Publications by authors named "Trudy G Shaw"

12 Publications

  • Page 1 of 1

Analysis of the Gene in FAMMM Syndrome Families Reveals Early Age of Onset for Additional Syndromic Cancers.

Cancer Res 2019 06 9;79(11):2992-3000. Epub 2019 Apr 9.

Hereditary Cancer Center, Creighton University, Omaha, Nebraska.

Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary cancer syndrome that results from mutations in several genes, including the gene. In addition to melanoma, certain other malignancies such as pancreatic cancer are known to occur more frequently in family members who carry the mutation. However, as these families have been followed over time, additional cancers have been observed in both carriers and noncarriers. We sought to determine whether these additional cancers occur at higher frequencies in carriers than noncarriers. We performed survival analyses using 10 FAMMM syndrome families ( = 1,085 individuals) as well as a mixed effects Cox regression, with age at last visit to the clinic or age at cancer diagnosis as our time variable. This analysis was done separately for the known FAMMM-related cancers and "other" cancer groups. The survival curves showed a significant age effect with carriers having a younger age at cancer onset than noncarriers for FAMMM-related cancers (as expected) as well as for newly associated cancers. The Cox regression reflected what was seen in the survival curves, with all models being highly significant ( = 7.15E-20 and = 5.00E-13 for the FAMMM-related and other cancers, respectively). These analyses support the hypothesis that mutation carriers in FAMMM syndrome families have increased risk for early onset of several cancer types beyond the known cancers. Therefore, these individuals should be screened for additional cancers, and mutation screening should be extended to more than first-degree relatives of an index carrier patient. SIGNIFICANCE: This study shows that carriers of mutations in the gene in FAMMM syndrome are at increased risk for early onset of several cancer types beyond the known cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1580DOI Listing
June 2019

Commentary on Almassalha et al., "The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer".

Cancer Res 2016 10 16;76(19):5602-5604. Epub 2016 Sep 16.

Department of Dermatology, Keck USC School of Medicine and the Hoag-USC Advanced Skin Cancer Program, Los Angeles, California.

In this issue of Cancer Research, Almassalha and colleagues have proposed a new concept of the development of malignancy, that of the greater genomic landscape. They propose a stressor-related exploration of intracellular genomic sites as a response mechanism. This process can express sites with beneficial or deleterious effects, among them those that promote cell proliferation. They point out that their conception is broader, although certainly inclusive, of the process of gene induction. The authors view the physical process of chromatin reorganization as central to the exploration of the genomic landscape. Accordingly, they advocate the development of agents to limit chromatin structural modification as a chemotherapeutic approach in cancer. We found their theory relevant to understand the phenotypic heterogeneity of malignancy, particularly in familial cancer syndromes. For example, the familial atypical multiple mole melanoma (FAMMM) syndrome, related to a gene mutation, is characterized by a diversity of melanocytic lesions, only some of which become malignant melanoma. This new conceptualization can do much to increase understanding of the diversity of malignancy in families with hereditary cancer. Cancer Res; 76(19); 5602-4. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2319DOI Listing
October 2016

Familial atypical multiple mole melanoma (FAMMM) syndrome: history, genetics, and heterogeneity.

Fam Cancer 2016 07;15(3):487-91

Department of Preventive Medicine, Creighton University, 2500 California Plaza, Omaha, NE, 68178, USA.

Approximately 5-10 % of cutaneous melanoma occurs in kindreds with a hereditary predisposition. Mutations in the CDKN2A gene are found to occur in approximately 20-40 % of these kindreds. The first historical mention of what is now called the familial atypical multiple mole melanoma syndrome appears to be from 1820, with more reports throughout the 1950s, 1960s, and later years. In 1991, Lynch and Fusaro described an association between familial multiple mole melanoma and pancreatic cancer and work continues to elucidate the syndrome's genotypic and phenotypic heterogeneity. Individuals at risk for familial melanoma need periodic screenings. Unfortunately, adequate screening for pancreatic cancer does not currently exist, but pancreatic cancer's prominence in the hereditary setting will hopefully act as a stimulus for development of novel screening measures.
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http://dx.doi.org/10.1007/s10689-016-9888-2DOI Listing
July 2016

Milestones of Lynch syndrome: 1895-2015.

Nat Rev Cancer 2015 03 12;15(3):181-94. Epub 2015 Feb 12.

Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Grant Building S169, 1291 Welch Road, Stanford, California 94305, USA.

Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.
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http://dx.doi.org/10.1038/nrc3878DOI Listing
March 2015

Practical genetics of colorectal cancer.

Chin Clin Oncol 2013 Jun;2(2):12

Department of Preventive Medicine and Public Health, Creighton University, Omaha, NE, USA.

Hereditary colorectal cancer (CRC) is highly heterogeneous, both genotypically and phenotypically. The most frequently occurring hereditary colorectal cancer syndrome is Lynch syndrome, accounting for approximately 3% of the total colorectal cancer burden. Polyposis syndromes, such as familial adenomatous polyposis, account for a lesser percentage. Familial colorectal cancer, defined by family history, occurs in an estimated 20% of all colorectal cancer cases. With a worldwide annual colorectal cancer incidence of over one million, and annual mortality of over 600,000, hereditary and familial forms of colorectal cancer are a major public health problem. Lynch syndrome is attributable to DNA mismatch repair germline mutations, with the MSH2, MLH1, MSH6, and PMS2 genes being implicated. The characteristics of Lynch syndrome-associated colorectal tumors, including early age of onset and predilection to the proximal colon, mandate surveillance by colonoscopy beginning by age 20 to 25 and repeated every other year through age 40 and annually thereafter. Besides colorectal cancer, Lynch syndrome also predisposes to a litany of extracolonic cancers, foremost of which is endometrial cancer, followed by cancer of the ovary, stomach, renal pelvis and ureter, small bowel, hepatobiliary tract, pancreas, glioblastoma multiforme in the Turcot's variant, and sebaceous skin tumors in the Muir-Torre variant and, more recently identified, cancers of the breast and prostate. The most common polyposis syndrome is familial adenomatous polyposis, caused by mutations in the APC gene. Affected individuals have multiple colonic adenomas and, without treatment invariably develop colorectal cancer. Colonic surveillance with polypectomy may be pursued until the appearance of multiple colonic adenomas, at which time prophylactic colectomy should be considered. Extra-intestinal manifestations include desmoid tumor, hepatoblastoma, thyroid carcinoma, and medulloblastoma. Other polyposis syndromes include the hamartomatous polyp syndromes, including juvenile polyposis syndrome, Peutz-Jeghers syndrome, Cowden syndrome, and Bannayan-Ruvalcaba-Riley syndrome.
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http://dx.doi.org/10.3978/j.issn.2304-3865.2013.03.04DOI Listing
June 2013

Hereditary gastrointestinal cancer syndromes.

Gastrointest Cancer Res 2011 Jul;4(4 Suppl 1):S9-S17

Department of Preventive Medicine and Public Health, Creighton University, Omaha, NE.

The rapid growth of molecular genetics and its attendant germline mutation discoveries has enabled identification of persons who are at an inordinately high cancer risk and, therefore, ideal candidates for prevention. However, one must fully appreciate the extensive genotypic and phenotypic heterogeneity that exists in hereditary cancer. Once the causative germline mutation has been identified in a patient, high-risk members of the family can be similarly tested and identified and provided highly targeted surveillance and management opportunities. DNA testing can change the individual's presumed risk status and affect decision making by patients and their physicians regarding surveillance and management. Our purpose is to describe familial/hereditary cancers of the gastrointestinal tract, including familial Barrett's esophagus, hereditary diffuse gastric cancer, gastrointestinal stromal tumors, familial adenomatous polyposis and desmoid tumors, Lynch syndrome, small bowel cancer, and familial pancreatic cancer. We use our discussion of Lynch syndrome as a model for diagnostic and clinical translation strategies for all hereditary gastrointestinal tract cancers, which clearly can then be extended to cancer of all anatomic sites. Highly pertinent questions from the patient's perspective include the following: What kind of counseling will be provided to a patient with a Lynch syndrome mutation, and should that counseling be mandatory? Does the proband have the responsibility to inform relatives about the familial mutation, even if the relatives do not want to know whether they carry it? Is the patient is responsible for notifying family members that a parent or sibling has Lynch syndrome? Can notification be forced and, if so, under what circumstances? These questions point out the need for criteria regarding which family members to inform and how to inform them.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283002PMC
July 2011

Commentary: The shifting role of family history in Lynch syndrome diagnosis.

Colorectal Dis 2009 Jun 13;11(5):461-3. Epub 2009 Apr 13.

Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha NE 68178, USA.

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http://dx.doi.org/10.1111/j.1463-1318.2009.01882.xDOI Listing
June 2009

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications.

Eur J Hum Genet 2006 Apr;14(4):390-402

Department of Preventive Medicine, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA.

Lynch syndrome is the most common form of hereditary colorectal cancer (CRC). This review covers the cardinal features of Lynch syndrome with particular emphasis upon its diagnostic criteria, molecular genetics, natural history, genetic counseling, surveillance and management. Considerable attention has been given to the etiologic role of mismatch repair (MMR) genes as well as low penetrance alleles and modifier genes. The American founder mutation, a deletion of exons 1-6 of MSH2, is discussed in some detail, owing to its high frequency in the US (19 000-30 000 carriers). Genetic counseling is essential prior to patients' undergoing DNA testing and again when receiving their test results. Families with a lower incidence of CRC and extracolonic cancers, in the face of being positive for Amsterdam I criteria but who do not have MMR deficiency by tumor testing, are probably not Lynch syndrome, and thereby should preferably be designated as familial CRC of undetermined type. Patients who are either noncompliant or poorly compliant with colonoscopy, and who are MMR mutation positive, may be candidates for prophylactic colectomy, while MMR mutation-positive women who are noncompliant with gynecologic surveillance may be candidates for prophylactic hysterectomy and bilateral salpingo-oophorectomy.
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http://dx.doi.org/10.1038/sj.ejhg.5201584DOI Listing
April 2006

Inherited predisposition to cancer: a historical overview.

Am J Med Genet C Semin Med Genet 2004 Aug;129C(1):5-22

Department of Preventive Medicine, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA.

The hereditary predisposition to cancer dates historically to interest piqued by physicians as well as family members wherein striking phenotypic features were shown to cluster in families, inclusive of the rather grotesque cutaneous findings in von Recklinghausen's neurofibromatosis, which date back to the sixteenth century. The search for the role of primary genetic factors was heralded by studies at the infrahuman level, particularly on laboratory mouse strains with strong susceptibility to carcinogen-induced cancer, and conversely, with resistance to the same carcinogens. These studies, developed in the 19th and 20th centuries, continue today. This article traces the historical aspects of hereditary cancer dealing with identification and ultimate molecular genetic confirmation of commonly occurring cancers, particularly of the colon in the case of familial adenomatous polyposis and its attenuated form, both due to the APC germline mutation; the Lynch syndrome due to mutations in mismatch repair genes, the most common of which were found to be MSH2, MLH1, and MSH6 germline mutations; the hereditary breast-ovarian cancer syndrome with BRCA1 and BRCA2 germline mutations; the Li-Fraumeni (SBLA) syndrome due to the p53 mutation; and the familial atypical multiple mole melanoma in association with pancreatic cancer due to the CDKN2A (p16) germline mutation. These and other hereditary cancer syndromes have been discussed in some detail relevant to their characterization, which, for many conditions, took place in the late 18th century and, in the more modern molecular genetic era, during the past two decades. Emphasis has been placed upon the manner in which improved cancer control will emanate from these discoveries.
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http://dx.doi.org/10.1002/ajmg.c.30026DOI Listing
August 2004

Challenging colonic polyposis pedigrees: differential diagnosis, surveillance, and management concerns.

Cancer Genet Cytogenet 2004 Jan;148(2):104-17

Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA.

Hereditary polyposis syndromes show extensive phenotypic and genotypic heterogeneity within and among families, a situation that may hinder diagnosis. In these settings, germline mutation testing may be the sine qua non for diagnosis if such a mutation is identified in a patient or family. We provide examples of phenotypically differing polyposis pedigrees depicting various challenges in hereditary polyposis syndrome diagnosis. Our purpose is to augment physician understanding of phenotypic variation and thus help identify high-risk presymptomatic family members who could benefit from highly targeted surveillance and management strategies. We describe nine familial polyposis pedigrees displaying anecdotal clinical problems that can confound the differential diagnosis. Emphasis was given to a multidisciplinary approach focusing on pathological confirmation with respect to number, histology, and location of polyps in the gastrointestinal tract; a detailed family history of cancer at all anatomic sites; noncancer phenotypic features of hereditary polyposis syndromes; and appropriate molecular genetic testing in concert with genetic counseling. Improved physician understanding of the clinical natural history features, genetic transmission patterns, and appropriate gene testing will help in diagnosis and, ultimately, surveillance and management for the various hereditary polyposis syndromes.
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http://dx.doi.org/10.1016/s0165-4608(03)00280-2DOI Listing
January 2004

Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: Problems in diagnosis, surveillance, and management.

Cancer 2004 Jan;100(1):53-64

Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.

Background: To the authors' knowledge, hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most commonly occurring hereditary disorder that predisposes to colorectal carcinoma (CRC), accounting for approximately 2-7% of all CRC cases diagnosed in the U.S each year. Its diagnosis is wholly dependent on a meticulously obtained family history of cancer of all anatomic sites, with particular attention to the pattern of cancer distribution within the family.

Methods: The objective of the current study was to illustrate various vexing problems that can deter the diagnosis of HNPCC and, ultimately, its management. This was an observational cohort study. Sixteen HNPCC and HNPCC-like families were selected from a large resource of highly extended HNPCC families. High-risk patients were selected from these HNPCC families. An ascertainment bias was imposed by the lack of a population-based data set. Personal interviews and questionnaires were used for data collection.

Results: There was an array of difficulties highlighted by limitations in compliance, lack of a clinical or molecular basis for an HNPCC diagnosis, ambiguous DNA findings, problems in genetic counseling, failure to meet Amsterdam or Bethesda criteria, small families, lack of medical and pathologic documentation, poor cooperation of family members and/or their physicians, cultural barriers, economic stress, frequent patient fear and anxiety, perception of insurance discrimination, and limited patient and/or physician knowledge regarding hereditary cancer.

Conclusions: The diagnosis and management of HNPCC is predicated on physician knowledge of its phenotypic and genotypic heterogeneity, in concert with the multifaceted problems that impact on patient compliance.
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http://dx.doi.org/10.1002/cncr.11912DOI Listing
January 2004