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Search Results: 1 - 10 of 122540 matches for " Henry T Lynch "
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Familial Pancreatic Cancer
Henry T. Lynch,Jane F. Lynch,Stephen J. Lanspa
Cancers , 2010, DOI: 10.3390/cancers2041861
Abstract: Pancreatic cancer’s high mortality rate equates closely with its incidence, thereby showing the need for development of biomarkers of its increased risk and a better understanding of its genetics, so that high-risk patients can be better targeted for screening and early potential lifesaving diagnosis. Its phenotypic and genotypic heterogeneity is extensive and requires careful scrutiny of its pattern of cancer associations, such as malignant melanoma associated with pancreatic cancer, in the familial atypical multiple mole melanoma syndrome, due to the CDKN2A germline mutation. This review is designed to depict several of the hereditary pancreatic cancer syndromes with particular attention given to the clinical application of this knowledge into improved control of pancreatic cancer.
Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients
Kristen M. Drescher,Poonam Sharma,Henry T. Lynch
Clinical and Developmental Immunology , 2010, DOI: 10.1155/2010/170432
Abstract: High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.
Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients
Kristen M. Drescher,Poonam Sharma,Henry T. Lynch
Journal of Immunology Research , 2010, DOI: 10.1155/2010/170432
Abstract: High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers. 1. Introduction Although Warthin described a classic cancer prone family (cancer family G) in the early 1900’s [1], relatively little attention was given to “cancer families” until the 1960s when Lynch described two large Midwestern cancer kindreds and hypothesized that they were due to hereditary factors [2]. This hypothesis was widely dismissed and other theories regarding the origins of cancer, such as exposure to an environmental agent, were favored. Lynch also assessed the cancer status of relatives of Warthin’s family G over six generations, revealing an autosomal dominant pattern of inheritance [3]. The hypothesis that cancer risk in such families could be inherited was validated in the 1990s when multiple groups identified regions of the genome associated with colorectal cancer development [4–6]. The recognition that some cancers were hereditary was significant, as it permitted increased surveillance and testing of individuals who were at the greatest risk for disease development. This also allowed patients to exercise some level of control (i.e., seek early diagnosis) over disease outcome. Lynch Syndrome is a hereditary colorectal cancer (CRC) syndrome. Patients with Lynch Syndrome experience early-onset CRC as well as an increased risk of developing certain extracolonic cancers [7–17] In sporadic cancers, there are often point mutations in tumor suppressor genes and protooncogenes including K-ras, p53 and APC [18–23]. These mutations are seldom observed in Lynch Syndrome cancers [24–26]. The primary defect in Lynch Syndrome cancers results in increased microsatellite instability due to a mutation in the DNA mismatch repair genes; microsatellite instability is not common in sporadic cancers [4–6, 27]. Lynch Syndrome tumors are more poorly differentiated compared to other CRCs and are frequently characterized by an excess of mucin,
HNPCC (Lynch Syndrome): Differential Diagnosis, Molecular Genetics and Management - a Review
Henry T Lynch, Jane F Lynch, Trudy G Shaw, Jan Lubiński
Hereditary Cancer in Clinical Practice , 2003, DOI: 10.1186/1897-4287-1-1-7
Abstract: The annual worldwide incidence of colorectal cancer (CRC) is approximately 944,717 (males: 498,754; females: 445,963) and its worldwide mortality incidence is approximately 492,411 (males: 254,816; females: 237,595). In Poland, the annual incidence of CRC is approximately 13,327 (males: 6,916; females: 6,411) and its mortality is approximately 7,877 (males: 3,883; females: 3,994) [1]. The lifetime CRC risk in the general population is about 5-6% [2], but there is considerable racial and ethnic variation. For example, the lifetime CRC risk for Ashkenazi Jews ranges between 9% and 15% [3].The familial clustering of two or more first - and/or second-degree relatives with CRC constitutes approximately 20% of the total CRC burden, while a Mendelian inherited (monogenic) etiology for CRC accounts for approximately 5-10% of the total CRC burden. Among hereditary CRC-prone syndromes with multiple colonic polyps (adenomatous, juvenile, Peutz-Jeghers, mixed [hamartomatous, hyperplastic, adenomatous]), the best known, namely familial adenomatous polyposis (FAP), accounts for less than 1% of the total CRC burden, while the other syndromes in this group combine to account for another fraction of a percent of the total CRC incidence [4,5]. In contrast to those hereditary CRC disorders, hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, represents 2-7% of the total CRC burden [6]. Herein, the Lynch syndrome is the most common form of hereditary CRC.Our purpose is to review the history, clinical, pathologic, and molecular genetic features of HNPCC (Lynch syndrome). Special attention will be given to its differential diagnosis and molecular genetics, in concert with state-of-the-art surveillance and management recommendations.Soliciting cancer family history information is crucial to diagnosing a hereditary cancer syndrome and the data should be recorded in every cancer-affected patient's medical chart. Given the variable genotypic and phenotypic featur
Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers
Joanne Kotsopoulos, Olufunmilayo I Olopade, Parviz Ghadirian, Jan Lubinski, Henry T Lynch, Claudine Isaacs, Barbara Weber, Charmaine Kim-Sing, Peter Ainsworth, William D Foulkes, Andrea Eisen, Ping Sun, Steven A Narod
Breast Cancer Research , 2005, DOI: 10.1186/bcr1293
Abstract: A matched case–control study was conducted in 1,073 pairs of women carrying a deleterious mutation in either BRCA1 (n = 797 pairs) or BRCA2 (n = 276 pairs). Women diagnosed with breast cancer were matched to control subjects by year of birth, mutation, country of residence, and history of ovarian cancer. Information about weight was derived from a questionnaire routinely administered to women who were carriers of a mutation in either gene. Conditional logistic regression was used to estimate the association between weight gain or loss and the risk of breast cancer, stratified by age at diagnosis or menopausal status.A loss of at least 10 pounds in the period from age 18 to 30 years was associated with a decreased risk of breast cancer between age 30 and 49 (odds ratio (OR) = 0.47; 95% confidence interval (CI) 0.28–0.79); weight gain during the same interval did not influence the overall risk. Among the subgroup of BRCA1 mutation carriers who had at least two children, weight gain of more than 10 pounds between age 18 and 30 was associated with an increased risk of breast cancer diagnosed between age 30 and 40 (OR = 1.44, 95% CI 1.01–2.04). Change in body weight later in life (at age 30 to 40) did not influence the risk of either premenopausal or postmenopausal breast cancer.The results from this study suggest that weight loss in early adult life (age 18 to 30) protects against early-onset BRCA-associated breast cancers. Weight gain should also be avoided, particularly among BRCA1 mutation carriers who elect to have at least two pregnancies.The inheritance of a deleterious mutation in either of the two breast cancer susceptibility genes, BRCA1 or BRCA2, has been associated with a lifetime risk of breast cancer of 45% to 87% [1,2]. Reports of increasing penetrance among women born in recent cohorts in comparison with those born in earlier years has prompted the search for factors that may influence the risk of cancer in genetically susceptible women [2-5]. To date, bo
Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers
Kelly A Metcalfe, William D Foulkes, Henry T Lynch, Parviz Ghadirian, Nadine Tung, Ivo A Olivotto, Ellen Warner, Olufunmilayo Olopade, Andrea Eisen, Barbara Weber, Jane McLennan, Ping Sun, Steven A Narod
Hereditary Cancer in Clinical Practice , 2005, DOI: 10.1186/1897-4287-3-2-53
Abstract: Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date) of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups.Women with prior bilateral oophorectomy presented with smaller tumours on average compared to women without prior oophorectomy (mean size 1.50 cm vs. 1.95 cm; p = 0.01). Additionally, although not statistically significant, women with intact ovaries were more likely to have high-grade tumour (70% vs. 54%: p = 0.10) and to have positive lymph nodes (34% vs. 18%; p = 0.11) compared to women with prior bilateral oophorectomy.Bilateral oophorectomy prior to breast cancer appears to favourably influence the biological presentation of breast cancer in BRCA1 and BRCA2 mutation carriers.Women with a BRCA1 or BRCA2 mutation have up to an 87% lifetime risk of developing invasive breast cancer [1]. The surgical removal of the ovaries in women with a BRCA1 or BRCA2 mutation has been shown to reduce the risk of developing breast cancer [2]. Nevertheless, some women who have had bilateral oophorectomy go on to develop breast cancer. Previous research has suggested that there may be an association between menopausal status and prognostic features of breast cancer [3], but this association has not been studied in women with a BRCA1 or BRCA2 mutation.Women with a BRCA1 or BRCA2 mutation are encouraged to consider the option of prophylactic oophorectomy to prevent both breast and ovarian cancers. The r
PCCR: Pancreatic Cancer Collaborative Registry
Simon Sherman, Oleg Shats, Marsha A. Ketcham, Michelle A. Anderson, David C. Whitcomb, Henry T. Lynch, Paola Ghiorzo, Wendy S. Rubinstein, Aaron R. Sasson, William E. Grizzle, Gleb Haynatzki, Jianmin Feng, Alexander Sherman, Leo Kinarsky and Randall E. Brand
Cancer Informatics , 2012, DOI: 10.4137/CIN.S6919
Abstract: The Pancreatic Cancer Collaborative Registry (PCCR) is a multi-institutional web-based system aimed to collect a variety of data on pancreatic cancer patients and high-risk subjects in a standard and efficient way. The PCCR was initiated by a group of experts in medical oncology, gastroenterology, genetics, pathology, epidemiology, nutrition, and computer science with the goal of facilitating rapid and uniform collection of critical information and biological samples to be used in developing diagnostic, prevention and treatment strategies against pancreatic cancer. The PCCR is a multi-tier web application that utilizes Java/JSP technology and has Oracle 10 g database as a back-end. The PCCR uses a “confederation model” that encourages participation of any interested center, irrespective of its size or location. The PCCR utilizes a standardized approach to data collection and reporting, and uses extensive validation procedures to prevent entering erroneous data. The PCCR controlled vocabulary is harmonized with the NCI Thesaurus (NCIt) or Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT). The PCCR questionnaire has accommodated standards accepted in cancer research and healthcare. Currently, seven cancer centers in the USA, as well as one center in Italy are participating in the PCCR. At present, the PCCR database contains data on more than 2,700 subjects (PC patients and individuals at high risk of getting this disease). The PCCR has been certified by the NCI Center for Biomedical Informatics and Information Technology as a cancer Biomedical Informatics Grid (caBIG ) Bronze Compatible product. The PCCR provides a foundation for collaborative PC research. It has all the necessary prerequisites for subsequent evolution of the developed infrastructure from simply gathering PC-related data into a biomedical computing platform vital for successful PC studies, care and treatment. Studies utilizing data collected in the PCCR may engender new approaches to disease prognosis, risk factor assessment, and therapeutic interventions.
RNase L Variants Do Not Appear to Impact on Clinical Features of Sporadic Prostate Cancer Patients  [PDF]
Frank T. D’Arcy, Ruth Foley, Thomas H. Lynch
Open Journal of Urology (OJU) , 2013, DOI: 10.4236/oju.2013.37054
Abstract:

Introduction: Prostate cancer is the most common non-cutaneous male cancers, contributing to significant mortality rates globally. Mutations of RNase L, an enzyme involved in inflammatory and immunological pathways, have been speculated to predispose to cancer. This study assesses three different mutations of the RNase L gene in Irish prostate cancer patients, including one linked with general cancer susceptibility never investigated before in prostate cancer (rs3738579), and reports on links with aggressive cancer. Methods: 134 patients had their RNase L mutation status determined by polymerase chain reaction (PCR) of serum DNA. Complementary clinical details for each patient are statistically analysed. Results: No link to age of diagnosis, high grade disease or prostate specific antigen (PSA) level at diagnosis was demonstrated with any of the studied single nucleotide polymorphisms (SNP). The SNP variation was consistent with that of published international series. Conclusion: SNP genotypic frequencies in Ireland are consistent with international findings. The studied RNase L mutations including rs3738579 do not appear to have a significant impact on our patient population.

Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers
Susan L Neuhausen, Sean Brummel, Yuan Ding, Christian F Singer, Georg Pfeiler, Henry T Lynch, Katherine L Nathanson, Timothy R Rebbeck, Judy E Garber, Fergus Couch, Jeffrey Weitzel, Steven A Narod, Patricia A Ganz, Mary B Daly, Andrew K Godwin, Claudine Isaacs, Olufunmilayo I Olopade, Gail Tomlinson, Wendy S Rubinstein, Nadine Tung, Joanne L Blum, Daniel L Gillen
Breast Cancer Research , 2009, DOI: 10.1186/bcr2414
Abstract: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.Women who carry mutations in the BRCA1 and BRCA2 genes have a substantially increased risk of developing breast cancer and ovarian cancers as compared with the general population. Estimates of the age-specific risk attributable to mutations at these loci vary depending on the ascertainment scheme. The cumulative risks of breast cancer by age 70 were estimated to be 65% and 45% for BRCA1 and BRCA2 mutation carriers, respectively, in a meta-analysis of population-based studies [1] - as compared with 56 to 80% for BRCA1 and BR
Breastfeeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers
Joanne Kotsopoulos, Jan Lubinski, Leonardo Salmena, Henry T Lynch, Charmaine Kim-Sing, William D Foulkes, Parviz Ghadirian, Susan L Neuhausen, Rochelle Demsky, Nadine Tung, Peter Ainsworth, Leigha Senter, Andrea Eisen, Charis Eng, Christian Singer, Ophira Ginsburg, Joanne Blum, Tomasz Huzarski, Aletta Poll, Ping Sun, Steven A Narod, the Hereditary Breast Cancer Clinical Study Group
Breast Cancer Research , 2012, DOI: 10.1186/bcr3138
Abstract: We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 (n = 1,243 pairs) or BRCA2 (n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer.Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43).These data extend our previous findings that breastfeeding protects against BRCA1-, but not BRCA2-associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.In the general population, reproductive factors, including late age at menarche, parity and breastfeeding, have been shown to protect against the development of breast cancer [1-3]. Various proposed mechanisms include reducing lifetime exposure to ovarian hormones, reducing the cumulative number of ovulatory cycles and differentiation of the breast lobules [4,5]. We and others have evaluated the impact of reproductive factors in the etiology of BRCA-associated breast cancer, although the results are conflicting and vary by BRCA1 or BRCA2 mutation [6-8]. With respect to breastfeeding and breast cancer risk in BRCA1 mutation carriers, two previous studies reported no relationship [9,10] and three studies reported a protectiv
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