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H T Lynch

Publications and source records attributed to H T Lynch.

At least 19 recordsLinked to original sources
PubMed2001

Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers.

DNA mismatch repair is of considerable scientific and medical importance because of its essential role in maintaining genomic integrity, and its association with hereditary non-polyposis colon cancer (HNPCC). Germline mutations in five mismatch repair genes (MLH1, MSH2, PMS1, PMS2, and MSH6) have been associated with HNPCC susceptibility. Our laboratory recently identified MLH3, a novel DNA mismatch repair gene. We screened the MLH3 coding sequence in 60 probands with increased genetic risk factors for colorectal cancer susceptibility and no mutations in the other candidate genes. No definite MLH3 germline mutations were found. We subsequently screened 36 colon tumors, and discovered an appreciable frequency of somatic MLH3 coding mutations in MSI-H tumors (25%). In four of six tumors, evidence of biallelic inactivation was noted. Furthermore, MLH3 nonsense mutations were identified in two of 12 microsatellite stable (MSS) tumors with 14q24 loss of heterozygosity. While our analyses do not exclude the existence of germline MLH3 mutations in patients with increased genetic risk factors for colorectal cancer susceptibility, they suggest such mutations are uncommon in this patient population. The finding of an appreciable frequency of somatic MLH3 mutations is consistent with a possible role for this gene in the progression of colorectal cancer tumorigenesis. Hum Mutat 17:389-396, 2001. Published 2001 Wiley-Liss, Inc.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Update on familial pancreatic cancer.

Approximately 5% to 10% of patients with pancreatic cancer have one or more first-degree relatives with this disease. A subset of these individuals have a hereditary form of pancreatic cancer designated by association with such hereditary disorders as familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, hereditary pancreatitis, or familial atypical multiple mole melanoma (FAMMM) syndrome. A subset of those FAMMM kindred with the CDKN2A (p16) germline mutation that expresses both pancreatic cancer and malignant melanoma may constitute a new hereditary pancreatic cancer-prone syndrome.

Adenocarcinoma↗
PubMed2001

Parental communication of BRCA1/2 genetic test results to children.

The aim of this study was to evaluate the likelihood, correlates, and psychological impact of parental communication to children of parents' BRCA1/2 genetic test results for breast cancer risk. Subjects were 133 adult members of high risk families. Sociodemographic, clinical, and psychological distress variables were assessed during a baseline telephone interview conducted prior to patient education and test result notification. Parental communication of test results to children and parental psychological distress and coping efforts were assessed 1 month post-genetic counseling and receipt of test results. Mothers (versus fathers), and persons with higher levels of baseline general distress, were significantly more likely to communicate their test results to children. Post-counseling coping efforts, both active and avoidant, were positively associated with post-counseling distress levels. However, communication of test results to children did not relate to changes in distress. In conclusion, parents with higher levels of pre-counseling general psychological distress may be more likely to communicate their genetic test results to children; however, this act does not minimize their distress and could possibly generate distress in their youngsters. Research is needed to evaluate the process and content of post-test disclosure episodes and the impact on participant, child, and family functioning.

Adaptation, Psychological↗
PubMed2001

Current status of prophylactic surgery for hereditary breast and gynecologic cancers.

Given the limitations regarding the impact of screening and the uncertainties concerning chemoprevention for women with significant genetic susceptibilities to breast, endometrial and ovarian cancers, recent research and publications on prophylactic surgery for cancer prevention and improved long-term survival for women at hereditary risk have increasing importance.

Breast Neoplasms↗
PubMed2000

Evaluation of the needs of male carriers of mutations in BRCA1 or BRCA2 who have undergone genetic counseling.

To date, the concerns of men at risk of inheriting a BRCA1 mutation or a BRCA2 mutation have received little attention. It had been anticipated that few men would be interested in predictive testing when a BRCA mutation was identified in their family. However, these men are often affected emotionally by diagnoses of breast cancer in their relatives and may themselves harbor fears that cancer will develop. Male carriers of BRCA1/2 mutations are at increased risk of development of cancers of several types, including those of the breast and prostate. We conducted an evaluation of the needs and experiences of 59 male carriers of BRCA1/2 mutations followed at either the University of Toronto or Creighton University. We assessed their motivations for seeking genetic counseling and testing, involvement in family discussions of breast and ovarian cancer, risk perception, changes in cancer-screening practices, and overall satisfaction with the genetic-counseling process. The principal motivation for seeking genetic counseling was concern for their daughters. The majority (88%) of men participated in family conversations about breast and ovarian cancer, and 47% participated in conversations about prophylactic surgery. Most men believed that they were at increased risk of development of cancer (prostate, breast, colorectal, and skin cancers). However, fewer than one-half (43%) of the men with no previous diagnosis of cancer stated that their prostate cancer-surveillance practices had changed after they had received genetic test results. More than one-half (55%) had intrusive thoughts about their cancer risk. Although levels of satisfaction were high, practitioners should be aware of (a) potential pressures influencing men to request predictive testing, (b) the difficulties that men encounter in establishing surveillance regimens for breast and prostate cancer, and (c) the general lack of information about men's particular experiences in the medical community.

Adult↗
PubMed2000

Lynch syndrome: genetics, natural history, genetic counseling, and prevention.

Lynch syndrome is the most common hereditary form of colorectal cancer (CRC). Its natural history has been investigated extensively, so that highly targeted surveillance and management strategies, melded to its natural history, have proven effective in cancer control. Most important is the early age of onset of cancer (approximately 44 years), involving CRC and the several extracolonic cancers that are integral to the syndrome. With respect to CRC, approximately 70% of cases occur proximal to the splenic flexure. Synchronous and metachronous CRCs are extremely common. Full colonoscopy should be initiated when the patient is between the ages of 20 and 25, and because of the accelerated carcinogenesis of CRC, it should be performed every 1 to 2 years. The presence of initial CRC requires subtotal colectomy, given the mentioned increased frequency of metachronous cancer. Options available for germ-line mutation carriers, in addition to cancer screening, include prophylactic colectomy as well as prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy. The discovery of mismatch repair germ-line mutations (most commonly MSH2 or MLH1) has added significantly to the recognition of this disease as well as to the search for high-risk individuals throughout families who, with genetic counseling, may become candidates for germ-line mutation testing. Clearly, hereditary nonpolyposis colorectal cancer provides an excellent opportunity for learning about the etio-pathogenesis of cancer at the molecular and clinical levels and how this knowledge might ultimately be exploited for cancer control. A search for chemoprevention agents, such as cyclo-oxygenase 2 inhibitors, as well as for putative environmental effects and how they may interact with the genetic component in CRC etiology should abet this entire cancer control process.

Awards and Prizes↗
PubMed2000

E-cadherin mutation-based genetic counseling and hereditary diffuse gastric carcinoma.

The E-cadherin mutation has been identified in a subset of families with multiple cases of diffuse gastric carcinoma. However, the true penetrance of this mutation and its association with other carcinomas in such families remains elusive. We aim to show the importance of DNA-based genetic counseling in hereditary diffuse gastric carcinoma. The proband was self-referred after three of his siblings died of diffuse gastric carcinoma. Medical and pathology records confirmed diagnoses. The family was educated about diffuse gastric carcinoma. Analysis for the 70G-->T mutation was performed by sequencing genomic DNA from lymphocyte pellets. DNA results and genetic counseling were provided individually to those tested. Twenty-four family members were tested for the E-cadherin mutation. Nine were found to be positive and 15 were negative. Three who tested positive and were affected are now deceased. None of the 19 patients counseled wanted results sent to their physicians once they recognized the potential for insurance discrimination. None had undergone endoscopic ultrasound. Three who were positive for the E-cadherin mutation expressed strong interest in prophylactic gastrectomy. The E-cadherin mutation strongly predicts susceptibility to diffuse gastric carcinoma. Emotional stress in at-risk patients, the limited knowledge of the mutation's penetrance, and limitations of available screening mandate patient-centered genetic counseling.

Cadherins↗
PubMed2000

Predominance of brain tumors in an extended Li-Fraumeni (SBLA) kindred, including a case of Sturge-Weber syndrome.

BACKGROUND: Li-Fraumeni syndrome (LFS) is characterized by a plethora of cancers, most prominent of which is carcinoma of the breast followed by sarcomas, brain tumors, leukemia, lymphoma, lung carcinoma, and adrenocortical carcinoma (therefore, also referred to by the acronym SBLA syndrome). METHODS: The family reported herein was first described 2 decades ago. Now extensive follow-up has shown the predictable occurrence of these tumor types, in addition to an excess of brain tumors and the finding of Sturge-Weber syndrome (SWS) in an LFS-affected family member. RESULTS: A possible new feature of the disorder, suggestive of SWS, was identified in a patient in the direct genetic lineage. This patient had a rhabdomyosarcoma of the eyelid at age 29 months and at age 14 years was diagnosed with lymphoblastic lymphoma/acute lymphoblastic leukemia. A remarkable excess of brain tumors was identified in this family through this current update. The p53 germ-line mutation was not identified in any affected member of this family. CONCLUSIONS: To the authors' knowledge, this is the first example of SWS in the context of LFS. Brain tumors appear to be an important component of the tumor spectrum of LFS, as evidenced in this family.

Adult↗
PubMed2000

Hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is the most common form of hereditary colorectal cancer (CRC). A well-orchestrated cancer family history is essential for its diagnosis since, unlike its familial adenomatous polyposis (FAP) hereditary cancer counterpart, HNPCC lacks distinguishing clinical stigmata of its cancer genetic risk. Discoveries in the 1990s of germ-line mutations, the most common of which are hMSH2 and hMLH1, have added enormous power to the diagnosis of Lynch syndrome. Its medical management is contingent upon its natural history. For example, approximately 70% of CRCs occur proximal to the splenic flexure, with one-third of the cancers occurring in the cecum, thereby mandating full colonoscopy. A high rate of metachronous CRCs indicates the need for no less than a subtotal colectomy for the management of initial CRC. Genetic counseling is essential prior to DNA testing, and at the time of disclosure of the results. Education of patients as well as physicians about all facets of this disorder is extremely important. If patients are to show compliance with germ-line testing, screening, and management options, they must understand the natural history and the significance of their genetic risk status. Physicians must also be aware of clinical nuances of this disorder to provide the necessary care.

Colectomy↗
PubMed2000

Histology of prophylactically removed ovaries from BRCA1 and BRCA2 mutation carriers compared with noncarriers in hereditary breast ovarian cancer syndrome kindreds.

OBJECTIVE: The literature reports conflicting studies claiming premalignant histological features in benign ovaries from women who may have hereditary predilections for ovarian carcinoma. To test the veracity of these claims, this investigation studied ovaries prophylactically removed from members of hereditary breast ovarian cancer (HBOC) syndrome families who carry BRCA1 and BRCA2 mutations and compared these with the ovaries of mutation-negative women from the same HBOC syndrome kindred. METHODS: Sixty cases of women from HBOC syndrome families who had undergone prophylactic oophorectomies and whose BRCA1 and BRCA2 mutation status had been tested were selected from our database. Thirty had tested positive for BRCA1 mutations, 3 carried BRCA2 mutations, and 27 were negative for both BRCA1 and BRCA2 germline mutations. Histologic material from each case was examined by light microscopy blinded to the mutation status. Histologic features, previously reported to be possible precursor lesions for ovarian cancer, were quantified. Data from BRCA1 and BRCA2 mutation carriers were compared with those from mutation-negative cases in the direct line of genetic inheritance from the same HBOC syndrome families. RESULTS: Statistical analysis found that a more frequent occurrence of ovarian surface micropapillae in 87% of mutation carriers compared with just 55% of mutation-negative cases was the only histologic feature which was significantly different between the two groups (P = 0.39). Cortical clefts tended to be deeper in the ovaries of mutation carriers, but this did not reach significance (P = 0.051). There were no other significant histologic differences between the ovaries removed from mutation carriers and those from noncarriers. CONCLUSIONS: The results of our large and prospectively controlled, blinded study contrast with those reported from smaller, unblinded investigations. Except for the possible biological significance of surface micropapillae on ovaries from BRCA1 and BRCA2 mutation carriers, we found no histologic evidence for a genetically determined ovarian carcinoma precursor lesion.

Adult↗
PubMed2000

Prophylactic surgery decisions and surveillance practices one year following BRCA1/2 testing.

BACKGROUND: Although genetic testing for breast cancer risk is clinically available, its impact on health-related behaviors is unknown. This study examined prophylactic surgery and surveillance behavior during the year following BRCA1/2 gene testing. METHODS: Participants were female members (n = 216) of hereditary breast-ovarian cancer families (84 mutation carriers, 83 noncarriers and 49 test decliners). In this prospective observational study, utilization of prophylactic surgery and surveillance behavior were assessed 1-year following BRCA1/2 testing. RESULTS: Only 3% of the unaffected carriers obtained prophylactic mastectomy during the 1-year follow-up period. Among the remaining females, carriers had significantly higher rates of mammography (68%) than noncarriers (44%); (OR = 7.1; C.I. = 1.36-37.1; P = 0.02). However, the adherence rate in carriers was unchanged from baseline, suggesting that this difference is attributable to a reduction in screening among noncarriers. Women ages 25-39 years were significantly less likely to obtain mammograms than those aged 40 years and older. Cancer-related distress had a positive but nonsignificant (P < 0.07) association with adherence in bivariate but not multivariate analysis. With regard to ovarian risk, only 13% of carriers obtained prophylactic oophorectomy; of the remaining female carriers, only 21% reported a CA125 and 15% reported a transvaginal ultrasound. CONCLUSION: The vast majority of BRCA1/2 carriers may not opt for prophylactic surgery, and many do not adhere to surveillance recommendations. Greater attention to risk communication and medical decision-making is warranted.

Adult↗
PubMed2000

Hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay.

PURPOSE: We updated an Uruguayan family with hereditary nonpolyposis colorectal cancer first described in 1977, incorporating knowledge of how the hMLH1 germline mutation has been established and shown to segregate in accord with the expected autosomal dominant mode of genetic transmission. METHODS: DNA-based molecular genetic testing was performed in conjunction with genetic counseling. Individuals were provided with their genetic test results, so that at-risk family members would be able to benefit from targeted management programs. RESULTS: We counseled 19 members of this kindred, 13 of whom were positive for the hMLH1 germline mutation. Specific recommendations for surveillance and management were provided. We were able to describe follow-up, including anecdotal cancer survival and pathology findings extending from the initial 1977 report of this family to the present. A remarkable sibship within this kindred was comprised of eight siblings, six of whom underwent resections for colorectal carcinoma between 1963 and 1971. Colon carcinomas before 1977 in this sibship were treated with classic hemicolectomies. Of those who had hemicolectomies for their first primary colorectal cancers, two had a second colon cancer primary, and two had a third colon cancer primary. CONCLUSIONS: Attention given to this extended family with hereditary nonpolyposis colorectal cancer has had a positive impact on the physician community in Uruguay, leading to the identification of additional families with hereditary nonpolyposis colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2000

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↗