Anticipation in familial Hodgkin's lymphoma.
Anticipation is discussed in relation to Hodgkin's lymphoma, non-Hodgkin's lymphoma, and familial cancer.
Age of Onset↗
Biomedical subjects
H T Lynch
Publications and source records attributed to H T Lynch.
Hereditary pancreatic adenocarcinoma. A clinical perspective.
Although the total number of patients in these various high-risk groups is relatively small, they nevertheless provide excellent models for studying the cause, natural history, pathogenesis, and treatment of pancreatic cancer. These patients would also benefit greatly from procedures capable of detecting cancer at an early stage. This knowledge would be useful for the much commoner sporadic form of pancreatic cancer, in which diagnosis is almost always late and prognosis fatal. With early diagnosis, surgical resection before the cancer's extension beyond the organ's anatomic confines could be curative. The establishment of a National Familial Pancreatic Cancer Registry is essential and would increase the availability of these invaluable families for medical research.
Adenocarcinoma↗
The dermatologist, genetic counseling, and cancer-associated genodermatoses.
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Biomarkers, Tumor↗
MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability.
DNA mismatch repair is important because of its role in maintaining genomic integrity and its association with hereditary non-polyposis colon cancer (HNPCC). To identify new human mismatch repair proteins, we probed nuclear extracts with the conserved carboxy-terminal MLH1 interaction domain. Here we describe the cloning and complete genomic sequence of MLH3, which encodes a new DNA mismatch repair protein that interacts with MLH1. MLH3 is more similar to mismatch repair proteins from yeast, plants, worms and bacteria than to any known mammalian protein, suggesting that its conserved sequence may confer unique functions in mice and humans. Cells in culture stably expressing a dominant-negative MLH3 protein exhibit microsatellite instability. Mlh3 is highly expressed in gastrointestinal epithelium and physically maps to the mouse complex trait locus colon cancer susceptibility I (Ccs1). Although we were unable to identify a mutation in the protein-coding region of Mlh3 in the susceptible mouse strain, colon tumours from congenic Ccs1 mice exhibit microsatellite instability. Functional redundancy among Mlh3, Pms1 and Pms2 may explain why neither Pms1 nor Pms2 mutant mice develop colon cancer, and why PMS1 and PMS2 mutations are only rarely found in HNPCC families.
Amino Acid Sequence↗
Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families.
The mortality from pancreatic cancer coincides closely with its incidence, indicating a dismal outlook. Hereditary factors probably account for approximately 5%-10% of the pancreatic cancer burden. The molecular genetic etiology of pancreatic cancer is only beginning to be identified. We describe our genetic counseling experience with 2 large families prone to pancreatic cancer-malignant melanoma in which p16 (CDKN2) germline mutations had been identified. Members of each family underwent intensive counseling before and at the time of disclosure of p16 germline mutation findings. Two non-cancer-affected siblings from each of the 2 families had p16 mutations identified in DNA from their peripheral blood lymphocytes. In each case, a parent affected with pancreatic cancer also harbored the p16 mutation identified in DNA from their respective tumor blocks. The sibling pairs stated that they would seriously consider prophylactic pancreatectomy if biomarkers or imaging findings suggested a precancerous state. Our experience highlights limited options for managing these families and emphasizes the need for better tools to diagnose pancreatic cancer at a curable stage.
Adult↗
The FAMMM syndrome: epidemiology and surveillance strategies.
Research into the epidemiology of the melanoma-prone FAMMM syndrome, molecular genetics of the occurrences of melanoma, the photobiology of DNA damage/repair, diagnostic epiluminescence, microscopic/imaging techniques, and a new concept of photoprotection have altered melanoma strategies in surveillance and prevention. Molecular genetic research has implicated the importance of hereditary aspects of melanoma and associated malignancies. High-risk pedigrees can be identified through an informatic analysis of the occurrence patterns of melanoma and systemic cancers in kindreds. All ultraviolet radiation results in cutaneous DNA damage and in high-risk individuals may cause melanoma. We may reverse the epidemic trend in melanoma occurrences in these high-risk pedigrees if we are willing to change our cultural approach to sunlight exposure with restrictive sunlight behavior, wearing of ultraviolet protective clothes, the use of broad-spectrum ultraviolet protection from nightly topical dihydroxyacetone coupled with daytime UVB sunscreens, and periodic surveillance.
Dihydroxyacetone↗
Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part I: Studies of cancer in families.
Hereditary cancer represents approximately 5-10% of the total cancer burden and may account for 60,000 to 120,000 new cancer occurrences this year in the United States. New developments in molecular genetics and the cloning of cancer-prone genes have intensely fueled interest in dealing with hereditary forms of cancer. The authors provide an algorithm that depicts the process for the identification, study, and DNA-based genetic counseling of families being investigated under a research proposal at the Hereditary Cancer Institute of Creighton University School of Medicine. They have studied 56 hereditary nonpolyposis colorectal carcinoma families; in 18 of them, associated genomic mutations have been identified in affected members. DNA-based genetic counseling has been provided for seven of these families. The authors have also evaluated 131 hereditary breast-ovarian carcinoma families. BRCA1 and BRCA2 mutation searches have been performed for 76 of these families; BRCA1 mutations were found in 38 families and BRCA2 mutations in 9. The study of cancer-prone families is a powerful approach to cancer control, particularly when the germ-line mutation is identified in the family and individuals at high risk can be tested, once they provide informed consent, and receive DNA-based genetic counseling. Discovery of the germ-line mutation for cancer proneness provides an unparalleled opportunity to predict patients' life-time risk for cancer of specific anatomic sites, inclusive of a pattern of multiple primaries. Surveillance and management protocols, when melded to the particular syndrome's natural history, can be life-saving.
Clinical Protocols↗
Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part II: Hereditary nonpolyposis colorectal carcinoma as a model.
Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common hereditary form of colorectal carcinoma (CRC) and may account for 5-10% of the total CRC burden. The discovery of DNA mismatch repair (MMR) genes, inclusive of hMSH2, hMLH1, hPMS2, and hMSH6, has enabled the identification of who has and who does not have inordinately increased susceptibility to CRC as well as a litany of extracolonic cancers. Mutation testing has focused on hMSH2 and hMLH1, the most common mutations in HNPCC. The protocol for DNA testing and DNA-based genetic counseling is described in Part I of this study. One hundred ninety-nine bloodline relatives were tested and counseled from five hMLH1 and two hMSH2 families. Their major reason for seeking genetic counseling and DNA testing was to inform their children and other loved ones of their mutation status. Those who sought counseling overestimated their risk for inheriting the mutation and showed a high rate of interest in prophylactic surgery, and many were greatly concerned about insurance discrimination. Knowledge about HNPCC, its molecular genetic diagnosis, surveillance and management opportunities, and genetic counseling implications are still emerging, all in the face of a greater need for physician education regarding all facets of hereditary cancer.
Adaptor Proteins, Signal Transducing↗
Integration of family history and medical management of patients with hereditary cancers.
The family histories of individuals affected by a wide variety of cancers have provided information about the principal features of hereditary cancer. Surveillance protocols, indicating the most appropriate modalities and the age at which to initiate them, have been derived from what has been learned about the age of onset and the cancer sites associated with specific cancer syndromes. Likewise, cancer management has been based on what is known of the natural history of the syndrome cancers from studying multiple affected families. Family history has even been an essential tool for molecular geneticists as they have mapped and eventually identified genes for such cancer syndromes as hereditary breast ovarian carcinoma (HBOC), familial adenomatous polyposis (FAP), and hereditary nonpolyposis colon carcinoma (HNPCC). Despite the rapid integration of molecular genetics into the diagnosis and management of individuals at high risk for hereditary cancer, family history remains an essential tool in all aspects of cancer genetic health services. Recognition of a hereditary cancer syndrome through a family's history offers a primary care provider an opportunity to intervene on behalf of not just one patient but an entire family. Once hereditary cancer is identified, the information that has been learned and the protocols developed from numerous family histories can be applied to one individual or family based on their specific family history.
Adenomatous Polyposis Coli↗
Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2.
BACKGROUND: Early age at first full-term pregnancy and increasing parity are associated with a reduced risk of breast cancer. However, whether pregnancy decreases the risk of early-onset hereditary breast cancer is unknown. There is concern that pregnancy may increase breast-cancer risk in carriers of BRCA1 and BRCA2 germline mutations. We aimed to establish whether pregnancy is a risk factor for hereditary breast cancer. METHODS: We did a matched case-control study of breast cancer in women who carry deleterious BRCA1 or BRCA2 mutations. Cases were carriers who developed breast cancer by age 40 years, and controls were carriers of the same age without breast cancer, or who were diagnosed with breast cancer after age 40 years. Women who had undergone preventive mastectomy, hysterectomy, or oophorectomy, or who were diagnosed with ovarian cancer before the age at which breast cancer was diagnosed in the matched case were excluded. Information about pregnancies and pregnancy outcome was derived from a questionnaire completed by women in the course of genetic counselling. FINDINGS: A higher proportion of cases than controls had had a full term pregnancy (173/236 vs 146/236; odds ratio 1.71 [95% CI 1.13-2.62], p=0.01). The mean number of births was also greater for cases than for controls (1.62 vs 1.38, p=0.04). The risk increased with the number of births and did not diminish with time since last pregnancy. There were no significant differences in age at first birth or age at last birth between cases and controls. INTERPRETATION: Carriers of the BRCA1 and BRCA2 mutations who have children are significantly more likely to develop breast cancer by age 40 than carriers who are nulliparous. Each pregnancy is associated with an increased cancer risk. An early first pregnancy does not confer protection for carriers of BRCA1 or BRCA2 mutations.
Adult↗
The genetic epidemiology of male breast carcinoma.
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BRCA1 Protein↗
Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers.
BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. METHODS: We studied a cohort of women with disease-associated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. RESULTS: We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.33-0.84). This risk reduction was even greater in women who were followed 5-10 (HR = 0. 28; 95% CI = 0.08-0.94) or at least 10 (HR = 0.33; 95% CI = 0.12-0.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. CONCLUSIONS: Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations.
Age Factors↗
Microsatellite instability and expression of MLH1 and MSH2 in normal and malignant endometrial and ovarian epithelium in hereditary nonpolyposis colorectal cancer family members.
Mismatch repair deficiency is a characteristic molecular finding in hereditary nonpolyposis colorectal cancer (HNPCC), and has been demonstrated in both colorectal cancers and benign adenomas. Endometrial and ovarian cancers are common extracolonic tumors in this syndrome; however, few studies have investigated whether genetic changes occur in histologically normal endometrial and ovarian epithelia from HNPCC family members. If early genetic changes exist, they might be used as molecular markers to detect susceptibility to endometrial and ovarian cancers. In this study, we analyzed microsatellite instability (MSI) and MLH1 and MSH2 immunohistochemical expression in 20 histologically normal epithelia (12 endometrial and 8 ovarian) and 8 cancers (4 endometrial and 4 ovarian) obtained from 20 individuals representing 7 unrelated HNPCC families. While MSI was observed in endometrial (75%) and ovarian (100%) cancers, no case was determined to exhibit MSI in histologically normal epithelia of the endometrium or ovary. Similarly, in immunohistochemical expressions for MLH1 and MSH2, histologically normal epithelia had no genetic changes predisposing to malignancy. In cancer cases, a correlation existed between the expression of MLH1 and MSH2, the presence of germline mutations in the hMLH1 and hMSH2 genes, and the presence of tumor MSI. These data suggest that MSI and MLH1 and MSH2 expression are not useful biomarkers for the early detection of endometrial and ovarian malignancy in cancer-unaffected HNPCC germline mutation carriers. Further studies of other genetic changes in normal and premalignant precursor lesions are needed.
Adaptor Proteins, Signal Transducing↗
Genetic testing in families with hereditary nonpolyposis colon cancer.
CONTEXT: Genetic testing for hereditary nonpolyposis colon cancer (HNPCC) is available, but the rates of acceptance of testing or barriers to participation are not known. OBJECTIVE: To investigate rates and predictors of utilization of genetic testing for HNPCC. DESIGN: Cohort study conducted between July 1996 and July 1998. SETTING: Hereditary nonpolyposis colon cancer family registry. PARTICIPANTS: Adult male and female members (n = 208) of 4 extended HNPCC families contacted for a baseline telephone interview. INTERVENTIONS: Family education and individual genetic counseling. MAIN OUTCOME MEASURE: Participant acceptance of HNPCC test results. RESULTS: Of the 208 family members, 90 (43%) received test results and 118 (57%) declined. Of 139 subjects (67%) who completed a baseline telephone interview, 84 (60%) received test results and 55 (40%) declined. Of the 84 subjects who received test results, 35 (42%) received information indicating that they had HNPCC-associated mutations and 49 (58%) that they did not. Test acceptors had higher education levels (odds ratio [OR], 3.74; 95% confidence interval [CI], 2.49-5.61) and were more likely to have participated in a previous genetic linkage study (OR, 4.30; 95% CI, 1.84-10.10). The presence of depression symptoms significantly reduced rates of HNPCC test use (OR, 0.34; 95% CI, 0.17-0.66). Although rates of test use were identical among men and women, the presence of depression symptoms resulted in a 4-fold decrease in test use among women (OR, 0.25; 95% CI, 0.08-0.80) and a smaller, nonsignificant reduction among men (OR, 0.49; 95% CI, 0.19-1.27). CONCLUSIONS: Despite having significantly elevated risks of developing colon cancer, a relatively small proportion of HNPCC family members are likely to use genetic testing. Barriers to test acceptance may include less formal education and the presence of depression symptoms, especially among women. Additional research is needed to generalize these findings to different clinical settings and racially diverse populations.
Adult↗
Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions.
Most previous BRCA1 mutation screening studies conducted on breast cancer families were aimed at identifying mutations in the coding sequence and splice sites. Mutations in the promoter and untranslated regions, and large rearrangements are missed by standard mutation detection strategies. To look specifically for such germ-line mutations in the BRCA1 gene, we have analyzed a series of 27 American and 51 French breast cancer families in which no BRCA1 mutation was identified by classical techniques. No mutations were detected in either the promoter or untranslated regions, and we did not find any deletion of the whole gene. Four families were found to carry distinct deletions. Two of them, probably generated by Alu-mediated homologous recombination, were internal deletions of 3 and 23.8 kb, encompassing exon 15 and exons 8-13, respectively. These alterations both lead to a frameshift in the mutant mRNA and to premature stop codon-mediated mRNA decay. The other two deletions encompass exons 1 and 2. On the basis of previous and present analyses, rearrangements represent 8% (3/37) of all mutations in our set of BRCA1 American families. Consequently, the search for rearrangements appears mandatory in BRCA1 mutation screening studies.
3' Untranslated Regions↗
Pros and cons of genetic screening for breast cancer.
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Anxiety↗
A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome).
One of the earliest references to heredity in colorectal cancer dates to Aldred Warthin's now-famous recollection of his seamstress' distress regarding "cancer excess" in her family history. Her prediction of an early demise secondary to cancer of the female organs, colon, or stomach proved true. The slow, arduous investigation that ensued followed a tortuous route of nearly eight decades before the implications of such family histories were widely acknowledged through the designation of hereditary nonpolyposis colorectal cancer or Lynch Syndrome Variants I and II. The story of hereditary nonpolyposis colorectal cancer is one of chance meetings, the selfless sharing of information, perseverance in the face of adversity, meticulous scientific documentation, and ultimate vindication by a scientific process that yielded molecular genetic evidence through the identification of the culprit mutations (hMSH2, hMLH1, hPMS2, and hMSH6). Our purpose is to provide a brief outline of the course charted by the study of the genetics of hereditary nonpolyposis colorectal cancer. This should be of particular interest to the readers of this Journal as we celebrate 100 years of dedication to the diagnosis and treatment of diseases of the colon, rectum, and anus through the efforts of The American Society of Colon and Rectal Surgeons.
Colorectal Neoplasms, Hereditary Nonpolyposis↗
Failure to diagnose hereditary colorectal cancer and its medicolegal implications: a hereditary nonpolyposis colorectal cancer case.
PURPOSE: We describe a patient who had precancerous colonic symptoms and a positive family history of multiple occurrences of early-onset colorectal cancer in her first-degree and second-degree relatives consistent with hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer diagnosis had not been made before her diagnosis of carcinoma of the cecum with liver metastasis. She died at age 20, leading to litigation. Controversies about standards of care, their malpractice implications, and pertinent legal issues are discussed. METHODS: Review of the medical and family history was made by the expert witness (HTL) with appropriate documentation of the chronology of symptoms, as derived from depositions. These documents revealed that the patient's mother had repeatedly discussed with the caregivers her concern about the family history of colon cancer and the need for appropriate surveillance. RESULTS: The patient's colonic symptoms progressed for a period of three years. Flexible sigmoidoscopy was performed by a nonphysician. The physician who ordered the procedure considered this appropriate because isolated polyps were reported in the patient's father and paternal uncle, which apparently led him to believe that the diagnosis was familial adenomatous polyposis. During litigation procedures, a pedigree was constructed and found to be consistent with hereditary nonpolyposis colorectal cancer. The case was settled in favor of the plaintiff before trial. CONCLUSION: It is essential to understand the natural history of hereditary nonpolyposis colorectal cancer, inclusive of the need for surveillance colonoscopy in patients at increased risk by virtue of their position in their family pedigree.
Adenomatous Polyposis Coli↗