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H T Lynch

Publications and source records attributed to H T Lynch.

At least 19 recordsLinked to original sources
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

Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers.

BACKGROUND: Mutations of the tumor suppressor gene p53 have been identified in breast cancer cell lines, and some breast carcinomas are detectable by immunohistochemical assay because of p53 protein accumulation. PURPOSE: This study was designed to determine whether p53 protein accumulation in breast cancers correlates with p53 gene mutation, with survival, and with five pathobiologic factors associated with prognosis. METHODS: IgG1 monoclonal antibody to human p53 protein (PAb 1801) and immunohistochemical methods were used to detect p53 protein accumulation in archival formalin-fixed, paraffin-embedded, randomly selected carcinomas. We studied 295 invasive ductal carcinomas from the Massachusetts General Hospital; 151 were determined to be sporadic (not hereditary). We also studied 97 invasive ductal carcinomas--21 sporadic and 76 familial (hereditary)--from Creighton University. In addition, we examined 31 archival in situ carcinomas, 15 snap-frozen invasive ductal carcinomas, primary cell cultures from three benign breast tissue samples, and breast carcinoma cell lines MDA-MB-231 and MDA-MB-468. RESULTS: Nuclear p53 protein was observed in 16% of the 31 in situ carcinomas, 22% of the 172 sporadic carcinomas, 34% of the 50 tumors from patients with familial breast cancer, 52% of the 23 tumors from patients with the familial breast and ovarian cancer syndrome, and all three tumors from two patients with the Li-Fraumeni syndrome. There was complete concordance between p53 gene mutation and p53 protein accumulation in the 15 snap-frozen carcinomas and in both breast carcinoma cell lines. Statistically significant associations of p53 protein accumulation with estrogen receptor negativity and with high nuclear grade were found. There were statistically significant associations, independent of other prognostic factors, between p53 protein accumulation and metastasis-free and overall survival, for randomly accrued and for both sporadic and familial tumors. CONCLUSIONS: Immunohistochemically detected p53 protein accumulation was an independent marker of shortened survival and was seen more often in familial than in sporadic carcinomas. Our findings also suggest a correlation between p53 protein accumulation and p53 gene mutation.

Age Factors↗
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

Hereditary flat adenoma syndrome: a variant of familial adenomatous polyposis?

We describe the clinical and pathologic features in four extended kindreds that are consistent with the hereditary flat adenoma syndrome (HFAS). This colon cancer susceptibility disorder is believed to be inherited as an autosomal dominant. The principal phenotypic marker is multiple colonic adenomas (usually less than 100), with a tendency for proximal location. The majority of these adenomas are flat or slightly raised and plaquelike, as opposed to polypoid. Colon cancers have typically developed in middle age and show no unusual histologic features. There are a variety of extracolonic manifestations, including adenomas and carcinomas of the small bowel and fundic gland polyps. The HFAS is contrasted with hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis (FAP) and shown to be distinct from both in the numbers and distribution of colonic adenomas and the typical age of cancer diagnosis. The clinical implications of these findings are discussed. Given its linkage to the FAP locus on 5q and the phenotypic parallels between HFAS and FAP, we conclude that HFAS is a variant of FAP.

Adenoma↗
PubMed1992

Epidemiologic characteristics of the flat adenoma of Muto. A prospective study.

UNLABELLED: The flat adenoma is an endoscopically visible lesion that histologically consists of adenomatous change near the luminal surface of colonic tubules. We have described three families with hereditary colon cancer with later age of onset than familial adenomatous polyposis (FAP) and with multiple proximal colonic flat adenomas. These families have been linked to the FAP locus on chromosome 5. Our aim was to determine whether the flat adenoma is pathognomonic of this hereditary flat adenoma syndrome (HFAS) or merely an atypical or early tubular adenoma with occurrence in patients other than those from colon cancer-prone families. METHODS: We prospectively examined a population referred for colonoscopy within a one-year period. During colonoscopy, flat adenomas were specifically sought and all lesions were removed endoscopically and evaluated histologically. Members of known hereditary colon cancer families were excluded. RESULTS: One hundred forty-eight patients underwent colonoscopy (64 men and 84 women). Median age was 61 years. Fifty-seven patients had 157 polyps. One hundred thirty-six polyps were reviewed histologically. Thirty-five (23.6 percent) of the referred patients had adenomas, of whom twelve patients had only flat adenomas while six had both flat and other adenomas (18 = 12 percent of 148). The associations between flat adenoma occurrence and various predictors (sex, race, prior colonic neoplasms, family history of cancer, synchronous adenomas) were similar to those seen with other adenomas. Flat adenomas were found in nearly equal proportions of patients under or over age 61 years (11 percent and 13 percent, respectively). Other adenomas were significantly more common in the older group (6 percent vs. 25 percent; P less than 0.002 by Fisher's exact test). CONCLUSION: In a referral practice, the flat adenoma has the same prevalence and associated risk factors as other adenomas, except for younger age of onset. Our data suggest that the flat adenoma represents an early stage of adenoma development that is manifested in a subset of patients from the general population and that, as an isolated event, does not provide a marker for a hereditary colon cancer-prone syndrome.

Adenoma↗
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

Hereditary ovarian cancer: a clinicopathological study.

Hereditary ovarian cancer (HOC) is rare and little recognized. Over the years, we have identified 37 HOC patients from HOC syndrome kindreds with documented cancers of ovary, breast, colon, or endometrium in two or more first-degree relatives. The age and clinical stage at diagnosis and overall 5-year survival of HOC patients were compared with those of ovarian cancers in the unselected patients. The gross and microscopic features of the tumors are compared with a set of 34 consecutively chosen ovarian cancer cases with documented negative family histories. The mean age of HOC patients at diagnosis was significantly lower (50.2 years) than that of the unselected control population (59 years) (p less than 0.001). Detailed pedigree analysis breaks down the HOC group into (a) site-specific ovarian cancer, 5 cases, 56.4 years mean age; (b) breast-ovarian cancer syndrome, 28 cases, 50.46 years mean age; and (c) Lynch syndrome II (colon/endometrial cancer), 4 cases, mean age 41 years. The age differences were statistically significant (p = 0.050). The most prevalent International Federation of Gynecology and Obstetrics clinical stage at diagnosis of HOC (stage III) was the same as for the control group. Histologically, all (100%) HOC tumors were surface epithelial cancers with predominance of serous papillary type moderate to high grade (89 versus 71% in control, p = 0.07). No other pathologic features appeared to be significant. In conclusion, HOC is a serous papillary tumor and characterized by early age of onset and excess of breast/ovary/colon-endometrial cancers in first-degree relatives of patients with specific HOC syndromes.

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↗
PubMed1992

Nucleotide sequence polymorphism in a hotspot mutation region of the p53 gene.

By screening for mutations in the p53 coding sequence by means of single-strand conformation polymorphism (SSCP) in a series of breast tumors we detected a novel polymorphism. This change in the SSCP pattern was detected in 6.2% of the tumor DNAs analysed and implied an A to G substitution at the last base of codon 213, thus representing a neutral change. First suspecting a somatic mutation we confirmed its presence in matched sets of DNAs from normal tissues. Extending our study to a series of 60 ovarian carcinomas and 70 healthy blood donors we noticed that this polymorphism represented only 3% and 2.6% respectively. We wondered if the difference in frequency in the breast cancer population might not be related to familial breast cancer and analysed 26 DNAs from patients showing predisposition to the disease. Two patients presented this polymorphism and one corresponding kindred was analysed, revealing a mendelian mode of transmission but no correlation with the cancer phenotype.

Base Sequence↗
PubMed1991

Familial breast-ovarian cancer locus on chromosome 17q12-q23.

Familial breast cancer has been linked to the D17S74 locus on chromosome 17q. To confirm this finding and to investigate whether ovarian cancer is also linked to this locus, five large families with a hereditary predisposition to cancer of the breast and ovary were investigated. Three families were positive for linkage. For the largest family the lod score was 2.72. These findings suggest that the chromosomal region 17q12-q23, previously shown to contain a gene for early-onset breast cancer, is also associated with a proportion of hereditary ovarian cancers.

Adult↗
PubMed1991

A follow-up study of colonic epithelial proliferation as a biomarker ina Native-American family with hereditary nonpolyposis colon cancer.

A 7-year follow-up study of colonic mucosa proliferation markers was conducted on members of a Native-American family with hereditary nonpolyposis colon cancer. Reproducibility of a tritiated thymidine autoradiography assay for labeling indexes during this 7-year biologically significant time frame was established. A good correlation between tritiated thymidine and a newer technique, bromodeoxyuridine immunoperoxidase staining, was seen. No confounding effect could be attributed to standard colon preparation. On average, both baseline and follow-up values for epithelial proliferation were within the accepted normal range. The presence of essentially normal labeling indexes among colon cancer patients and their high-risk offspring suggests the possibility of the significant effect of dietary factors in reducing proliferation. Such factors may account for the low risk of colon cancer that characterizes the Native-American population in the American Southwest.

Adult↗
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↗