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Familial Mediterranean fever is an autosomal recessive disease manifested by recurrent short episodes of fever associated with polyserositis. It is common in a variety of Mediterranean and near Eastern populations. The biochemical defect is unknown, and there have been few studies of genetic marker associations or linkage with the disease. We have screened blood samples from members of 14 nuclear Armenian families, the population with the highest known gene frequency, for 19 different polymorphic phenotypic genetic markers. These 14 families included 31 affected and 43 unaffected family members. No association was found with any of the markers studied. Linkage could be excluded at the distance of 0-15% recombination with 14 markers. Linkage could not be excluded with 5 other markers. These results exclude the FMF gene from those portions of the human gene map that are at least 0.5% recombination distance from these 14 genetic markers, and represent the first comprehensive step in the eventual localization and isolation of the FMF gene.

To provide health care providers, patients, and the general public with a responsible assessment of currently available data on the management of hepatitis B.A non-DHHS, nonadvocate 12-member panel representing the fields of hepatology and liver transplantation, gastroenterology, public health and epidemiology, infectious diseases, pathology, oncology, family practice, internal medicine, and a public representative. In addition, 22 experts from pertinent fields presented data to the panel and conference audience.Presentations by experts and a systematic review of the literature prepared by the Minnesota Evidence-based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience.The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government.The most important predictors of cirrhosis or hepatocellular carcinoma in persons who have chronic HBV are persistently elevated HBV DNA and ALT levels in blood. Other risk factors include HBV genotype C infection, male sex, older age, family history of hepatocellular carcinoma, and co-infection with HCV or HIV. The major goals of anti-HBV therapy are to prevent the development of progressive disease, specifically cirrhosis and liver failure, as well as hepatocellular carcinoma development and subsequent death. To date, no RCTs of anti-HBV therapies have demonstrated a beneficial impact on overall mortality, liver-specific mortality, or development of hepatocellular carcinoma. Most published reports of hepatitis therapy use changes in short-term virologic, biochemical, and histologic parameters to infer likelihood of long-term benefit. Approved therapies are associated with improvements in intermediate biomarkers, including HBV DNA, HBeAg loss or seroconversion, decreases in ALT levels, and improvement in liver histology (Table). Although various monitoring practices have been recommended, no clear evidence exists for an optimal approach. The most important research needs include representative prospective cohort studies to define the natural history of the disease and large RCTs of monotherapy and combined therapies, including placebo-controlled trials, that measure the effects on clinical health outcomes. Table. Criteria Useful in Determining for Whom Therapy is Indicated: Patients for whom therapy is indicated: Patients who have acute liver failure, cirrhosis and clinical complications, cirrhosis or advanced fibrosis and HBV DNA in serum, or reactivation of chronic HBV after chemotherapy or immunosuppression; Infants born to women who are HBsAg-positive (immunoglobulin and vaccination). Patients for whom therapy may be indicated: Patients in the immune-active phase who do not have advanced fibrosis or cirrhosis. Patients for whom immediate therapy is not routinely indicated: Patients with chronic hepatitis B in the immune-tolerant phase (with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy); Patients in the inactive carrier or low replicative phase (with low levels of or no detectable HBV DNA in serum and normal serum ALT levels); Patients who have latent HBV infection (HBV DNA without HBsAg). We recommend routine screening for hepatitis B of newly arrived immigrants to the United States from countries where the HBV prevalence rate is greater than 2%. Screening will facilitate the provision of medical and public health services for infected patients and their families and provide public health data on the burden of disease in immigrant populations. The screening test should not be used to prohibit immigration.

Irritable bowel syndrome (IBS) runs in families. Prior family studies surveyed patients inquiring about family history without surveying family members. The stigma associated with IBS may lead relatives to not share information with others, resulting in underestimates of familial aggregation of IBS. The aim of the study was to evaluate the accuracy of patient-report of family history of IBS in cases and controls, and to estimate familial aggregation of IBS using both a case–control and a family-study design. Fifty cases and 53 controls completed symptom questionnaires and provided contact information for first-degree relatives. Questionnaires were mailed to relatives. Relatives were considered to have IBS if they met Rome criteria and did not have an alternate GI diagnosis. Cases and controls identified 573 relatives in their families. A total of 202 (51%) of 396 living relatives participated. The kappa statistics between proband- and relative-reported IBS for case- and control-relatives were 0.27 and 0.04. Cases reported 21% of relatives had IBS; relative-reports showed 37% (P = 0.003). Controls reported 4% of relatives had IBS; relative-reports showed 16% (P = 0.013). Regardless of whether the proband or the relative themselves were the information source, case-relatives were threefold as likely to have IBS than control-relatives (P < 0.05). However, overall rates were higher when data collected from relatives were used. Regardless of approach, strong familial aggregation of IBS was observed. Cases and controls underestimated the frequency of IBS in their relatives and agreement between proband- and relative-report of IBS status was extremely poor, thus emphasizing the need for direct data collection from relatives in IBS family studies.

Juvenile polyposis (JP) is an inherited condition predisposing to upper gastrointestinal (UGI) polyps and colorectal cancer. Two genes are known to predispose to JP, SMAD4 and bone morphogenetic protein receptor type 1A (BMPR1A). The object of this study was to determine the differences in phenotype of patients with SMAD4 or BMPR1A mutations (MUT+) compared with those without (MUT-).DNA was extracted from 54 JP probands and used for polymerase chain reaction of all exons of SMAD4 and BMPR1A. Products were then sequenced and analyzed for mutations. Medical record data were used to create a JP database, and statistical analysis was performed using Fisher's exact and unpaired t-tests.Nine of 54 patients had germline SMAD4 mutations, 13 had BMPR1A mutations, and 32 had neither. There were no significant differences between SMAD4+ and BMPR1A+ cases in terms of clinical factors examined, except for a family history of UGI involvement (P.01). There was a higher prevalence of familial cases in MUT+ patients (P =.09),10 lower gastrointestinal polyps (P =.06), and frequency of family history of gastrointestinal cancer compared with MUT- patients (P =.01).Patients with germline SMAD4 or BMPR1A mutations have a more prominent JP phenotype than those without, and SMAD4 mutations predispose to UGI polyposis.

Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States and will be responsible for an estimated 28,900 deaths in 2001. Relatively little is known of its etiology, and the only well-established risk factor is cigarette smoking. Studies over the past 3 decades have shown that 4%-16% of patients with pancreatic cancer have a family history of the disease. A small fraction of this aggregation can be accounted for in inherited cancer syndromes, including familial atypical multiple-mole melanoma, Peutz-Jeghers syndrome, hereditary breast-ovarian cancer, hereditary pancreatitis, and hereditary nonpolyposis colorectal cancer. These syndromes arise as a result of germline mutations in the BRCA2, pl6 (familial atypical multiple-mole melanoma), mismatch repair (hereditary nonpolyposis colorectal cancer), and STK11 (Peutz-Jeghers syndrome) genes. In addition, hereditary plays a role in predisposing certain patients with apparently sporadic pancreatic cancer. Many patients with pancreatic cancers caused by a germline mutation in a cancer-causing gene do not have a pedigree that is suggestive of a familial cancer syndrome. A recent prospective analysis of the pedigrees in the National Familial Pancreatic Tumor Registry found that individuals with a family history of pancreatic cancer in multiple first-degree relatives have a high risk of pancreatic cancer themselves. The identification of such high-risk individuals will help clinicians target screening programs and develop preventive interventions with the hope of reducing the mortality of pancreatic cancer in these families.

Colorectal cancer can be prevented through endoscopic removal of adenomatous polyps. Because screening endoscopy rates are low, it is critical to identify correlates of screening behavior that are amenable to interventions to improve screening rates. Our purpose was to identify the correlates of endoscopic screening among persons at risk for colorectal cancer.We surveyed 1,160 healthy, adult, first-degree relatives of colorectal cancer patients in 583 kindreds, for a 43% response rate. Using multiple logistic regression analysis, we tested the association between screening behavior and perceived risk for colorectal cancer, the belief that colorectal cancer can be prevented, demographic factors, strength of family history, and practical barriers to screening.Persons screened at least once were older, were male, had stronger family histories, had a regular doctor, and had health insurance. After these fixed factors were accounted for, the belief that colorectal cancer can be prevented and higher perceived risk were associated with significantly greater odds of screening.This study establishes the need for trials evaluating the cancer prevention potential of the link between screening behavior and health beliefs. Physicians must be aware of their patients' family colorectal cancer history and recommend appropriate endoscopic screening for those at increased risk, particularly women. Patients should be educated about their cancer risk and about preventing colorectal cancer.

It has been estimated that familial aggregation and genetic susceptibility play a role in as many as 10% of patients with pancreatic cancer (PC). The quantified prospective risk of PC among first-degree relatives of PC patients has not been investigated. Families enrolled in the National Familial Pancreas Tumor Registry (NFPTR) prior to September 1, 1998 were followed to estimate the risk and incidence of PC among first-degree relatives of patients with PC. Analyses were performed separately on kindreds with at least two first-degree relatives with PC (familial pancreatic carcinoma (PC); n = 150) at the time the kindred was enrolled in the NFPTR and on kindreds without a pair of affected first-degree relatives (sporadic PC; n = 191). A subanalysis was performed on familial PC kindreds containing three or more affected members at the time of enrollment in the NFPTR (n = 52). Risk was estimated by comparing observed new cases of PC during the observation period with expected numbers based on the United States population-based Surveillance, Epidemiology and End Results program data. Incidence was estimated using person-years risk analyses. During the observational period, six incident PCs developed in the first-degree relatives: two in the sporadic PC kindreds, and four in the familial PC kindreds. The PC risk in the sporadic PC kindreds was not significantly greater than expected [observed/expected = 6.5 (95% CI = 0.78-23.3)] with an incidence rate of 24.5/10(5)/ year. There was a significantly increased 18-fold risk (95% CI = 4.74-44.5) of PC among first-degree relatives in familial PC kindreds, with an incidence of 76.0/10(5)/year. In the subset of familial PC kindreds with three or more affected family members at the time of enrollment, there was a 57-fold (95% CI = 12.4-175) increased risk of PC and an incidence of 301.4/10(5)/year compared with the Surveillance, Epidemiology and End Result age-adjusted incidence of PC in the U.S. (8.8/10(5)/year). When stratified by age, the risk was largely confined to relatives over the age of 60. This study is the first analysis of incident PC occurring in familial PC kindreds. The risk and incidence of PC is exceptionally high among at-risk first-degree relatives in familial PC kindreds in which at least three first-degree relatives have already been diagnosed with PC. Familial PC kindreds are a reasonable high-risk group for PC screening and chemoprevention research.

In this study we describe inbreeding in a large pedigree from Tangier Island, Virginia, in which we compare two commonly used methods to estimate inbreeding in humans: pedigree and isonymy (identical surnames of spouses). Genealogical data on 3,512 individuals dating back to 1722 were used. Using the pedigree method, we determined an average inbreeding coefficient (F) of 0.00873 for the community as a whole, and 0.018 for inbred individuals. Analysis of temporal trends showed that inbreeding began around 1800 and peaked at 0.0109 in 1824-1849 and 1875-1899. Thereafter, inbreeding steadily declined to 0.00565 in 1975-1997. Analysis of pedigree structure complexity over time showed that close consanguinity contributes to inbreeding in the earlier cohorts, and remote consanguinity accounts for much of the inbreeding in the later cohorts. The number of common ancestors increases over time, as does the number of paths connecting inbred individuals to these common ancestors. Inbreeding estimates based on the isonymy approach yielded a 2.2-fold higher value of F (0.01945) compared to the pedigree method. Total isonymy estimates over 25-year cohorts overestimated inbreeding values from pedigree data between 1. 5-8-fold. We speculate that the overestimation is probably due to the inability of our data to satisfy the method's assumption of monophyletic origin of each surname. In conclusion, inbreeding in the Tangier Island population is consistent with the isolated nature of its population, and temporal trends reflect patterns in emigration and a breakdown in isolation over time.

The APC I1307K gene mutation is associated with increased colorectal cancer (CRC) risk in Ashkenazi Jews. Factors predicting acceptance of this and other hereditary colon cancer mutation tests in a clinical setting are unknown. We analyzed sex, age, family history, personal history, and gene test results of patients at increased risk for cancer who sought cancer risk counseling at the Johns Hopkins (JH) CRC Risk Assessment Clinic (n = 91), and those submitting samples to the JH Pathology Molecular Diagnostic Laboratory (n = 256) for APC I1307K testing. Of patients seen at the JH Clinic, 77/91 (84.6%) elected APC I1307K testing after pretest counseling (acceptors). There were no statistically significant differences in demographic characteristics between acceptors and decliners. In comparison, only 8 of 57 (14.0%) patients offered HNPCC testing proceeded with testing (P0.001). Of 256 individuals tested at the JH laboratory, most were male (61.3%) and most had a personal or family history of colorectal cancer or polyps. Test positivity correlated with increasing risk of colorectal cancer. Acceptance of testing for the APC I1307K mutation is high, with more men than women pursuing counseling and testing. The reported association between the APC I1307K mutation and colon cancer risk was supported by a correlation in these data between personal or family history of CRC or polyps and a gene mutation.

The discovery of genes responsible for inherited forms of colorectal cancer have the potential to improve cancer risk assessment and counseling. Germline mutations (nonsense, frameshift) of APC are associated with familial adenomatous polyposis, an autosomal dominant syndrome, clinically characterized by young onset, hundreds of adenomatous polyps in the colon, and increased risk for extracolonic tumors. Mutations in APC are also associated with forms of attenuated familial adenomatous polyposis. Germline mutations in five mismatch repair related genes (hMSH2, hMLH1, hMSH6, hPMS1, and hPMS2) cause hereditary nonpolyposis colorectal cancer and are associated with increased risk of somatic genetic alterations and high DNA microsatellite instability. Hereditary nonpolyposis colorectal cancer is characterized by young onset colorectal cancer, proximal colon location, and increased risk of extracolonic cancers. A missense mutation in APC (I1307K) is associated with some familial colorectal cancer in Ashkenazic Jews. For persons at risk for hereditary forms of colorectal cancer, testing algorithms and gene test interpretations depend on identification of the pedigree germline gene mutation. Careful evaluation of the kindred for characteristic aggregation of tumor types among affected individuals and the availability of affected persons for testing are important issues in implementing genetic testing and follow-up management. Case reports illustrate the importance of genetic counseling as a component of cancer genetic risk assessment. The genetic counseling process includes exploration of patient risk perception, sources of anxiety related to cancer risk, patient education (specific cancer-related issues, prevention/intervention options), discussion of possible gene test options, test limitations, and consequences of various gene test outcomes.

For many years anecdotal case reports have suggested that pancreatic cancer aggregates in some families.Two recent advances have established that this is in fact the case. First, large registries, such as the National Familial Pancreas Tumor Registry (NFPTR) at Johns Hopkins, have identified a number of families in which multiple family members have been diagnosed with pancreatic cancer. As a result, the patterns of inheritance of pancreatic cancer can now be studied on a scale not possible before. Second, advances in molecular genetic techniques make it possible to test members of these families for germline mutations in known candidate cancer causing genes. As a result, some of the genetic alterations responsible for the familial aggregation of pancreatic cancer have been identified in some families.The NFPTR has enrolled 362 families in which at least one family member has been diagnosed with pancreatic cancer. These include 151 families in which at least two first-degree relatives have been diagnosed with pancreatic cancer. Analysis of these families has revealed that even second-degree relatives of patients from these families are at increased risk of developing pancreatic cancer. In addition, a number of kindreds which exhibit aggregation of cancer have been tested for germline mutations in known cancer causing genes. Germline mutations in BRCA2 have been shown to predispose to both breast and pancreatic cancer, germline mutations in p16 to melanoma and pancreatic cancer (the FAMMM syndrome), and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS).Pancreatic cancer aggregates in some families, and relatives of patients with pancreatic cancer have an increased risk of developing pancreatic cancer themselves. The genetic basis for the familial aggregation of pancreatic cancer has been shown to be germline mutations in known cancer causing genes in some of these families.

Genetic discoveries in hereditary nonpolyposis colorectal cancer (HNPCC) have made possible genetic testing to determine susceptibility to this form of colorectal cancer (CRC). This study measured the uptake of genetic testing for HNPCC among first-degree relatives of CRC patients and conducted a preliminary analysis of the predictors of test uptake.We compared 77 test acceptors and 181 decliners on demographic, medical history, and psychological characteristics, controlling for distance from the testing center. The psychological factors studied were risk perception for CRC, frequency of cancer thoughts, and perceived ability to cope with unfavorable genetic information.In the final regression model, after accounting for all variables, the significant predictors of test uptake were increased risk perception, greater perceived confidence in ability to cope with unfavorable genetic information, more frequent cancer thoughts, and having had at least one colonoscopy. The association between risk perception and uptake was dependent on frequency of cancer thoughts. Among those who thought about getting CRC more often, the probability of testing increased as perceived risk increased to approximately 50% likelihood of getting CRC and then leveled off. In contrast, among those who never or rarely thought about getting CRC, risk perception was unrelated to testing decision.Our findings are consistent with the associations reported between psychological factors and other cancer screening behaviors.

Various studies have identified psychosocial factors that may influence attitudes toward colon cancer gene testing. Whereas family history of colon cancer has been associated with interest in gene testing, this has not been examined extensively. We hypothesized that the strength of family history of colon cancer is associated with risk perception and willingness to undergo gene testing.We evaluated attitudes toward colon cancer gene testing among persons who had at least one first-degree relative with colon cancer. A total of 2680 at-risk relatives in 863 kindreds were identified and mailed an extensive survey regarding sociodemographic variables, family history, health behaviors and knowledge, and willingness to take a colon cancer gene test. A total of 56.6% of persons completed and returned surveys. We conducted a brief telephone survey of a random sample of 200 persons who did not respond to the mail survey.The combined study sample of 1373 people was 42% male, had a mean age of 55 +/- 15 years, was 96% white, and had moderate-to-high SES. A total of 77.4% were very likely to take the gene test, and 92.4% were somewhat or very likely to take the gene test. A total of 78% of the sample perceived a higher colon cancer risk, although patterns of risk perception and worry differed significantly between mail survey and telephone survey respondents. More of the telephone survey respondents were also somewhat unlikely or very unlikely to take the gene test compared to the mail survey respondents (13.7% versus 6.9%). In the combined sample, concern about developing colon cancer and risk perception increased with number of relatives with colon cancer (P0.0001). Eight percent expressed no concern about developing colon cancer; 4.8% felt their chance of developing colon cancer was lower than others of the same age, sex, and race; and 3.3% felt that they were very unlikely to develop colon cancer in their lifetime. However, there was strong interest in gene testing regardless of the number of affected relatives, and persons with more affected relatives were generally willing to pay more for the gene test (up to $1000).The strength of family history of colon cancer is associated with risk perception but not with willingness to undergo gene testing.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.

Cancer of the pancreas is a genetic disease. Sporadic cancers of the pancreas are frequently associated with the activation of an oncogene, K-ras, and the inactivation of multiple tumor suppressor genes, including p53, DPC4, p16, and BRCA2. An improved understanding of the genetics of pancreas cancer should lead to new tests to screen for this disease and novel rational gene-based therapies.

Anecdotal reports of hereditary colorectal cancer suggest that genetic anticipation (earlier appearance in successive generations) occurs, but ascertainment bias and cohort effects confound this interpretation. Using approaches that correct for such biases, we examined the age at diagnosis of colorectal cancer from family history questionnaires completed by subjects in the Johns Hopkins Hereditary Colorectal Cancer Registry; 475 parent-offspring pairs in 308 pedigrees were studied. We observed the expected cohort effect among offspring, in that the mean ages at diagnosis of those born before 1921, between 1921 and 1930, and after 1930 were 63 +/- 13 (SD), 57 +/- 10, and 42 +/- 10 years, respectively, while their parents' mean ages were 65 +/- 14, 66 +/- 14, and 58 +/- 15 years, respectively. In the cohort born before 1921, in which observation periods for both parents and offspring were comparable, there was no difference in age at diagnosis by pairwise comparison or life table analysis (P = 0.15 and 0.23, respectively; r = 0.32). Subgroup analysis of 67 pairs from 38 families that met the International Collaborative Group (ICG) criteria for hereditary nonpolyposis colorectal cancer (HNPCC) and of 14 pairs from 7 families with known germline mutations of DNA mismatch repair genes also showed no significant differences (mean age at diagnosis: 56 +/- 14 years for parents and 57 +/- 16 years for offspring from ICG families, and 45 +/- 10 years for parents and 44 +/- 12 years for offspring in families with known mutations). We also found no evidence for effect of parental gender on age at diagnosis in offspring of either gender, nor a secular trend toward younger onset colorectal cancer in this sample. In conclusion, there is no evidence for genetic anticipation or genomic imprinting of age at diagnosis in this sample of colorectal cancer families. Apparent anticipation appears to reflect a birth cohort bias of ascertainment.

Germline mutations in BRCA2 predispose carriers to the development of breast, ovarian, and a variety of other cancers. The original localization of the BRCA2 gene was aided by its homozygous deletion in a pancreatic carcinoma; indeed, an excess of pancreatic carcinoma has been seen in some BRCA2 cancer families. To determine the involvement of BRCA2 in pancreatic carcinomas, we screened for BRCA2 alterations in an unselected panel of 41 adenocarcinomas of the pancreas (30 pancreatic adenocarcinoma xenografts and 11 pancreatic cancer cell lines). Of the 15 (27%) that had allelic loss at the BRCA2 locus, 4 (9.8%) had abnormalities in the second allele upon screening of the entire BRCA2 gene by in vitro synthesized protein assay. Three of the four mutations were considered germline in origin (7.3% overall; two were confirmed in normal tissue, and one was the 6174delT mutation from the pancreatic cancer cell line CAPAN-1, for which normal tissue was unavailable). The identification of two 6174delT mutations in this series prompted us to evaluate the prevalence of this mutation in an overlapping consecutive series of 245 patients who underwent pancreatoduodenectomy for adenocarcinoma of the pancreas. Sequence analysis of this limited region of the gene identified two additional mutations: (a) one additional germline 6174delT mutation (2 of 245, 0.8% overall); and (b) a second nearby germline 6158insT mutation. One of the patients with a germline mutation had a single relative with breast cancer, and another had a single relative with prostate cancer. None had a family history of pancreatic cancer. The incidence of germline BRCA2 mutations in apparently sporadic pancreatic cancer may be at least as high as in breast or ovarian cancer. Our results suggest that some familial risks for carcinoma will be evident only through a population-based application of gene screening techniques because a low disease penetrance of the germline mutations in some families often evades clinical suspicion.

In contrast to our rapidly increasing knowledge of the genetic basis of colorectal cancer and new molecular technologies, we are only in the early stages of characterizing the impact that this information will have on patients, their families and society. From our research and clinical experience with hereditary colorectal cancer syndromes, we have developed a framework for risk assessment that includes criteria for identifying those at higher genetic risk and guidelines for genetic counseling, predictive genetic testing and follow-up management. More research is needed to optimally translate this framework into wider clinical practice, including characterizing genetic heterogeneity and phenotype correlations, documenting the efficacy of screening and surgical interventions, and maximizing the awareness of health professionals on genetic counseling and the promise and limitations of gene tests.

Testing for adenomatous polyposis coli (APC), the gene responsible for familial adenomatous polyposis (FAP), can now be offered to family members in FAP kindreds. With the availability of this test, genetic counseling has become a crucial tool for helping FAP patients and their relatives understand the syndrome and its implications and for assisting at-risk individuals in making informed decisions about whether or not to undergo genetic testing. Genetic counseling can occur at several time points: when FAP is diagnosed, when an FAP patient is considering reproductive options, when a patient is deciding whether to have his or her children screened, and when an at-risk person is considering genetic testing. Based on our experiences from working with families in a large FAP registry, we explore the different issues that emerge in each of these settings, and how the genetic counselor or clinician can help FAP patients, family members, and at-risk persons deal with these issues.

It has recently been shown that hereditary nonpolyposis colorectal cancer (HNPCC) is caused by hereditable defects in DNA mismatch repair genes. However, the fraction of HNPCC due to defects in any one repair gene and the nature of these mutations are not known. We analyzed 29 HNPCC kindreds for mutations in the prototype DNA mismatch repair gene hMSH2 by a combination of linkage analysis, polymerase chain reaction-based screening, and sequencing of the coding region. The complete intron/exon structure of the gene was ascertained to facilitate this analysis. The results suggest that at least 40% of classic HNPCC kindreds are associated with germline mutations in hMSH2 and that most of these mutations produce drastic alterations in the predicted protein product.

By an iteration of a regular summation matrix B = (bmn) with a regular matrix A = (amn), or B.A, we shall mean the summation method defined by the matrix B operating on the sequence {tn} of A transforms of a sequence {sn}. Thus the sequence {τn} of B. A is given by

By a submethod of a regular matrix method A we mean a method (see 1 or 3) whose matrix is obtained by deleting a set of rows from the matrix A. We establish a one-one correspondence between the submethods of A and the points of the interval 0 < ξ ≤We designate the submethod which corresponds to 𝞷 by A (𝞷) and are accordingly able to speak of sets of submethods of measure 0, of the first category, etc.

We suppose that 0

It is our purpose in this paper to present concise proofs of four theorems which take up the greater part of a paper due to Brudno (1). The proofs of Theorems 1 and 2 have appeared already ((2), (3)), but we present them again so that comparisons can be made with the other two.

Let A = (am, n) be a (regular summability) matrix. Then will denote the set of bounded sequences which are summed by A. If {Ai} (i = 1, 2, …, N) is a finite set of such matrices, and if consists of every bounded sequence then we shall say that the matrices span the bounded sequences. Ifx = {xn} belongs to then we denote the value to which A sums x by A-lim x. If y = {yn} is any sequence, then the A-transform of y (if it exists) is the sequence {Aμ(y)}, where

In this note we shall discuss certain matrix methods of summation, though otherwise, §1 and §2 are not connected.In this section, we shall study some properties of the method (Bh) where we say the series ∑uv is summable (Bh) whenThe method (Bh) has been studied in special cases airsing from different values of h by Rogosinski [11; 12], Bernstein [2], and more recently by Karamata [3; 4].

If A = (am, n) is a regular matrix, then for any sequence x = {xn}, Am(x) will denote the transform and A-lim x denotes if that limit exists. We shall denote by the set of bounded sequences which are summed by A. If B is another regular matrix with then we say that B is b-stronger than A. In that case B must be b-consistent with A (see (4) and (6)), i.e. if thenIf {μn} is a sequence of positive real numbers with we say that A and B are (μn)-consistent if every sequencer x = {xn} satisfying xn = 0(μn) which is summed by both A and B is summed to the same value by both matrices. A finite set of matrices A1, A2, …, AN is said to be simultaneously (μn)-inconsistent (b-consistent) if whenever is summed by Ai with (i = l, 2, …, N) then implies that The set of sequences, is denoted by

Let {s(n)} be a real sequence and let x be any number in the interval 0 < x ⩽ 1. Representing x by a non-terminating binary decimal expansion we shall denote by {s(n,x)} the subsequence of {s(n)} obtained by omitting s(k) if and only if there is a 0 in the decimal place in the expansion of x. With this correspondence it is then possible to speak of “a set of subsequences of the first category,” “an everywhere dense set of subsequences,” and so on.