditary nonpolyposis colorectal cancer was evaluated in a group of colorectal cancer patients under age 50 diagnosed in southern Alberta between 1973 and 1987. Families were identified as positive for this syndrome if three-first-degree relatives in the kindred had colorectal cancer. Of the 390 patients with adenocarcinoma, 318 patients participated. The frequency of hereditary nonpolyposis colorectal cancer was 3.1% (12 families) in this group (Ci₉₅ 1.6–5.3%). Clinical characteristics reported on from the index patients include tumor location, Dukes stage at presentation, frequency of synchronous and metachronous tumors, frequency of second primaries, and survival. The 5- and 10-year actuarial survival was 86% and 69%, respectively.This work was supported by grants from Alberta Cancer Board and Foothills Hospital Foundation.Presented in part at the annual American Gastroenterological Association meeting (1990).     

Accumulation Profile of Frameshift Mutations During Development and Progression of Colorectal Cancer From Patients With Hereditary Nonpolyposis Colorectal Cancer

Purpose Role and timing of frameshift mutations during carcinogenesis in hereditary nonpolyposis colorectal cancer have not been examined. This study was designed to clarify the relationship between frameshift mutations and clinicopathologic features in colorectal cancer from patients with hereditary nonpolyposis colorectal cancer. Methods Thirty-one colorectal cancers from patients with hereditary nonpolyposis colorectal cancer at different clinicopathologic stages were analyzed for frameshift mutation in 18 genes. Results The frameshift mutations of the ACVR2 and PTHLH genes were found to have an extremely high frequency (94–100 percent) in all pathologic stages, and mutation of the MARCKS gene also was high (94 percent) in Dukes B and C cancers. These frequencies were higher than the frequency of TGFβRII gene inactivation (64–88 percent). Mutations of the hMSH3, TCF4, CASP5, RIZ, RAD50, and MBD4 genes were comparatively frequent (>35 percent) in all stages. Frequencies of inactivation of the MARCKS, BAX, IGFIIR, and PTEN genes were significantly higher in Dukes B and C cancers than in Dukes A cancer (P < 0.05). The number of accumulated frameshift mutations was larger in Dukes B and C cancers (9.4) than in Dukes A cancer (6.8) (P = 0.003). Conclusions The present data suggest that the disruption of the transforming growth factor-β super-family signaling pathway by the alteration of the ACVR2 and/or TGFβRII genes and the disruption of antiproliferative function by the PTHLH gene alteration contribute to the development of early colorectal cancer. Moreover, the further accumulation of alterations in the MARCKS, BAX, IGFIIR, and PTEN genes seem to be associated with progression from early to advanced colorectal cancer from patients with hereditary nonpolyposis colorectal cancer.     

Patterns of surgery in patients belonging to amsterdam-positive families

INTRODUCTION: The phenotype of hereditary nonpolyposis colorectal cancer includes an 80 percent lifetime risk of colorectal cancer, a predominance of lesions proximal to the splenic flexure, and a high incidence of synchronous and metachronous neoplasia. Although prophylactic colectomy is rarely advised for patients with a hereditary nonpolyposis colorectal cancer genotype and a normal colon, the presence of advanced neoplasia in the context of a qualifying family history or a hereditary nonpolyposis colorectal cancer genotype has led to such recommendations. We performed this study to document the patterns of colorectal surgery performed for cancer-bearing patients who are part of an Amsterdam criteria–positive family and to compare rates of metachronous cancers that follow index total or segmental colectomy. METHODS: Family trees fulfilling the classic Amsterdam criteria for hereditary nonpolyposis colorectal cancer were identified, and all patients for whom surgical and pathology records were available were included in the study. Type of surgery and the outcome of subsequent follow-up were abstracted. Patients were divided into those treated at the Cleveland Clinic and those treated elsewhere. RESULTS: There were 39 families with 93 affected patients. These patients had 127 colorectal cancers, 76 (60 percent) of which were right sided (proximal to the splenic flexure). Median age at diagnosis of the index cancer was 47 (range, 26–81) years. Sixteen patients (17 percent) had metachronous cancers and multiple surgeries, whereas four (4 percent) had synchronous cancers. Median follow-up for patients who underwent surgery at the Cleveland Clinic was 13 (range, 4–49) years, whereas that for those who underwent surgery elsewhere was 14 (range, 1–42) years. Sixteen (48 percent) of the 33 patients who underwent surgery at the Cleveland Clinic had a total colectomy vs. 7 (12 percent) of the 60 who had surgery elsewhere (Fishers exact test, P < 0.001). Only one patient who had surgery at the Cleveland Clinic had a second operation for a metachronous cancer (1/17 patients having a segmental resection). Fifteen patients who underwent surgery elsewhere needed a second resection for metachronous cancer (15/53 patients having a segmental resection; Fishers exact test, P = 0.094). CONCLUSION: We conclude that there is high risk of metachronous colorectal cancer if an index cancer in a hereditary nonpolyposis colorectal cancer patient (defined according to Amsterdam criteria) is treated by partial colectomy. However, this risk can be lowered by performing a total colectomy at the time of index surgery, or possibly by effective postoperative surveillance.     

Colorectal Cancer in Egypt – Does it Differ?

Colorectal cancer is a disease of the elderly, and affects the younger population with an incidence of 2 to 6%. An increasing number of young colorectal carcinoma patients attending at Mansoura University Hospital, Mansoura, Egypt, was noted. This report represents our data of the last 5 years, and compares these results with those of other countries and those previously reported from Egypt. Data were collected retrospectively from the patient records of 400 consecutive patients who had colorectal cancer form January 1994 to March 1999 at Mansoura University Hospital. The maximum incidence was seen in the 5th and 6th decades (mean age was 45 years). A total of 29% of patients were younger than 30 years of age and 26% of them above the age of 60 years. The rectum was the most common site involved (68% of patients), followed by the sigmoid (colon/rectal ratio was 4 : 8.5). Two percent of cases were Dukes A Stage, 26% Dukes B, 31% Dukes C, and 41% Dukes D. The percentage of patients who underwent potentially curative resection was 66% (263 patients). Colorectal carcinoma in Egypt shares the epidemiological characteristics of developing countries which are higher incidence in younger patients and carcinoma of the rectum predominates     

Screening for hereditary non-polyposis colorectal cancer: a study of 22 kindreds in The Netherlands

PURPOSE: Identification of the hereditary non-polyposis colorectal carcinoma syndrome (HNPCC) is a basis for secondary prevention. The objectives of this study are to investigate the natural history of HNPCC and to assess the effect of screening. PATIENTS AND METHODS: Screening for colorectal carcinoma was performed in 22 HNPCC families (colonoscopy or double-contrast barium enema and sigmoidoscopy). The patients were subdivided into two groups. Group A comprised patients with colorectal cancer who were referred because they were symptomatic. Group B included family members of these patients who were found to have a colorectal lesion by screening. We compared these groups with respect to the stage of tumor growth. RESULTS: Histologic examination of the tumors in Group A (87 patients) revealed Dukes A carcinomas in six patients, Dukes B carcinomas in 37, Dukes C carcinomas in 21, and Dukes D carcinomas in 10 patients (classification unknown in 13 patients). In Group B (20 patients), adenoma was found in 14 and carcinoma in six patients (Dukes A in two and Dukes B in four patients). A total of 93 patients, including those whose tumors were detected by screening, had a colorectal carcinoma. The age at diagnosis ranged from 24 to 81 years (mean age: 46 years). The location of the colonic tumors was proximal in 60 percent. Multiple primary tumors were found in 26 percent. CONCLUSION: These results suggest that screening leads to the early detection of colorectal carcinomas and adenomas in asymptomatic members of HNPCC families. Screening should be initiated at the age of 20 and continued during the life of the individual. Careful examination of the right colon is indicated because of the frequent occurrence of tumors in the proximal colon. A subtotal colectomy is indicated at the time of diagnosis of the initial colon cancer because of the risk of multiple primary tumors.     

Clinical implications of multiple colorectal carcinomas in hereditary nonpolyposis colorectal carcinoma

PURPOSE: An increased incidence of multiple (synchronous and metachronous) colorectal carcinomas has been reported in hereditary nonpolyposis colorectal cancer. This review was undertaken to determine the clinical implications of multiple colorectal carcinomas in hereditary nonpolyposis colorectal cancer. METHODS: A retrospective review of the records of patients in the hereditary nonpolyposis colorectal cancer registry at Roswell Park Cancer Institute who had either synchronous or metachronous colorectal carcinomas was conducted. RESULTS: Twenty-five of 93 patients with documented pathology were found to have multiple colorectal carcinomas. The mean age at diagnosis of the index colorectal carcinoma was 46.7 (range, 28–65) years. There were 7 (7.5 percent) patients with synchronous colorectal carcinomas and 20 (21.5 percent) patients with metachronous colorectal carcinomas. Two of the seven (28.6 percent) patients with synchronous colorectal carcinomas developed a metachronous colorectal carcinoma. In the patients with metachronous colorectal carcinomas, 29 metachronous events were noted: colon (23) and rectum (6). The mean and median time interval for metachronous colorectal carcinomas were 10.9 and 11.8 (range, 1.5–43.8) years, respectively. The mean times to first, second, and third events were 11.7 (range, 1.5–43.5), 7.9 (range, 2.7–18.7), and 12.3 (range, 11.8–12.7) years, respectively. The majority of patients with metachronous colorectal carcinomas did not have stage progression at the diagnosis of the metachronous colorectal carcinomas: 13 patients had lower or same stage at first event, 4 had lower or same stage at second event, and 2 patients had lower stage at third event. Three of 20 patients with metachronous colorectal carcinomas died of their disease. CONCLUSION: Multiple colorectal cancers are common in hereditary nonpolyposis colorectal cancer. Even though stage progression may not be evident at diagnosis of metachronous colorectal cancer, some of these patients will nevertheless die of their disease.Presented at the annual meeting of the Southeastern Surgical Congress, Atlanta, Georgia, February 2 to 4, 1998.     

Metachronous colorectal cancer in young patients: Expression of the hereditary nonpolyposis colorectal cancer syndrome?

The cumulative incidence rate of metachronous colorectal cancer in patients younger than 40 years of age at diagnosis of the primary cancer has been shown to be 30 percent. Metachronous colorectal cancer is predominantly located in the right colon with a decreasing frequency toward the rectum. The risk of developing a metachronous colorectal cancer was found to be 16–29 times increased when compared with the risk of having a primary colorectal cancer. Because of the resemblance between characteristics of metachronous colorectal cancer and the features of hereditary nonpolyposis colorectal cancer (HNPCC), it is proposed that young colorectal cancer patients developing metachronous colorectal cancer could in fact be HNPCC patients.     

Colonic cancer in a 34-yr-old woman: should it prompt microsatellite instability studies and mismatch repair gene testing?

It remains debatable whether young patients with colorectal tumors should undergo genetic testing with the aim of identifying new hereditary nonpolyposis colorectal cancer families. We describe a case of a young woman with colon cancer with no clinical criteria of hereditary nonpolyposis colorectal cancer, whose genetic analysis showed that the tumor displayed microsatellite instability, and in whom a truncated protein in hMSH2 gene was found, which was also present in two at-risk relatives.     

Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer

PURPOSE: The present study was designed to determine the frequency of germline mutations in the hMLH1 and hMSH2 genes in 31 families suspected of having hereditary nonpolyposis colorectal cancer who do not fulfill the criteria of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer but in whom a genetic basis for colon cancer is strongly suspected and 45 patients with sporadic early-onset colorectal cancer who developed colorectal cancer before the age of 40 years without any family history of colorectal cancer. METHODS: Genomic DNAs were prepared from peripheral blood samples of patients who were tested. All coding exons and exon-intron borders of these two genes were screened, first with the polymerase chain reaction-single-strand conformation polymorphism method, followed by sequencing of the DNA fragments displaying an abnormal single-strand conformation polymorphism pattern. RESULTS: In 31 families with suspected hereditary nonpolyposis colorectal cancer, we found six different germline mutations in seven unrelated families, including one missense mutation and three frame-shift mutations in the hMLH1 gene and one missense mutation and one frame-shift mutation in the hMSH2 gene. Totally, frequency of mutation was 23 percent, 16 percent and 7 percent in the hMLH1 and hMSH2, respectively. Only one missense mutation of the hMSH2 gene was identified in 45 patients (2 percent) with sporadic early-onset colorectal cancer. The mutation detection rate in families with suspected hereditary nonpolyposis colorectal cancer was significantly higher than that of patients with sporadic early-onset colorectal cancer (P<0.05). CONCLUSION: Our definition of suspected hereditary nonpolyposis colorectal cancer is useful in the diagnosis of hereditary nonpolyposis colorectal cancer and for identifying those families who need genetic presymptomatic diagnosis. Our results indicate that it may be important to perform DNA testing in families suspected of having hereditary nonpolyposis colorectal cancer. On the other hand, we only detected a low mutation rate (2 percent) in 45 patients with sporadic early-onset colorectal cancer.Supported, in part, by the 1997 Good Health R & D Project, the Ministry of Health and Welfare of the Republic of Korea, and the Korea Science and Engineering Foundation (KOSEF-CRC-94K2-0402-04-00-3) through the Cancer Research Center at Seoul National University.Read at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 26, 1997. Winner of the Southern California Society of Colon and Rectal Surgeons Award.     

ras and c-myc protein expression in colorectal carcinoma

This study was performed to determine the correlation of tumor ras and c-myc oncogene expression with clinical and prognostic variables in patients prone to develop colorectal cancer. One hundred eighteen patients with colorectal cancer were studied; mean age was 40 years. Fifty-three were young patients (age 40 or less), 49 had ulcerative colitis, and 16 had multiple polyposis coli. Immunoperoxidase stains of paraffin-embedded cancer sections were performed for the c-myc and ras proteins. ras staining was found to correlate with Dukes stage and prognosis. Patients with tumors negative for ras protein stain had an actuarial five-year survival of 61 percent versus 44 percent for those tumors with a positive stain (P less than 0.05). This correlation was not seen with the c-myc stain. Positive ras oncogene stain appears to be a useful indicator of advanced stage and poor prognosis in colorectal cancer occurring in cancer-prone patients.     

Impact of gender and parent of origin on the phenotypic expression of hereditary nonpolyposis colorectal cancer in a large Newfoundland kindred with a common MSH2 mutation

PURPOSE: This study was designed to provide precise estimates of death and cancer risks, by gender and parent of origin, in hereditary nonpolyposis colorectal cancer independent of mutation, geographic variation, and ascertainment bias. METHODS: A group of 12 families with a founder MSH2 mutation (nucleotide 943+3, A --> T) causing hereditary nonpolyposis colorectal cancer was identified in Newfoundland. Genetic testing was offered to those at 50 percent risk of inheriting the mutation. Medical records were reviewed to identify cancer types, age at onset of cancer, and age at death. Ascertainment bias was limited by analyzing only sibships with good ascertainment of genetic status (> or =50 percent of sibships had known genetic status). RESULTS: Of 302 family members with hereditary nonpolyposis colorectal cancer or at 50 percent risk, 151 (50 percent) were considered to be mutation carriers, 96 (32 percent) were mutation negative, and 55 (18 percent) were of unknown mutation status. By age 50 years, 72 percent of males and 72 percent of females who were hereditary nonpolyposis colorectal cancer mutation carriers had developed cancer. The age-related risks of colorectal cancer or of death of cancer were significantly higher in males than in females (relative risk = 2.8, P = 0.0001 and relative risk = 2.1, P = 0.01, respectively). The mutation was transmitted by the mother more frequently than the father. Females who inherited the mutation from their father had an increased risk of developing colorectal cancer (relative risk = 2.5, P = 0.05) and of dying of cancer (relative risk = 2.7, P = 0.04) compared with females who inherited the mutation from their mother. CONCLUSIONS: Investigation of large kindreds from the same geographic area who share the same MSH2 mutation and in whom family members have been identified with little ascertainment bias suggests that the risks for colorectal cancer and death of cancer are higher for male mutation carriers than for females and that females who inherit the mutation from their father are at higher risk of colorectal cancer than females who inherit the mutation from their mother.     

Histologic comparison of hereditary nonpolyposis colorectal cancer associated with MSH2 and MLH1 and colorectal cancer from the general population

PURPOSE: Hereditary nonpolyposis colorectal cancer is reported to have special histologic features. This study compares the histologic features of hereditary nonpolyposis colorectal cancer to colorectal cancers from the general population when hereditary nonpolyposis colorectal cancer cases are restricted to families with known MSH2 and MLH1 mutations. METHODS: Thirty-seven cancers from kindreds carrying MSH2 mutations, 27 cancers from kindreds carrying MLH1 mutations, and 37 colorectal cancers from the general population were reviewed by a pathologist blinded to hereditary nonpolyposis colorectal cancer gene status. Tumor grade, growth pattern, Crohn's-like lymphoid reaction, mucin production, extent of disease in the bowel wall, and lymph node status were evaluated. RESULTS: Poor differentiation and Crohn's-like reaction were a feature of 44 and 49 percent of hereditary nonpolyposis colorectal cancer compared with 14 percent (P=0.002) and 27 percent (P=0.049) of colorectal cancers from the general population, respectively. There was no difference in growth pattern, mucin production, lymph node involvement, or local extent of disease between hereditary nonpolyposis colorectal cancer and colorectal cancers from the general population. Poor differentiation and lymph node metastases were found in 57 and 49 percent of MSH2 compared with 26 percent (P=0.002) and 10 percent (P=0.03) of MLH1-associated cancers, respectively. There was no difference in growth pattern, mucin production, Crohn's-like lymphoid reaction, or local extent of disease between subgroups of hereditary nonpolyposis colorectal cancer. CONCLUSIONS: Poor differentiation and Crohn's-like reaction are more common in hereditary nonpolyposis colorectal cancer than colorectal cancers from general population. Poor differentiation and lymph node metastases are more commonly seen in MSH2-associated cancers than MLH1. Evaluation of the natural history, pathogenesis, and prognosis of colorectal cancer in hereditary nonpolyposis colorectal cancer should include consideration of which mismatch repair genes are mutated and what the specific mutations are.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 27, 1997.     

Hereditary susceptibility to colorectal cancer

Close relatives of patients with colorectal cancer are at an increased risk of developing a colorectal malignancy themselves. PURPOSE: A study was conducted to compare risks in relatives of patients diagnosed at different ages. METHODS: Family histories were taken from two cohorts of patients with colorectal cancer: Group A, a population group of 65 patients diagnosed at or under 45 (median, 42) years; Group B, 212 patients of all ages (median, 68 years) treated in a single surgeon's practice. RESULTS: Overall relative risk of colorectal cancer in first-degree relatives was 5.2 in Group A and 2.3 in Group B. There was familial clustering of colorectal cancers suggestive of hereditary nonpolyposis colorectal cancer in 13 (20 percent) families to Group A but to only 3 (1.5 percent) families in the second group. Cumulative incidence of colorectal cancer for relatives of the young cohort rose steeply from 40 years, reaching 5 percent at age 50 years and 10 percent at age 70 years. This contrasts with risk for relatives of older patients, in whom the shape of the curve resembles that of the overall population risk, reaching 5 percent at age 70 years and 10 percent at age 80 years. CONCLUSIONS: There appears to be a quantitative and qualitative increase in risk to relatives of patients diagnosed at a young age compared with those diagnosed later to life, at least part of which is likely to be the result of a hereditary susceptibility. Close relatives of early onset cases warrant more intensive endoscopic screening and at an earlier age than relatives of patients diagnosed at older ages.Supported by the Imperial Cancer Research Fund. All work was performed in the Imperial Cancer Research Fund Genetic Epidemiology Laboratory, Leeds, United Kingdom.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canaday, May 7 to 12, 1995.     

Favorable Influence of Age on Tumor Characteristics of Sporadic Colorectal Adenocarcinoma

PURPOSE: Age is reported as a risk factor for carcinogenesis, even though age can affect cancer behavior both positively and negatively. Young patients with colorectal cancer reveal different tumor characteristics than average-age and older-age groups, although few studies report the influence of age among the entire range of patient ages. The influence of age on clinicopathologic characteristics of sporadic colorectal cancer was analyzed. Whether an age group with distinct tumor characteristics was present was determined. METHODS: A total of 5,436 patients who underwent colectomy in a single institute within a seven-year period were studied. Data on clinical and histopathologic features of colorectal cancer were collected from the cancer registry and medical records. These characteristics were analyzed according to ten-year age groups. RESULTS: Eighty-three patients (1.6 percent) were 30 years of age or younger, whereas 285 (5.5 percent) were 31 to 40 years of age. Most patients (74.6 percent) were 51 to 80 years of age. The proportion of localized tumors (Dukes A and Dukes B) significantly increased as age increased, from 31.3 percent in the 30 years or younger age group to 49 percent in the 80 years or older group (P < 0.001). The proportion of poorly differentiated tumors tended to decreased as age increased (from 16.9 percent in the 30 years or younger group to 6.2 percent in the 80 years or older group; P = 0.009). A similar trend in the proportion of mucin-producing tumors was also observed (36 percent in the younger group vs. 7.5 percent in the older group; P < 0.001). There was no significantly different distribution of tumor locations among the different age groups. CONCLUSIONS: Age appears to favorably influence the clinicopathological characteristics of sporadic colorectal cancer. As age increased, the characteristics of tumor stage at diagnosis, tumor differentiation, and mucin production improved.     

Limitations of family cancer history assessment at initial surgical consultation

PURPOSE: Although important for the diagnosis of familial clustering of colorectal cancer and hereditary nonpolyposis colorectal cancer, the accuracy of familial cancer history assessment in the office setting has been questioned. Furthermore, there are few publications describing the optimal method for accurately capturing a family cancer history. The purpose of this study was to determine how well family cancer history is assessed in patients with early age-of-onset colorectal cancer at initial surgical consultation compared with a telephone interview and mailed questionnaire. METHODS: Medical records of patients 40 years old or younger at the time of colorectal cancer surgery were reviewed for documentation of family cancer history at initial surgical consultation. In addition, family cancer history was solicited from surviving patients or their next of kin by telephone and a mailed questionnaire. The kappa coefficient was used to measure degree of correlation between family cancer history obtained at initial surgical consultation and subsequent telephone interview and questionnaire. RESULTS: One hundred twenty-five patients were available for analysis. Family cancer history was documented on the initial surgical consultation report in 78 percent of cases. Although 31.2 percent were identified as having no family cancer history at initial surgical consultation, this proportion decreased to 13.5 percent after telephone interviews and questionnaires. Family history assessment at initial surgical consultation also failed to identify 7 of 11 individuals meeting Amsterdam criteria for hereditary nonpolyposis colorectal cancer and 10 of 16 individuals meeting modified clinical criteria for hereditary nonpolyposis colorectal cancer. CONCLUSIONS: Although family cancer history was commonly obtained during the initial surgical consultation of patients with colorectal cancer, there was a tendency to underestimate the extent of familial cancer. A telephone interview and questionnaire conducted at a later date may reveal a more comprehensive family cancer history. This is an important observation, because individuals identified as high-risk for hereditary nonpolyposis colorectal cancer or familial clustering of colorectal cancer require special consideration with respect to screening, surveillance, and surgical management.