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Biomedical subjects

H T Lynch

Publications and source records attributed to H T Lynch.

At least 91 records · Page 5Linked to original sources
PubMed1998

Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes.

BACKGROUND: Smoking has carcinogenic effects, and possibly antiestrogenic effects as well, but it has not been found to be a risk factor for breast cancer in women in the general population. However, hereditary breast cancer is primarily a disease of premenopausal women, and interactions between genes and hormonal and environmental risk factors may be particularly important in this subgroup. METHODS: We conducted a matched case-control study of breast cancer among women who have been identified to be carriers of a deleterious mutation in either the BRCA1 or the BRCA2 gene. These women were assessed for genetic risk at one of several genetic counseling programs for cancer in North America. Information about lifetime smoking history was derived from a questionnaire routinely administered to women who were found to carry a mutation in either gene. Smoking histories of case subjects with breast cancer and age-matched healthy control subjects were compared. Odds ratios for developing breast cancer were determined for smokers versus nonsmokers by use of conditional logistic regression for matched sets after adjustment for other known risk factors. RESULTS: Subjects with BRCA1 or BRCA2 gene mutations and breast cancer were significantly more likely to have been nonsmokers than were subjects with mutations and without breast cancer (two-sided P = .007). In a multivariate analysis, subjects with BRCA1 or BRCA2 mutations who had smoked cigarettes for more than 4 pack-years (i.e., number of packs per day multiplied by the number of years of smoking) were found to have a lower breast cancer risk (odds ratio = 0.46, 95% confidence interval = 0.27-0.80; two-sided P = .006) than subjects with mutations who never smoked. CONCLUSIONS: This study raises the possibility that smoking reduces the risk of breast cancer in carriers of BRCA1 or BRCA2 gene mutations.

Breast Neoplasms↗
PubMed1998

Novel germline p16(INK4) allele (Asp145Cys) in a family with multiple pancreatic carcinomas. Mutations in brief no. 148. Online.

As part of a search for causative genes of familial pancreatic carcinoma, the p16 genes were sequenced in members of 21 families with a phenotype of familial pancreatic carcinoma (2 or more first degree relatives affected). One family was found in which members carried a novel p16 allele with a G to T transversion at position 451, creating a missense amino acid change at codon 145 (Asp to Cys) and possibly disrupting the donor splice site of the exon 2/3 boundary. This coding change is not a known polymorphism, and occurs at a codon position in which another missese/splicing change has been shown to be linked to familial melanoma/pancreas cancer.

Alleles↗
PubMed1998

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

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

Adaptor Proteins, Signal Transducing↗
PubMed1998

Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences.

A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P < 0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germline hMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 and P = 0.0001, respectively). Frameshift mutation of the transforming growth factor beta type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2 mutation than in those with germline bMLH1 mutation (100% (8/8) versus 40% (2/5), P = 0.04), and mutation of the Bax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras, E2F-4, and Bax genes), but not others (eg, transforming growth factor beta type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers.

Adaptor Proteins, Signal Transducing↗
PubMed1998

An update on Lynch syndrome.

Recent advances in hereditary nonpolyposis colorectal cancer (HNPCC) have been made based on the discovery early in this decade that germline mutations in genes responsible for repair of DNA mismatches formed the molecular basis for the syndrome. Several studies during the past year described the prevalence of germline mutations in those deemed at risk for HNPCC and helped define who should be tested for such mutations. Investigators are also beginning to make connections between genotype and phenotype; it appears that certain mutations are more likely than others to generate a broad spectrum of extracolonic tumors. Carcinogenetic mechanisms in HNPCC also received attention; evidence continues to accumulate that the critical somatic mutations driving malignant transformation in HNPCC (and in sporadic colorectal cancer with microsatellite instability) are different from the critical mutations seen in most colon cancers. Finally, several contributions dealt with the complicated question of how to manage germline carriers and affected individuals.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1998

Genetics of colonic cancer.

Research in hereditary forms of colorectal cancer (CRC) has increased almost logarithmically thanks in a major way to momentous discoveries in molecular genetics during the past decade. Between 10 and 20% of the total CRC burden is due to Mendelian-inherited CRC syndromes. The paradigm for hereditary CRC is familial adenomatous polyposis (FAP), wherein the APC germ-line mutation has been identified. This has contributed to the elucidation of genomic and clinical heterogeneity within the syndrome, wherein an attenuated form of FAP has been identified as a result of intragenic mutations within this large APC gene. The most common form of hereditary CRC is hereditary nonpolyposis colorectal cancer (HNPCC). Several mutator genes, namely hMSH2, hMLH1, hPMS1, hPMS2 and, more recently, hMSH6/GTBP, have been identified. These molecular genetic discoveries are providing new insights into the pathogenesis of CRC. Individuals within these kindreds who are harbingers of these germ-line mutations will benefit from screening and, one day, chemoprevention.

Adenomatous Polyposis Coli↗
PubMed1998

What you don't know can hurt you: adverse psychologic effects in members of BRCA1-linked and BRCA2-linked families who decline genetic testing.

PURPOSE: To identify members of hereditary breast and ovarian cancer families who are at risk for adverse psychologic effects of genetic testing. PATIENTS AND METHODS: A prospective cohort study with baseline (preeducation) assessments of predictor variables (ie, sociodemographic factors, cancer history, and cancer-related stress symptoms) was performed. The primary outcome variable (presence of depressive symptoms) was assessed at baseline and at 1- and 6-month follow-up evaluations. Participants were 327 adult male and female members of BRCA1- and BRCA2-linked hereditary breast and ovarian cancer families, who were identified as carriers, noncarriers, or decliners of genetic testing. RESULTS: The presence of cancer-related stress symptoms at baseline was strongly predictive of the onset of depressive symptoms in family members who were invited but declined testing. Among persons who reported high baseline levels of stress, depression rates in decliners increased from 26% at baseline to 47% at 1-month follow-up; depression rates in noncarriers decreased and in carriers showed no change (odds ratio [OR] for decliners v noncarriers=8.0; 95% confidence interval [CI], 1.9 to 33.5; P=.0004). These significant differences in depression rates were still evident at the 6-month follow-up evaluation (P=.04). CONCLUSION: In BRCA1/2-linked families, persons with high levels of cancer-related stress who decline genetic testing may be at risk for depression. These family members may benefit from education and counseling, even if they ultimately elect not to be tested, and should be monitored for potential adverse effects.

Adolescent↗
PubMed1998

Genetics and ovarian carcinoma.

Ovarian cancer is a disease that will affect approximately 1% of American women during their lifetime, and contributes to more than 14,000 deaths annually. If not detected early, this disease has a 5-year survival rate of less than 20%. Ovarian cancer develops predominantly from the malignant transformation of a single cell type, the surface epithelium. Although the biological mechanisms of transformation remain unclear, it is probably a multistep process requiring an accumulation of genetic lesions in a number of different gene classes. Several proto-oncogenes, such as AKT2 and Ki-RAS, are activated during ovarian cancer development, with putative oncogene-containing chromosomal regions showing imbalances and DNA amplifications. A number of chromosomal regions are also lost in ovarian tumors, indicating that the inactivation of tumor suppressor genes, such as TP53, may also contribute to cancer development. An important recent advancement in the field of ovarian cancer research is the identification of the breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2. Mutations in these two tumor suppressor genes are responsible for the majority of heritable forms of epithelial ovarian cancers. A second class of genes involved in DNA mismatch repair (MMR) are responsible for most cases of hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC or Lynch II cancer syndrome patients are also at an increased risk for developing ovarian cancer. Individuals in cancer-prone kindreds are currently being screened for germline mutations in BRCA1, BRCA2, and several MMR genes (eg, MSH2, MLH1), and mutant allele carriers counseled for cancer risks. Issues related to counseling and management of women at high risk for developing ovarian cancer are discussed. Although BRCA1, BRCA2, and a number of MMR genes have been identified, many more genes involved in gynecologic malignancies remain to be discovered and the clinical significance of the cancer genes already known is still in its infancy.

BRCA1 Protein↗
PubMed1997

Cancer genetics in the new era of molecular biology.

The role of primary genetic factors in the etiology of cancer has become of intense interest to the research and clinical community. This interest has been heightened by recent discoveries that germ-line mutations such as BRCA1 and BRCA2 in hereditary breast cancer are responsible for an increasing percentage of common solid tumors. A potpourri of proto-oncogenes and tumor-suppressor genes has been identified in hereditary as well as certain common sporadic and rare cancer types, and new cancer genes will likely be discovered every month to account for the 5 to 10% of the cases of cancer that can be attributed to primary genetic factors. Molecular mechanisms in the pathogenesis of hereditary cancer can result in more-targeted cancer-control measures. At least four mutator genes (MHS2, MLH1, PMS1 and PMS2) appear to account for 70-80% of hereditary nonpolypoid colorectal cancer (HNPCC). When one of these germ-line mutations is present in an HNPCC family, the physician is then able to determine the patient's lifetime cancer destiny with an accuracy of about 90% (limited only by the penetrance of the gene). This will enable highly targeted surveillance to be initiated early, such as colonoscopy beginning at ages 20 to 25 or prophylactic subtotal colectomy. Also, in multiple endocrine neoplasia syndromes (MEN 2A and 2B), the identification of the culprit RET proto-oncogene now enables a secure diagnosis and permits testing of children who might benefit from prophylactic total thyroidectomy. Central to translation of these momentous molecular genetic discoveries into patient care is the necessity of determining who requires DNA testing. The cancer family history is the linchpin in making this decision.

Adaptor Proteins, Signal Transducing↗
PubMed1997

A descriptive study of BRCA1 testing and reactions to disclosure of test results.

BACKGROUND: The identification of the BRCA1 gene is a powerful tool for predicting a patient's lifetime risk for carcinoma of the breast and ovary when she has hereditary breast/ovarian carcinoma (HBOC) syndrome. The process of BRCA1 testing and genetic counseling and participants' reactions to test results, are described. METHODS: Education about the natural history of HBOC syndrome and the pros and cons of genetic testing was provided to 14 HBOC families comprised of 2549 bloodline relatives. Of these, 388 underwent DNA testing. After informed consent was given by participants, formal linkage analysis and gene mutation studies were performed on the families. Qualitative data on intentions and emotional reactions were collected by physicians/counselors during the genetic counseling sessions. RESULTS: Of those tested, 181 received their results after further genetic counseling. Seventy-eight of them were positive and 100 were negative for BRCA1 gene mutation. Three had ambiguous findings. The most common reasons given for seeking DNA testing were concern about risk to children and concern about surveillance and prevention. Prophylactic mastectomy was considered by 35% of women who tested positive, whereas prophylactic oophorectomy was considered an important option by 76%. Twenty-five percent of both BRCA1 positive and negative individuals were concerned about discrimination by insurance companies. Eighty percent of those who tested negative reported emotional relief, whereas over one-third of those who tested positive reported sadness, anger, or guilt. CONCLUSIONS: DNA testing of patients with HBOC syndrome must be performed in the context of genetic counseling. The authors' results demonstrate the many complex clinical and nonclinical issues that are important in this process.

Adult↗