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H T Lynch

Publications and source records attributed to H T Lynch.

At least 109 records · Page 6Linked to original sources
PubMed1997

A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17.

Although more than 100 different BRCA1 germ-line mutations have already been identified in breast and/or ovarian cancer families, we report for the first time a deleterious genomic rearrangement in BRCA1. A 1-kb deletion comprising exon 17 was found in a large breast and ovarian cancer family, leading to a frameshift in the mutant mRNA due to the absence of exon 17. This deletion is probably the result of a recombination between two closely related Alu sequences. It was not detected by conventional PCR-based methods involving the genomic screening of the 22 coding exons or reverse transcription-PCR because the transcript without exon 17 is unstable in lymphoblastoid cell lines. Therefore, rearrangements in the BRCA1 gene should be sought in breast/ovarian cancer families in which no mutations have been found by PCR-based methods in the coding region or in the splice sites.

BRCA1 Protein↗
PubMed1997

Automated detection of hereditary syndromes using data mining.

Computer-based data mining methodology applied to family history clinical data can algorithmically create highly accurate, clinically oriented hereditary disease pattern recognizers. For the example of hereditary colon cancer, the data mining's selection of relevant factors to assess for hereditary colon cancer was statistically significant (P < 0.05). All final recognizer-formulated patterns of hereditary colon cancer were independently confirmed by a clinical expert. Applied to previously analyzed family histories, the recognizer identified the definitive hereditary histories, correctly responded negatively to the putative hereditary histories, and correctly responded negatively to empirically elevated colon cancer risk situations. This capability facilitates patient selection for DNA studies in search of gene mutations. When genetic mutations are included as parameters in a patient database for a genetic disease, the process yields an expert system which characterizes variations in clinical disease presentations in terms of genetic mutations. Such information can greatly improve the efficiency of gene testing.

Adult↗
PubMed1997

An update of HNPCC (Lynch syndrome).

Genetic epidemiology studies of colorectal cancer (CRC) can identify persons who are at inordinately high risk and who thereby might benefit from targeted early detection and primary prevention programs, inclusive of prophylactic surgery in selected cases. The discipline of molecular genetics has identified germline mutations that include APC in familial adenomatous polyposis (FAP) and mutator genes, namely MSH2, MLH1, PMS1, and PMS2 in hereditary nonpolyposis colorectal cancer (HNPCC). These discoveries have significantly enhanced our ability to identify individuals whose cancer destiny can literally be determined at birth. This review updates HNPCC's differential diagnosis, heterogeneity, tumor spectrum, newly found evidence of accelerated colonic adenoma to CRC, survival advantage, and currently available surveillance and management programs. Emphasis has been on how knowledge of the genetics and natural history of HNPCC can be used effectively to promote early diagnosis or prevention of cancer.

Adenomatous Polyposis Coli↗
PubMed1997

The influence of psychological distress on use of genetic testing for cancer risk.

The recent identification of BRCA1, a breast cancer susceptibility gene, offers an unprecedented opportunity for high-risk individuals to learn whether they are genetically predisposed to develop breast or ovarian cancer. This study examined the relationships between psychological distress and use of BRCA1 testing by 149 high-risk individuals from hereditary cancer families. After a baseline assessment of demographics, objective risk, cancer-specific distress, and global distress (depressive symptoms), study participants were offered the opportunity to receive genetic counseling and to learn whether they carry a mutation in the BRCA1 gene. Overall, 58% of study participants requested BRCA1 test results, and 42% declined to learn their genetic status. After controlling for demographic factors and risk status, cancer-specific distress was significantly and positively related to BRCA1 test use, whereas global distress was unrelated to test use.

Adult↗
PubMed1997

Familial neuroendocrine tumors as a model of hereditary cancer.

Familial neuroendocrine tumors are reviewed. The most dramatic advances have been in the application of molecular genetic techniques to define the affected genes and to develop predictive testing for patients with multiple endocrine neoplasia syndromes. Germline mutations at specific loci of the RET proto-oncogene have been demonstrated in patients with multiple endocrine neoplasia types IIA, IIB, and familial medullary thyroid carcinoma not associated with multiple endocrine neoplasia. This has led to direct DNA testing for these mutations in patients at risk for these syndromes. The approach to predictive testing, diagnosis, and early treatment of these patients is discussed as a model for the approach to hereditary cancers. Linkage testing with DNA markers is still required for patients with multiple endocrine neoplasia type I because the responsible gene has not yet been isolated. Efforts to clarify the etiologies of other familial neuroendocrine tumors not associated with multiple endocrine neoplasia continue. Familial pheochromocytoma, neuroblastoma, and carcinoid also are reviewed. The use of molecular genetic techniques as a powerful tool for the early identification and treatment of susceptible individuals is emphasized.

Algorithms↗
PubMed1997

Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma.

A first-degree relative with pancreatic cancer is found in 5% to 10% of patients with pancreatic carcinomas, suggesting an inherited predisposition for this neoplasm. The recently identified DPC4 tumor suppressor gene is a strong candidate for the gene responsible for the familial form of pancreatic carcinoma. DPC4 was identified in a consensus area of homozygous deletion in pancreatic carcinomas, and it is biallelically inactivated in approximately 50% of sporadic pancreatic carcinomas. The coding sequence of this gene is 1660 nucleotides in length, covering 11 exons. We describe optimized primers and conditions used in polymerase chain reaction and cycle sequencing of the entire DPC4 coding sequence of 25 individuals (eight with pancreatic carcinoma) from 11 kindreds with a familial aggregation of pancreatic carcinoma. No mutations in the coding sequences of the DPC4 gene were found; hence, it appears that germline mutations in DPC4 cannot account for many of the familial aggregations of pancreatic carcinoma.

Carcinoma↗
PubMed1997

Mutations in BRCA1 and BRCA2 in breast cancer families: are there more breast cancer-susceptibility genes?

To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers were thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene.

BRCA1 Protein↗
PubMed1997

Using data mining to characterize DNA mutations by patient clinical features.

In most hereditary cancer syndromes, finding a correspondence between various genetic mutations within a gene (genotype) and a patient's clinical cancer history (phenotype) is challenging; to date there are few clinically meaningful correlations between specific DNA intragenic mutations and corresponding cancer types. To define possible genotype and phenotype correlations, we evaluated the application of data mining methodology whereby the clinical cancer histories of gene-mutation-positive patients were used to define valid or "true" patterns for a specific DNA intragenic mutation. The clinical histories of patients with their corresponding detailed attributes without the same oncologic intragenic mutation were labeled incorrect or "false" patterns. The results of data mining technology yielded characterizing rules for the true cases that constituted clinical features which predicted the intragenic mutation. Some of the initial results derived correlations already independently known in the literature, adding to the confidence of using this methodological approach.

Age of Onset↗
PubMed1997

Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications.

We estimate that 5-10% of virtually all forms of cancer are due to a primary hereditary etiology. However, a hereditary cancer diagnosis is often missed because the family history of cancer is given short shrift in medical practice. Hereditary nonpolyposis colorectal cancer (HNPCC) certainly fits this estimate, although some studies suggest that a minimum of 2% with a range as high as 10% of the total colorectal cancer burden is due to HNPCC. Mutations in one of the four mismatch repair genes, i.e., hMSH2, hMLH1, hPMS1, and hPMS2, account for about 70% of HNPCC kindreds. Other germ-line mutations are likely to be identified to account for the remainder of HNPCC patients. By far the most common HNPCC mutations involve hMSH2 and hMLH1, with hPMS1 and hPMS2 accounting for only about 3% of such families. Prior to these molecular genetic discoveries, the genetic counselor could only provide the patient with an estimate of a 50% likelihood of manifesting HNPCC based on the counselee having one or more first-degree relatives manifesting syndrome cancers in their direct genetic lineage. Because DNA testing has become available in families with known mutations, we have provided pretest group education in the form of a family information service with intensive education about the natural history, genetic risk, surveillance, and options for management of HNPCC, as well as discussion of the potential for fear, anxiety, apprehension, and insurance or employer discrimination that might impact on this DNA testing. Following informed consent, these relatives were then counseled on a one-to-one basis. Using DNA-based genetic counseling involving hMSH2 or hMLH1, we have provided this service to four extended HNPCC kindreds. Details of this genetic counseling experience on these four kindreds will be discussed.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Autonomy of the epithelial phenotype in human ovarian surface epithelium: changes with neoplastic progression and with a family history of ovarian cancer.

Epithelial ovarian carcinomas originate in the ovarian surface epithelium (OSE). In culture, OSE undergoes epithelio-mesenchymal conversion, an event mimicking a wound response, while ovarian carcinomas retain complex epithelial characteristics. To define the onset of this increased epithelial autonomy in ovarian neoplastic progression, we examined mesenchymal conversion in OSE from 25 women with no family histories (NFH-OSE) and 13 women with family histories (FH-OSE) of breast/ovarian cancer (including 8 with mutated BRCA1 or 17q linkage) and in 8 ovarian cancer lines. After 3-6 passages in monolayer culture, most NFH-OSE exhibited reduced keratin expression and high collagen type III expression. In contrast, keratin remained high but collagen expression was lower in p. 3-6 FH-OSE. This difference was lost in SV40-transformed lines, which all resembled FH-OSE. Most carcinoma lines remained epithelial and did not undergo mesenchymal conversion. In 3-dimensional (3-D) sponge culture, NFH-OSE cells dispersed and secreted abundant extracellular matrix (ECM). FH-OSE remained epithelial and did not secrete ECM. ECM production was also reduced in SV40-transformed lines. Carcinoma lines in 3-D formed epithelial cysts, aggregates and papillae and lacked ECM. Sponge contraction (a mesenchymal characteristic) was greater in NFH-OSE than in FH-OSE both before and after SV40 transformation and was absent in the cancer lines. Our results suggest that increased autonomy of epithelial characteristics is an early indicator of ovarian neoplastic progression and that phenotypic changes indicative of such autonomy are found already in overtly normal OSE from women with histories of familial breast/ovarian cancer.

Biomarkers, Tumor↗
PubMed1996

Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies.

BACKGROUND: The occurrence of approximately 5% of common epithelial malignant tumors of the ovary can be traced to inheritance of risk. One prophylactic strategy to decrease the probability of development of disease in individuals within families where this mendelian-dominant pattern of occurrence is apparent is to remove the ovaries of individuals at risk for ovarian cancer. The procedure, when done for this purpose, is recommended soon after completion of childbearing. PURPOSE: Our goal was to compare the histologic features of the ovaries of women at increased risk for ovarian cancer to those at no known increased risk for the disease. METHODS: Ovaries removed for prophylaxis from 20 women considered to be at increased risk for developing ovarian cancer were examined histologically. During the course of this work, it seemed apparent that these ovaries contained numerous atypical features compared with the expected appearance of normal ovaries. Hence, we expanded the study to include a control group whose ovaries were removed for reasons unrelated to cancer. The study, therefore, was not blinded. The increased risk in the cancer-prone individuals was determined by family history, specifically the presence of at least one first-degree relative and one second-degree relative with ovarian and/or breast cancer and positive linkage or mutational analysis of BRCA1 in some. The difference in mean ages of patients in the control and high-risk groups was not statistically significant. The difference among both groups with respect to the number of atypical features as well as the intensity of those features was ascertained by computing probabilities using Fisher's exact test (two-sided) for rows x columns contingency tables. RESULTS: Two unanticipated microscopic or near-microscopic malignant neoplasms and other benign and borderline tumors were discovered in the ovaries of the high-risk individuals. Of substantial interest was the finding that among the ovaries of high-risk women, 85% presented two or more and 75% presented three or more of the following histologic features: surface epithelial pseudostratification; surface papillomatosis; deep cortical invaginations of the surface epithelium, frequently with multiple papillary projections within small cystic spaces (microscopic papillary cystadenomas); epithelial inclusion cysts, frequently with epithelial hyperplasia and papillary formations; cortical stromal hyperplasia and hyperthecosis; increased follicular activity; corpus luteum hyperplasia; or hilar cell hyperplasia. Two or more or three or more such changes were observed in a lesser percentage (30% or 10%, respectively) of ovaries obtained from the control individuals, with a statistically significant difference (P = .001 or P = .00007, respectively), particularly considering that a detailed determination of a family history of cancer in the control group was not possible. CONCLUSIONS: The frequency of these changes in the high-risk ovaries compared with control ovaries suggests a characteristic histologic preneoplastic phenotype defined by an increased frequency and intensity of the above-described histologic features in the high-risk ovaries. Limited access to numerous small (stage I) ovarian cancers or cancer-prone ovaries by any one pathologist may explain the failure to identify the phenotype in the past. IMPLICATIONS: We suggest that the ovaries removed from ovarian cancer-prone individuals as a preventative measure should be thoroughly examined histologically to identify or rule out microscopic or near-microscopic invasive neoplasms.

Adult↗
PubMed1996

Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.

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.

Adenocarcinoma↗
PubMed1996

Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1.

BACKGROUND: We tested the hypothesis that ovarian cancers associated with germ-line mutations of BRCA1 have distinct clinical and pathological features as compared with sporadic ovarian cancers. METHODS: We reviewed clinical and pathological data on patients with primary epithelial ovarian cancer found to have germ-line mutations of BRCA1. Survival among patients with advanced-stage cancer and such mutations was compared with that in control patients matched stage, grade, and histologic subtype of the tumors. A combination of single-strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice-donor and splice-acceptor regions of BRCA1 for mutations in pathological specimens. Alternatively, some patients were known to be obligate carriers of the mutant BRCA1 gene because of their parental relationships with documented mutant-gene carriers. RESULTS: We identified 53 patients with germ-line mutations of BRCA1. The average age at diagnosis was 48 years (range, 28 to 78). Histologic examination in 43 of the 53 patients showed serous adenocarcinoma. Thirty-seven tumors were of grade 3, 11 were of grade 2, 2 were of grade 1, and 3 were of low malignant potential. In 38 patients, the tumors were of stage III; 9 patients (including those with tumors of low malignant potential) had stage I disease, 5 had stage IV, and 1 had stage II. As of June 1996, with a median follow-up among survivors of 71 months from diagnosis, 20 patients had died of ovarian cancer, 27 had no evidence of the disease, 4 were alive with the disease, and 2 had died of other diseases. Actuarial median survival for the 43 patients with and advanced-stage disease was 77 months, as compared with 29 months for the matched controls (P<0.001). CONCLUSIONS: As compared with sporadic ovarian cancers, cancers associated with BRCA1 mutation appear to have a significantly more favorable clinical course.

Actuarial Analysis↗
PubMed1996

Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Aldred Warthin's description of Family G a century ago. The phenotype features an excess of early onset colorectal carcinoma (CRC) with a propensity to involve the proximal colon, and a variety of extracolonic cancers, particularly carcinoma of the endometrium, ovary, stomach, small bowel, ureter, and renal pelvis. The recent discovery that HNPCC patients carry germline mutations in DNA mismatch repair genes has engendered great interest in the syndrome. METHODS: This is a description of HNPCC based on the authors' experience with more than 170 families and a review of the world literature. RESULTS: This review describes the genotypic and phenotypic features of HNPCC. The distinctive natural history of the syndrome is discussed in light of the recent discovery that ineffective DNA mismatch repair is the principal abnormality in affected individuals. CONCLUSIONS: Clinical and molecular genetic knowledge about HNPCC is now available to physicians, and should enable them to provide highly targeted surveillance and management for patients with a high cancer risk. Genetic counseling can prove lifesaving. The study of HNPCC will likely contribute to knowledge about the causes and control of common forms of cancer in the general population.

Adult↗
PubMed1996

Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome.

BACKGROUND: The hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome is an autosomal dominant genetic disorder caused by the inheritance of a mutation in one of a family of genes encoding DNA mismatch repair (MMR) proteins. HNPCC manifests as genetic instability in linked tumors. Clinically, the syndrome is characterized by early onset malignancies, primarily of the colon and endometrium, with an increased incidence of tumors at other gastrointestinal sites, upper urologic tract, ovary, and pancreas as well. However, the inclusion of breast cancer as an integral tumor of this syndrome is controversial. METHODS: Mutation screening of MMR genes was carried out by single strand conformation polymorphism (SSCP) and sequencing analyses of genomic DNA prepared from normal lymphocytes. Expression analysis was performed by SSCP. Sequence analyses of cDNA was prepared from breast tumor tissue and normal lymphocytes. Genetic instability was assessed by comparing the electrophoretic mobility of polymerase chain reaction (PCR) products using multiple microsatellite markers. RESULTS: A 4-bp frameshift mutation in the hMLH1 gene was found to segregate with disease in the germlines of the affected members of a large kindred HNPCC. Expression of only the mutant allele was observed in the breast cancer tissue of one family member, however both alleles were observed in her normal tissue. This breast cancer exhibited widespread microsatellite instability, as did breast cancers obtained from several other HNPCC kindreds. CONCLUSIONS: These data indicate that breast cancer may result from the inheritance of a mutant MMR gene, and that breast cancer may occur as an integral tumor in the HNPCC syndrome.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch Syndrome).

Hereditary non-polyposis colorectal cancer (HNPCC) predisposes to cancers of the colon, endometrium and several other extra-colonic sites in the absence of premonitory physical stigmata (Muir-Torre syndrome excepted). Discovery of the several DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2) holds the potential for determining the cancer destiny of patients, theoretically in utero. Pre-symptomatic DNA testing is now possible in patients from HNPCC families and will be clinically available once inexpensive and simple tests for these germ-line mutations have been effected. Genetic counseling will be mandatory, given the myriad socio-psychological, insurance, and potentially other personal issues which may impact this knowledge. New findings in the pathology of HNPCC, particularly an increased frequency of interval cancers and the likely accelerated rate of the adenoma to cancer sequence, indicate the need for more frequent colonoscopic surveillance with an option for prophylactic subtotal colectomy in germ-line-positive individuals.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1996

Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage.

BACKGROUND: The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1-related and BRCA2-related hereditary breast cancer (HBC) and non-HBC. METHODS: On the basis of linkage to chromosomes 17q or 13q and/or the presence of ovarian and male breast cancer, HBC families were classified as either "BRCA1-related" (26 families, 90 breast cancer pathology cases) or "Other" (26 families, 85 cases), in which most BRCA2 cases were likely to reside. Cases were compared with 187 predominantly non-HBC cases. Tumors were assessed for histologic type, grade, and ploidy and S-phase fraction by quantitative DNA flow cytometry. Clinical presentation and available follow-up data were obtained. RESULTS: BRCA1-related and Other HBC patients each presented at lower stage (P = 0.003) and earlier age than non-HBC patients (mean, 42.8 years and 47.1 years vs. 62.9 years, P = 0.0001). Compared with non-HBC, invasive BRCA1-related HBC had a lower diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA index (1.53 vs. 1.73; P= 0.002), and strikingly higher proliferation rates (mitotic grade 3; odds ratio [OR]= 4.42; P= 0.001; aneuploid mean S-phase fraction 16.5% vs. 9.3%, P < 0.0001). Other HBC patients, including patients in two BRCA2- linked families, had more tubular-lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were independent of age. A nonsignificant trend toward better crude survival in both HBC groups was age- and stage-dependent. Compared with Other HBC, BRCA1-related HBC patients had fewer recurrences (P = 0.013), a trend toward lower specific death rates, and fared no worse than breast cancer patients at large. Other HBC patients, despite neutral prognostic indicators, fared worse. CONCLUSIONS: BRCA1-related HBCs are more frequently aneuploid and have higher tumor cell proliferation rates compared with Other HBC. Despite these adverse prognostic features, BRCA1-related HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the "Other" HBC group may be associated with BRCA2 linkage.

Adult↗