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Biomedical subjects

J F Lynch

Publications and source records attributed to J F Lynch.

At least 55 records · Page 3Linked to original sources
PubMed1993

Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology.

Mild homocysteinemia occurs surprisingly often in patients with premature vascular disease. We studied the possible enzymatic sources of this mild hyperhomocysteinemia and the control of homocysteine levels in plasma by treatment of patients with the cofactors and cosubstrates of homocysteine catabolism. We assessed homocysteine metabolism in 131 patients who had premature disease in their coronary, peripheral, or cerebrovascular circulation by using a standard oral methionine-load test. Impaired homocysteine metabolism occurred in 28 patients. We assayed levels of the primary enzymes of homocysteine catabolism in cultured skin fibroblast extracts from 15 of these 28 patients. The patients' cystathionine beta-synthase levels (3.68 +/- 2.52 nmol/h per milligram of cell protein, mean +/- SD) were markedly depressed compared with those from 31 healthy adult control subjects (7.61 +/- 4.49, P < .001). The patients' levels of 5-methyltetrahydrofolate: homocysteine methyltransferase were normal. While betaine: homocysteine methyltransferase was not expressed in skin fibroblasts, 24-hour urinary betaine and N,N-dimethylglycine measurements were consistent with normal or enhanced remethylation of homocysteine by betaine: homocysteine methyltransferase in the 13 patients tested. When treated daily with choline and betaine, pyridoxine, or folic acid, there was a normalization of the postmethionine plasma homocysteine level in 16 of 19 patients. Our results indicate that mild homocysteinemia in premature vascular disease may be caused by either a folate deficiency or deficiencies in cystathionine beta-synthase activity. It does not necessarily involve deficiencies of either 5-methyltetrahydrofolate:homocysteine methyltransferase or betaine:homocysteine methyltransferase. Effective treatment regimens are also defined.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1992

Colon cancer genetics.

The terms "hereditary," "sporadic," and "familial" colorectal cancer (CRC) suggest a knowledge of causation; however, current understanding of CRC does not permit categorization of differing CRC risks in accord with their cause per se. Despite these serious shortcomings, these terms are defined operationally on the basis of a family history of cancer, and when available, additional phenotypic information. The sporadic type occurs in the absence of a family history of CRC in a first-degree relative. The familial type occurs when at least one first-degree relative has CRC. Both these categories require the exclusion of hereditary CRC. In the case of hereditary CRC, this type is defined as a family history of CRC occurring in a pattern that indicates autosomal-dominant inheritance, which also may involve certain phenotypic signs (depending on the specific disorder, i.e., florid adenomatous polyps, benign and malignant extracolonic lesions, cancer of unusually early onset, and multiple primary cancer, particularly synchronous and metachronous CRC). Although this operational classification does not produce etiologically homogeneous groups, it is believed to have pragmatic utility with respect to planning targeted surveillance and management strategies. Because of the distinctive natural history of CRC in hereditary syndromes, it is of paramount clinical importance to identify hereditary CRC when it does occur. Even in patients with no evidence of hereditary CRC syndrome, their family history may be second only to age in determining the best CRC screening program for those who are asymptomatic. In an attempt to provide a perspective on the clinical evaluation of CRC risk, research was reviewed on pathologic features and biomarkers that may be related to CRC causes, especially the genetic basis of CRC susceptibility. The long-term objective of studies on the genetic epidemiology of CRC is primary and secondary prevention through development of targeted management and surveillance recommendations (based on an understanding of CRC causation) that is relevant to hereditary, familial, and sporadic CRC.

Adult↗
PubMed1992

Natural history and age at onset of hereditary breast cancer.

Hereditary breast cancer (HBC) is noteworthy for certain unique facets of its natural history and heterogeneity. Interfamily heterogeneity in age at initial breast cancer diagnosis was investigated in 217 family members with HBC. The mean age at diagnosis was 44.9 years (standard deviation +/- 12.5 years). A one-way analysis of variance in ages at diagnosis, using the family as a random effect factor, indicated that between-family differences were significant (P less than 0.002) and accounted for approximately 18% of the variance in ages at diagnosis. A subset of families with HBC was characterized by an extraordinarily early onset of breast cancer. A knowledge of the natural history of HBC with particular attention to age at onset allows for the development of more accurately targeted surveillance, genetic counselling, and management strategies.

Adult↗
PubMed1992

Homocysteine catabolism: levels of 3 enzymes in cultured human vascular endothelium and their relevance to vascular disease.

Elevated plasma homocysteine enhances the risk of thrombosis and premature arteriosclerosis. We have assessed the activity of the 3 prime enzymes of homocysteine metabolism in cultured human venous endothelial cells, in a study of their possible protective roles. In cells from 4 individuals, cultured in Dulbecco's modified Eagle medium, the mean activity +/- S.D. of cystathionine beta-synthase (nmol of product/h per mg of cell protein, at 37 degrees C) was 3.58 +/- 3.11 at pH 8.6. The assay used was our newly developed amino acid analyser-based procedure. The activity of 5-methyltetrahydrofolate:homocysteine methyltransferase at pH 7.4 was 4.12 +/- 1.25 and betaine:homocysteine methyltransferase (BHMT) was undetectable (< 1.4 nmol/h per mg protein). Cells were also cultured in a medium aimed at stimulating methionine biosynthesis, containing methionine-deficient Dulbecco's modified Eagle medium to which L-homocystine (100 mumol/l) and methylcobalamin (1 mumol/l) had been added. In these cells 5-methyltetrahydrofolate:homocysteine methyltransferase activity increased to 7.95 +/- 1.45, P < 0.001, there was a non-significant decrease in cystathionine beta-synthase activity to 2.16 +/- 1.52 and BHMT activity was still undetectable. These cells were more resistant to in vitro homocysteine-induced detachment than were cells from the same line cultured in Dulbecco's modified Eagle medium alone. Our findings establish that human endothelial cells express 2 of the 3 primary enzymes of homocysteine catabolism. They suggest that persons who are deficient in cystathionine beta-synthase or 5-methyltetrahydrofolate:homocysteine methyltransferase activity may not only develop homocysteinemia, but also have vascular endothelium which is more susceptible to damage by homocysteine than persons with normal enzyme levels.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1992

Gynecologic cancer clues to Lynch syndrome II diagnosis: a family report.

Lynch syndrome II was diagnosed when two sisters manifested early-onset synchronous carcinomas of the ovary and endometrium and a third sister was found to have Duke's A carcinoma of the cecum. A detailed cancer family history indicated paternal transmission of the deleterious genotype. The pattern of carcinoma of the colorectum and extracolonic sites throughout the extended family was then found to be consonant with this hereditary cancer-prone disorder. Lynch syndrome II may be exceedingly difficult to diagnose due to an absence of premonitory clinical signs or biomarkers of genotypic susceptibility. Its recognition is therefore dependent on a detailed cancer family history (all anatomic sites), coupled with knowledge of the pattern of the cancer spectrum, distribution, and natural history, as manifested in this hereditary disorder. We describe the decision logic that was involved in the diagnosis of Lynch syndrome II in this family and indicate the important role of the gynecologists in this process.

Adult↗
PubMed1992

Familial pancreatic cancer: a family study.

The etiology of pancreatic cancer remains elusive. Recent attention has been given to host factors, as evidenced by the recognition of familial aggregations of this disease and its association with several hereditary cancer-prone disorders. We have investigated a remarkable family wherein pancreatic cancer has been documented through three generations, including progeny from two of the progenitor's three marriages. The protocol involved a search for documentation of cancer of all anatomic sites. We did not find any pattern of extrapancreatic cancer occurrences, and age at onset of pancreatic cancer corresponded to population expectations. The recognition of patients at high risk for pancreatic cancer should lead to research into potential environmental factors interacting with host susceptibility for elucidation of etiology and for earlier diagnosis.

Adult↗
PubMed1992

Genetics of Hodgkin's and non-Hodgkin's lymphoma: a review.

Host susceptibility factors have been documented in both HD and NHL wherein a subset of pedigrees provide evidence for an autosomal dominantly inherited factor. Families with both HD and NHL occurring in genetically informative patients provide evidence in support of a possible common pathogenetic pathway for these diseases, as does recent cytogenetic and molecular genetic evidence. AIDS as an unmasking factor for familial predisposition to lymphoma and other cancers may be a powerful tool for identifying lymphoma- and cancer-prone families, but to date has not been employed. In concert with ecogenetic research, it will be important that lymphoma-prone families be subjected to multidisciplined research involving experimental designs developed by geneticists and epidemiologists in concert with pathologists, immunologists, and molecular geneticists.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Natural history of at-risk Lynch syndrome family members with respect to adenomas.

UNLABELLED: Our goal is to determine colon cancer surveillance strategy in patients at risk for Lynch's syndrome. Asymptomatic persons at 50% risk of having Lynch syndrome (age 25-70 years) were enrolled in colonoscopic screening. Those without adenomas were asked to return in one year. Those with adenomas were asked to return in six months because of concern for rapid malignant degeneration. RESULTS: Twenty-five males and thirty females participated. On initial exam, eight of fifty-five patients (14.5%) had adenomas. Logistic regression showed a significant effect of age on the probability of finding adenomas at initial examination (p < 0.02). Followup was available in 27 patients (mean 35.5 months). Kaplan-Meier estimation of time to finding new or previously missed adenomas was 58 months for patients clear on first colonoscopy and 16 months for patients who had adenomas on first exam (p < 0.01). One adenocarcinoma has been found arising in a tubulovillous adenoma. CONCLUSION: The short-term risk of colorectal cancer in Lynch syndrome relatives without adenomas is low, as is the risk in those who have had all visualized adenomas removed.

Adenoma↗
PubMed1992

Hereditary ovarian carcinoma.

No woman is at greater risk for ovarian carcinoma than one who is a member of a hereditary ovarian carcinoma syndrome kindred and whose mother, sister, or daughter has been affected with this disease and with an integrally related hereditary syndrome cancer. This article surveys the existing understanding about hereditary ovarian carcinoma. Emphasis is given to its diagnosis, heterogeneity, interpretation, and the application of this information to improving cancer control.

Disease Susceptibility↗
PubMed1991

Hereditary ovarian cancer. Heterogeneity in age at diagnosis.

An unknown fraction of the ovarian cancer burden occurs in women with a family history indicative of a putative autosomal dominantly inherited cancer susceptibility syndrome. The results from a five-generation, extended, hereditary breast-ovarian cancer kindred are described 10 years after it was initially ascertained. Significantly more cancers were observed in high-risk family members during this decade than were expected (P less than 0.001). The age of ovarian cancer diagnosis was studied in additional ovarian cancer-prone families of three types: site-specific ovarian cancer syndrome, the breast-ovarian cancer syndrome, and Lynch syndrome II. The age of onset in each of the three sets was significantly (P less than 0.001) earlier than the general population mean of 59, and there were significant differences in the age of onset (P = 0.050) among these three cohorts. Ovarian cancer histology was similar to that of patients with negative family histories. There may be clinically significant heterogeneity in the age at diagnosis of ovarian cancer among these ovarian cancer-prone syndromes. This has important implications for understanding its natural history and targeting surveillance-management strategies.

Adult↗
PubMed1991

Variable gastrointestinal and urologic cancers in a Lynch syndrome II kindred.

There are no premonitory physical signs or biomarkers which can identify the genotypic status in Lynch syndrome II. Diagnosis is therefore dependent on the pedigree, with attention to cancer of all anatomic sites, inclusive of those cardinal features of its natural history. The tumor spectrum in Lynch syndrome II has continued to expand commensurately with increasing interest in this disorder. We report a family showing the constant cancer features of this syndrome but, in addition, occurrences of carcinoma of the bile duct, urologic system, and extremely early-onset carcinoma of the pancreas, in patients in the direct genetic lineage who were considered to be candidates for having inherited the deleterious genotype. Diagnosis of Lynch syndrome II is crucial in targeting its surveillance and management.

Colonic Neoplasms↗
PubMed1991

Familial factors and genetic predisposition to cancer: population studies.

Hereditary cancer-prone families provide one of the most powerful and potentially cost-effective models for cancer prevention and control. The public health impact of this problem is enormous when considering that between 5 to 10% of the total cancer burden is hereditary. At least 200 well-defined hereditary cancer syndromes have been identified. In spite of its impact, attention to family history of cancer is often given short shrift and, consequently, clinical expertise in identifying hereditary forms of cancer is exceedingly limited. This may change as a result of recent advances in biomolecular genetics which, predictably, may lead to the cloning of many of these deleterious genes so that diagnostic and even pharmacologic and preventive potential may be achieved. We focus attention on advances which have been made in the recognition of hereditary forms of carcinoma of the breast and colon. Emphasis is given to biomarker research and the recognition of the distinctive natural history of these hereditary cancer syndromes. This will then enable surveillance and management strategies to be more effectively targeted.

Biomarkers, Tumor↗
PubMed1990

Genetic diagnosis of Lynch syndrome II in an extended colorectal cancer-prone family.

Knowledge of colon cancer genetics, with particular attention to precision in hereditary cancer syndrome diagnosis, can often enable highly targeted surveillance and management strategies for patients at high genetic risk. Unfortunately, the patient's family history of cancer is often given minimal attention, and knowledge of hereditary cancer syndromes is frequently limited. Indeed, many physicians still consider familial adenomatous polyposis (FAP) as the only genetic risk factor for colorectal cancer. This concern with FAP was noted in a colorectal cancer-prone kindred which for decades had been thought to manifest that syndrome. However, after meticulous genetic, medical, and pathologic studies, the cardinal phenotypic characteristics of Lynch syndrome II were observed. The potential for cancer control in current and future generations of families like this one clearly mandates the need for computerized registries which could transmit current information about hereditary colon cancer syndrome diagnosis, surveillance, and management.

Adolescent↗
PubMed1990

Phenotypic variation in colorectal adenoma/cancer expression in two families. Hereditary flat adenoma syndrome.

Clinical, pathologic, and genetic studies on two colorectal cancer-prone families have disclosed right-sided colonic flat adenomas and colorectal cancer. Adenomatous polyp counts exceeded those found in hereditary nonpolyposis colorectal cancer (HNPCC) but were fewer than in familial adenomatous polyposis (FAP). Colon cancer occurred at a later age than in HNPCC or FAP and showed right-sided predominance. The older age of patients with colonic cancer, the right-sided predominance of colon cancer, and the paucity of rectal adenomas make FAP unlikely. Vertical transmission of polyps and colon cancer fit the pattern of autosomal dominant inheritance. A characteristic feature of this phenotype is the predominance of flat adenomas. Molecular genetic studies, with careful description of phenotype, should help clarify classification.

Adenocarcinoma↗
PubMed1990

Clinical/genetic features in hereditary breast cancer.

Patients from hereditary breast cancer-prone (HBC) families provide one of the most powerful and potentially cost effective models for cancer prevention and control. Paradoxically, this opportunity is often missed in the clinical practice setting due, in part, to inattention to the family history and/or lack of knowledge about breast cancer genetics. We describe the family study process, wherein documentation of genealogy, medical, and cancer history through pathology verification is attained, often on extended families. The findings of such studies are illustrated by description of nine breast cancer-prone families. These families illustrate several important clinical/genetic features such as age of cancer onset, bilaterality and/or multiple primary cancer occurrences, incomplete gene penetrance, and the identification of putative obligate gene carriers. Interpretation of HBC pedigrees is dependent upon the understanding of these issues, which in turn may enable the physician to more readily identify those individuals who might benefit from highly targeted breast cancer control measures.

Adult↗
PubMed1990

Colorectal adenomas in the Lynch syndromes. Results of a colonoscopy screening program.

Forty-four asymptomatic putative Lynch syndrome patients participated in a colonoscopy screening program. There were 18 men and 26 women; mean age was 44 yr. Thirty percent of Lynch syndrome patients had at least one adenoma; 20% had multiple adenomas. In 18% of the patients, adenomas were discovered proximal to the splenic flexure. In a reference group of 88 age- and sex-matched patients, 11% had adenomas, 4% had multiple adenomas, and 1% had right-sided adenomas. Twenty-one Lynch syndrome patients had follow-up colonoscopies. Of 7 patients with adenomas on initial examinations, 6 had adenomas at follow-up. Of 14 patients with negative initial examination results, 3 had adenomas at follow-up. The prevalence of adenomas in the Lynch syndromes is greater than in an unselected reference group. The adenomas are more proximally located, corresponding to the site of cancer distribution in the Lynch syndromes. A high rate of synchronous and metachronous lesions is found. Our findings support the hypothesis that adenomatous changes are the premalignant lesion in the Lynch syndromes. We also found evidence of heterogeneity among Lynch syndrome families in adenoma incidence.

Adenoma↗
PubMed1990

The Lynch syndrome II and urological malignancies.

The role of host factors in the etiology of carcinoma of the ureter has received only limited attention. We describe 4 Lynch syndrome II kindreds in which carcinoma of the ureter, as well as other forms of urological cancer, have occurred either in obligate gene carriers and/or in association with multiple primary cancers that are integral to this autosomal dominantly inherited disorder. These new findings are in accord with increasing recognition of tumor heterogeneity in the Lynch syndrome II, which currently, in addition to an excess of proximal colonic cancer as well as carcinoma of the endometrium, ovary and small bowel, also may include carcinoma of the ureter as well as other urological forms of cancer as integral lesions in subsets of these families. These observations have important ramifications for better understanding of the etiology, pathogenesis and control of urological cancer in this disorder.

Adult↗