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.     

Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population

PURPOSE: This clinical case review aimed to identify phenotypic variations in colorectal and extracolonic cancer expression between hereditary nonpolyposis colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the general population. METHODS: Colorectal cancer onset and site distribution were compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and 1,189 patients from the general population. Synchronous and metachronous cancer rates, tumor stage, extracolonic cancer incidence, and survival were also compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years for MLH1, MSH2, and the general population, respectively (P<0.001). More proximal and fewer distal colon cancers were noted in HNPCC than the general population (P<0.001,P=0.04). Site distribution showed disparity of rectal cancers (8 percent MLH1vs. 28 percent MSH2;P=0.01) based on genotypes. Overall, synchronous colorectal cancer rates were 7.4, 6.7, and 2.4 percent for MLH1, MSH2, and the general population, respectively (P=0.016). Annual metachronous colorectal cancer rates were 2.1, 1.7, and 0.33 percent for MLH1, MSH2, and the general population, respectively (P=0.041). Colorectal cancer stage presentation was lower in HNPCC than the general population (P=0.0028). Extracolonic cancers were noted in 33 percent of MSH2 patients, compared with 12 percent of MLH1 patients and 7.3 percent of the general population with colorectal cancers (P<0.001). Combined MLH1 and MSH2 ten-year survival was 68.7 percent compared with 47.8 percent for the general population (P=0.009 stage stratified, hazard ratio 0.57). CONCLUSION: The presence of rectal cancer should not preclude the diagnosis of HNPCC, because the incidence of rectal cancer in MSH2 was comparable with that in the general population. Phenotypic variations, including the preponderance of extracolonic cancers in MSH2 patients, did not result in survival differences between genotypic subgroups. These phenotypic features of HNPCC genotypes may have clinical significance in the design of specific screening, surveillance, and follow-up for affected individuals.     

Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II)

Approximately 5 to 6 percent of the total colorectal cancer burden is accounted for by hereditary nonpolyposis colorectal cancer (HNPCC). Because clinical premonitory signs such as those seen in familial polyposis coli (FPC) are lacking, the clinician must recognize clinical findings and family history typical of HNPCC. The authors have described colorectal cancer expression from a survey of ten HNPCC kindreds. Kindred members with colorectal cancer differed significantly (P<.05) from patients with sporadic colorectal cancer: 1) mean age of initial colon cancer diagnosis was 44.6 years; 2) 72.3 percent of first colon cancers were located in the right colon, and only 25 percent were in the sigmoid colon and rectum; 3) 18.1 percent had synchronous colon cancers; and 4) 24.2 percent developed metachronous colon cancer, with a risk for metachronous lesions in ten years of 40 percent. Affecteds and their first-degree relatives should undergo early intensive education and surveillance. In families with an early age of onset, colonoscopy should begin at age 25, and biannually thereafter, with fecal occult blood testing of the stool semiannually. Third-party carriers must become more responsive to the costly surveillance measures required for these otherwise healthy patients. Supported by NIH Grants No. 5 RO1 CA41371-01 and 1 RO1 CA42705-01.     

Biologic behavior of resected BRCA-mutated pancreatic cancer: Comparison with sporadic pancreatic cancer and other BRCA-related cancers

BackgroundSince margin-negative resection is essential for the cure of pancreatic cancer (PC), early detection of PC is important. Although PC is the third most common cancer associated with BRCA1/2 mutations, clinical research regarding BRCA mutations in resected PC are rare. In this study, we investigated the oncologic characteristics of resected PC with BRCA mutation to suggest management strategies.MethodsWe retrospectively reviewed data from 493 patients who were confirmed to be pathogenic BRCA1/2 mutation carriers between January 2007 and December 2019. We investigated the oncologic characteristics of PC patients by comparing them with resected sporadic PC and other BRCA-related cancer groups (breast cancer, ovarian cancer, and others).ResultsTen BRCA mutation carriers (2.0%) experienced PC, and PC onset was significantly later than that of BRCA-related breast cancer (age: breast vs. pancreas, 45.0 vs. 53.5 years, p = 0.050). Six patients underwent pancreatectomy and their long-term survival outcomes did not differ from those of sporadic PC patients (disease free survival: BRCA1/2 vs. sporadic, 10.0 months vs. 9.0 months, p = 0.504; overall survival: BRCA1/2 vs. sporadic, 29.0 months vs. 35.0 months, p = 0.520).ConclusionBRCA-mutated PC occurs later than BRCA-mutated breast cancer. Active genetic testing to identify BRCA1/2 mutation carriers at the onset of breast cancer and continuous long-term surveillance of these patients can provide opportunities to detect BRCA-mutated PC at a resectable stage.     

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.     

Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia

The breast cancer susceptibility gene BRCA2 has recently been identified as identical to the Fanconi anemia (FA) gene FANCD1. Here we expand the clinical implications of this discovery. Notably, we identified 6 children in 5 kindreds exhibiting the co-occurrence of BRCA2 mutations, FA, and early onset acute leukemia. Leukemia occurred at a median of 2.2 years of age in the BRCA2 patients in contrast to a median onset of 13.4 years in all other FA patients in the International Fanconi Anemia Registry (IFAR; P <.0001). Breast cancer was noted in 4 of the 5 kindreds. Of the 6 children with leukemia, 4 were treated with bone marrow transplantation and 2 are alive at 3 and 9 months after treatment. Our results suggest that BRCA2 testing should be considered in all patients with FA in whom the complementation group cannot be defined or in whom leukemia is diagnosed at or before 5 years of age.     

遗传性非息肉病性大肠癌6家系临床分析

目的总结遗传性非息肉病性大肠癌(HNPCC)的临床特征,提高其早期诊断和治疗水平。方法对我院6个HNPCC家系进行调查,记录患者性别、发病年龄、肿瘤部位等。结果6个家系有大肠癌患者19例,占同期所有大肠癌的2.7%。其中男性10例,女性9例;发病年龄为26～74岁,中位年龄为53.4岁;共有大肠癌病灶23处,60.9%位于右半结肠,多原发大肠癌有4例。另有大肠腺瘤患者2例,白血病患者1例,原发性肝癌患者1例。结论HNPCC有明显的临床特征,利用这些特征有助于早期诊断和提高防治效果。     

Modifying effect of reproductive risk factors on the age at onset of breast cancer for GermanBRCA1 mutation carriers

Female carriers of mutations in theBRCA1 gene on chromosome 17q have a very high risk of developing breast and/or ovarian cancer during their life-time. There is, however, little knowledge of to what extent non-genetic risk factors, such as age at menarche, age at first birth, and body mass index, alter the age at onset of disease. We identified individuals showing a high probability of linkage toBRCA1 and examined the effect of other known risk factors on disease risk. A total of 43 families with at least three breast or ovarian cancer cases, including two affected before 60 years of age, were studied for linkage to the susceptibility locusBRCA1. Blood samples from relevant family members were used to genotype for at least three chromosome 17q polymorphic markers. Information on reproductive history, hormone use and lifestyle factors was collected from female members using a self-administered questionnaire. Diagnoses of breast and ovarian cancer were verified through pathology reports and paraffin blocks were obtained when available. Multipoint LOD (logarithm of the odds) scores were calculated and individuals from 10 families with a posteriori probability for linkage greater than 0.90 were used for further analysis. Forty-sixBRCA1 carriers were identified by the disease haplotype; 30 were affected with breast cancer and 5 with ovarian cancer. Proportional-hazards analysis of age at onset of breast cancer yielded increased relative risks of 1.74 for early age at menarche (<14 years), 1.58 for late age at first birth (25 years) or nulliparity, and 2.78 for recent year of birth (1940); however, none of the risk estimates was statistically significant. When both breast and ovarian cancer were considered as disease endpoints, the birth cohort effect was stronger and age at first birth showed no effect. Our data provide some evidence that reproductive risk factors for breast cancer have an effect on age at onset forBRCA1 carriers. However, considering that our analyses were based on limited numbers, these results warrant further clarification.     

Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer.

BACKGROUND AND AIMS: Polypectomy in the colon has been shown to prevent colorectal cancer in both the general population and in familial colorectal cancer. Individuals with a family history of colorectal cancer have an increased risk of the disease. Over a period of 10 years, 304 subjects at risk were included in ongoing surveillance with regular colonoscopies. To compile the medical findings and experience generated during this period, a retrospective cross sectional study was performed. SUBJECTS: Subjects were classified into three family groups: families with hereditary non-polyposis colorectal cancer (HNPCC); families with hereditary colorectal cancer (HCC, non-Lynch syndrome); and a third group of families with only empirical risk estimates based on a family history of two close relatives (TCR) with colorectal cancer. METHODS: The risk population was studied with regard to age at onset, prevalence, number, cancer risk, size, dysplasia, and distribution of adenomas. A comparison was made within the family groups and with a reference group representing the general population. RESULTS: In total, 195 adenomas and six cancers were detected among 85 individuals. The relative risk of having an adenoma in the whole risk population compared with the general population was 2.6. Subjects from TCR families had most adenomas and HNPCC subjects had the least. A shift from proximal adenomas to distal carcinomas in families with HCC and TCR suggested a higher cancer risk in distal adenomas in these syndromes. HNPCC families showed a younger age at onset and adenomas with a higher degree of dysplasia. In HNPCC, there was a similar localisation of adenomas and carcinomas, suggesting a high risk of cancer in all adenomas. CONCLUSIONS: There was clear overrepresentation of adenomas in all three family types compared with the reference population. In HNPCC, we found earlier onset of adenomas and faster progression to cancer. Families with HCC, and even more so TCR subjects, had a later onset and lower risk of cancer from proximal adenomas. Based on these results, surveillance protocols in Sweden have been revised.     

Hereditary nonpolyposis colorectal cancer in young colorectal cancer patients: high-risk clinic versus population-based registry

BACKGROUND & AIMS: Early onset colorectal cancer (CRC) is an important feature of hereditary nonpolyposis colorectal cancer (HNPCC). We sought to compare rates of genetically defined HNPCC among individuals with early onset CRC drawn from a high-risk clinic and a population-based cancer registry. METHODS: Probands with CRC diagnosed before 36 years of age were enrolled from a high-risk CRC clinic at the University of California, San Francisco (UCSF), and a population-based Kaiser Permanente (KP) Health Plan cancer registry. Probands provided cancer family histories and tumors for microsatellite instability (MSI) testing and MSH2/MLH1 protein immunostaining. Germline MSH2 and MLH1 mutational analysis was performed. RESULTS: Forty-three probands were enrolled from UCSF and 23 from KP. The UCSF and KP probands had similar median age of onset of CRC (30 vs. 31 years) and the percentage with any personal or family history of another HNPCC-related cancer (70% vs. 74%). However, 28 of 40 (70%) of the UCSF tumors were MSI-H compared with 6 of 18 (33%) of KP tumors (P = 0.01), and 13 germline MSH2 or MLH1 mutations were found in the UCSF group compared with 0 in the KP group (P = 0.0001). In a multivariate analysis, institution (P = 0.002) and the total number of colorectal cancers in the family (P = 0.0001) were independent predictors of MSH2 or MLH1 mutation. CONCLUSIONS: Family history of cancer is an important feature of HNPCC, even among individuals with early onset CRC. Caution must be undertaken when extrapolating data regarding HNPCC from high-risk clinic populations to the general population.     

Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families

Purpose: Germline mutations in either BRCA1 or BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. At present, over thousand distinct BRCA1 and BRCA2 mutations have been identified. Specific mutations are found to be common within particular populations, resulting from genetic founder effects. To investigate the contribution of germline mutations in these two genes to inherited breast cancer in Iran, we performed BRCA1/BRCA2 mutation analyses in ten Iranian high risk breast cancer families. This is the first study analysing the complete coding sequences of both genes that concerns the Iranian population. Methods: BRCA1/BRCA2 mutation detection included sequencing of the coding and the 3 and 5 untranslated regions. To detect large genomic rearrangements in the BRCA1 gene semi-quantitative multiplex PCR was performed. Results: Two pathogenic mutations in the BRCA2 gene were detected: a novel deletion c.4415_4418delAGAA and a previously described insertion c.6033_6034insGT. In addition, one intronic variation g.5075–53C>T and a deletion/insertion g.*381_389del9ins29 in the 3 untranslated region of BRCA1 were found in two of the investigated families. Both sequence alterations were absent in an age matched Iranian control group. The BRCA2 homozygous variation p.N372H, previously associated with an increased risk for developing breast cancer, was not identified in this study. We did not detect large genomic rearrangements in BRCA1 in patients tested negatively for disease causing mutations in both genes by standard sequencing. Conclusions: At present, the BRCA2 mutations c.4415_4418delAGAA and c.6033_6034insGT have not been identified in any investigated population except the Iranian. Whether both mutations are specific for the Iranian population or a special subgroup remains to be investigated in larger studies. The absence of BRCA1 mutations in the analysed families may suggest that penetrance or prevalence of BRCA1 mutations may be lower in Iran.     

The prevalence of BRCA1 and BRCA2 mutations in eastern Chinese women with breast cancer

To investigate the prevalence of BRCA1 and BRCA2 mutations among Chinese patients, we studied 70 Shanghai cases with early onset breast cancer and affected relatives, and mutation screening was performed in the whole-gene sequence of BRCA1 and BRCA2 by polymerase chain reaction-based denaturing high-performance liquid chromatography. Six disease-causing mutations in BRCA1 (8.6%) and two in BRCA2 (2.9%) were detected, including four novel mutations that were all in the BRCA1 gene (3449insA, IVS17-1G>T, IVS21+1G>C and 5587-1del8). Additional sequence variants identified included 30 polymorphisms (18 in BRCA1 and 12 in BRCA2) and a novel mis-sense mutation of unknown significance in BRCA2 (5911G>C). The 9.5 and 2.4% patients with breast cancer diagnosed before the age of 35 were BRCA1- and BRCA2-mutation carriers, and the prevalence of BRCA1 and BRCA2 mutations in the families with two or more affected individuals were 12.1 and 3.0%, respectively. In these families, all the BRCA1 and BRCA2 mutations were detected in the families containing at least one case diagnosed under the age of 40, and in the families whose youngest patients were diagnosed before the age of 35, the prevalence of BRCA1 and BRCA2 were as high as 40 and 20%, respectively. Based on this information, we conclude that genetic testing should be performed among patients with early onset breast cancer (<40 years), especially combined with family history.C-G. Song and Z. Hu contributed equally to the work.     

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.     

Coinheritance of BRCA1 and BRCA2 mutations with Fanconi anemia and Bloom syndrome mutations in Ashkenazi Jewish population: possible role in risk modification for cancer development

Fanconi anemia (FA) and Bloom syndrome (BS) are rare autosomal recessive genetic disorders manifesting in childhood, with a predisposition to cancer development in adolescence and adulthood. Both syndromes are relatively prevalent among the Ashkenazi Jewish population, and, in both syndromes, mutations specific to this population have been identified. Similarly, unique Ashkenazi mutations were found in the genes BRCA1 and BRCA2. These two genes, when mutated, play important roles in familial breast and ovarian carcinogenesis. The genes involved in the pathogenesis of the FA and BS belong to the general class of instability genes. Heterozygosity for the FA gene has no known promalignant potential, while the BS mutation carrier state was associated with an increased frequency of colorectal cancer. The especially frequent carrier state among the Ashkenazi Jewish population coupled with the high prevalence of BRCA1 and BRCA2 in the same population has led us to search for coinheritance affecting the potential for cancer development. One hundred Ashkenazi women with known BRCA1 and BRCA2 mutations were screened for the FA mutation IVS4+4 A-->T and the BS mutation blm(Ash). Our results indicate that there is an increased prevalence of both FA and BS mutation carriers among the population studied compared with the general Ashkenazi population (prevalence of FA mutation 4/100 women [4%] as compared to 35/3104 previously published controls [1.1%], P=0.031, and for BS mutation 3/100 [3.2%] as compared to 36/4001 [0.9%], P=0.058). There was no statistically significant effect of the coinheritance on cancer prevalence, type of cancer, or age of cancer onset. Coinheritance of FA and/or BS mutations seems to be more prevalent among BRCA mutation carriers, but a larger study encompassing more women may help in clarifying this issue.     

Hereditary ovarian cancer

At least 10% of ovarian tumors are hereditary and associated with highly penetrant, autosomal, dominant genetic predisposition. Three clinical manifestations of hereditary ovarian cancer have been identified: site-specific ovarian cancer, hereditary breast and/or ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. BRCA germline mutations account for more than 90% of all hereditary epithelial ovarian tumors whereas most of the remaining 10% are caused by MLH1 and MSH2 mutations, which are susceptibility genes of HNPCC. Genetic testing is available for each of the three hereditary syndromes above mentioned. The recommendations for OC surveillance in high-risk women having a strong family history or BRCA mutation carriers include transvaginal pelvic ultrasound with color Doppler and serum CA125 every 6 months. Bilateral salpingo-oophorectomy appears to be effective to reduce the risk of ovarian cancer in BRCA mutation carriers. Hysterosalpingo-oophorectomy should be considered in HNPCC women who undergo surgery for colorectal carcinoma.     

Colorectal cancer in Egypt

PURPOSE: The aim of this study was to review the age distribution and pathology features of colorectal cancer in Egypt. METHODS: A seven-year review (retrospective in first six years, prospective in the seventh) of all colorectal adenocarcinoma patients (N = 177; 104 males; mean age, 46; range, 19–74 years) presented to the Department of Surgery, Ain Shams University, was performed. Data from three other major hospitals throughout the country were retrieved and compared with Ain Shams data. Retrospective data were retrieved from patients files and surgery and pathology records. Family history of colorectal cancer and other characteristic hereditary nonpolyposis colorectal cancer tumors was obtained prospectively in all patients. RESULTS: According to Ain Shams data, the disease had no predilection to a specific age group. Thirty-eight percent of the tumors occurred in patients aged less than 40 years, and only 15 percent of patients were aged above 60 years. None of the young patients fulfilled the Amsterdam criteria for hereditary nonpolyposis colorectal cancer. Seventy-five percent of tumors occurred in the left side, 3 percent were Dukes A, and 58 percent were Dukes C. Synchronous and metachronous tumors occurred in 2.8 and 4.5 percent of patients, respectively. Adenomas were present in 5.6 percent of patients and bilharziasis in 3.4 percent of resection specimens. Data from different centers were remarkably similar to Ain Shams results. CONCLUSION: Colorectal cancer in Egypt has no age predilection and more than one-third of tumors affects a young population. The high prevalence in young people can neither be explained on a hereditary basis nor can it be attributed to bilharziasis. The disease usually presents at an advanced stage, and predisposing adenomas are rare. Similarity of the data from different centers suggests that this is the picture of colorectal cancer typical of Egypt.     

Genetic susceptibility to breast cancer

Deleterious mutations in two breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2 have been identified in breast and ovarian cancer families. Women with a BRCA1 or BRCA2 mutation are candidates for additional risk reduction measures such as intensive screening, prophylactic surgery or chemoprevention. Additional susceptibility genes have been identified, including PTEN, ATM, TP53, CHEK2, CASP8, PBRL and BRIP1. Yet, many women with a personal or family history suggestive of a hereditary susceptibility to breast cancer undergo genetic testing and no significant genetic alteration is found. Thus, there are other susceptibility genes that have not been identified, and it is likely that the remaining familial contribution to breast cancer will be explained by the presence of multiple low penetrance alleles that coexist to confer high penetrance risks (a polygenic model). The American Cancer Society has identified cancer prevention as a key component of cancer management and there is interest in developing individualized cancer prevention focused on identifying high risk individuals who are most likely to benefit from more aggressive risk reduction measures. Breast cancer risk assessment and genetic counseling are currently provided by genetic counselors, oncology nurse specialist, geneticists, medical and surgical oncologists, gynecologists and other health care professionals, often working within a multidisciplinary clinical setting. Current methods for risk assessment and predictive genetic testing have limitations and improvements in molecular testing and risk assessment tools is necessary to maximize individual breast cancer risk assessment and to fulfill the promise of cancer prevention.     

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.     

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.     

Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome

BACKGROUND & AIMS: Hereditary colorectal cancer is associated most commonly with the hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis syndromes. We investigated the prevalence of early onset colorectal cancer and the frequency of p53 germline mutations in 64 families from a Li-Fraumeni syndrome (LFS) registry. METHODS: Patients with documented colorectal cancer and a diagnosis at or before age 50 were included. P53 analyses were performed through germline mutational analyses using standard molecular techniques. RESULTS: Among the 397 patients and 64 families in the classic LFS registry, a total of 11 patients (2.8%) from 10 different families (15.6%) met criteria for classic LFS and had documented colorectal cancer at less than 50 years of age. The mean age at diagnosis in this group was 33 years and of these patients 4 developed colorectal cancer before age 21 (ages, 9, 11, 15, and 20 y). All families that were tested for p53 mutations (8 of 10) had evidence of germline mutations by sequence analysis; therefore, 12.5% of the total number of families in the registry had colorectal cancer at age less than 50 years and a documented germline p53 mutation. Mutations primarily were missense or nonsense and were located between exons 4-10. CONCLUSIONS: LFS patients with germline p53 mutations may have an increased susceptibility to colorectal cancer and present up to several decades earlier than the general population. LFS should be considered when a young patient presents with colorectal cancer.