Trudy G. Shaw

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

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.

Milestones of Lynch syndrome: 1895-2015

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 Warthins 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.

Hereditary Pancreatic Cancer

Hereditary pancreatic cancer (PC) appears to be exceedingly heterogeneous, as evidenced by its association with a variety of integrally associated diverse cancers and/or differing mendelian inherited cancer syndromes, which include the Lynch syndrome II variant of hereditary nonpolyposis colorectal cancer, hereditary breast-ovarian cancer syndrome in families with the BRCA2 mutation, hereditary pancreatitis, Peutz-Jeghers polyposis and the familial atypical multiple-mole melanoma syndrome in families with the CDKN2A(p16) germline mutation. Because of this heterogeneity, we provide a conservative estimate that about 5% (1,460) of PC cases in the US annually are hereditary. Although this number is relatively small, members of hereditary PC families serve as excellent models for studying the etiology, natural history, biomarkers, pathogenesis, potential carcinogenic exposures and their perturbation of underlying genetic events, and treatment of PC. These individuals would benefit greatly from method(s) capable of detecting cancer at an early stage, and such knowledge would also be useful for improving the diagnosis of the much more common ‘sporadic’ form of PC.

Inherited predisposition to cancer: A historical overview

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 Recklinghausens 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.

Screening for familial and hereditary prostate cancer.

Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in Man® Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC.

Communication and technology in genetic counseling for familial cancer

When a cancer predisposing germline mutation is detected in an index case, the presence of the underlying syndrome is confirmed and the potential for predictive testing of at‐risk relatives is established. However, the reporting of a positive family history does not routinely lead to communication of information about risk to close, much less distant relatives. This review summarizes information technology utilized to address penetration or ‘reach’ of knowledge of risk within extended families, including the use of telephone and video counseling to reach distant patients, and anticipate novel internet‐based processes for communication between investigators and relatives.

HNPCC (Lynch Syndrome): Differential Diagnosis, Molecular Genetics and Management - a Review

HNPCC (Lynch syndrome) is the most common form of hereditary colorectal cancer (CRC), wherein it accounts for between 2-7 percent of the total CRC burden. When considering the large number of extracolonic cancers integral to the syndrome, namely carcinoma of the endometrium, ovary, stomach, hepatobiliary system, pancreas, small bowel, brain tumors, and upper uroepithelial tract, these estimates of its frequency are likely to be conservative. The diagnosis is based upon its natural history in concert with a comprehensive cancer family history inclusive of all anatomic sites. In order for surveillance and management to be effective and, indeed, lifesaving, among these high-risk patients, the linchpin to cancer control would be the physician, who must be knowledgeable about hereditary cancer syndromes, their molecular and medical genetics, genetic counseling, and, most importantly, the natural history of the disorders, so that the entirety of this knowledge can be melded to highly-targeted management.

Practical genetics of colorectal cancer

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 Turcots 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.

Familial prostate cancer and HOXB13 founder mutations: geographic and racial/ethnic variations

Genome-wide association studies (GWAS) have recently made major contributions to the identification of mutations inclusive of G84E in HOXB13 for prostate cancer (Ewing et al. 2012) as featured in this editorial regarding the paper by Xu et al. (2012) published in this issue of the journal. However, along with the contributions of GWAS, there has been the rapid emergence of new technologies dealing with next-generation DNA sequencing (NGS) technology, which are providing unique opportunities to advance this knowledge. Specifically by sequencing the entire genome, entire exome or entire transcriptome, NGS allows an unbiased view to detect genetic defects in familial cancer aggregations as demonstrated by recent cancer genetic/ genomic studies (Thompson et al. 2012; Hellebrand et al. 2011). The exome sequencing method, first developed in 2009, uses the next-generation sequencers to sequence only the exome, that is, the coding part, of the targeted genome (Gnirke et al. 2009; Ng et al. 2009; Maher 2009; Choi et al. 2009). When compared to whole genome sequencing, the advantages of exome sequencing include its lower cost and simpler analysis of the sequences, while the mutations identified will provide functional information by focusing on the mutated gene. More importantly, as mutations in the coding region make up 85 % of the genetic disease-causing mutations (Cooper et al. 1995), identifying coding mutations should provide an opportunity with a high chance of determining the mutations contributing to a particular genetic disease. The major technical challenge of exome sequencing was the standardization of the exome DNA extraction process to ensure inclusion of exon DNA templates for NGS sequencing. This problem has been solved with the development of commercial exome extraction kits by NimbleGen, Agilent, and Illumina companies in 2010–2011. Exome sequencing has become a matured method for genetic study, and provides a powerful means to detect genetic alterations affecting known genes in cancers (Gnirke et al. 2009; Ng et al. 2009; Maher 2009; Choi et al. 2009). This background is being discussed in this editorial with respect to the Xu et al. (2012) paper, given the potential that exome sequencing advances have for scientifically enhancing GWAS. A recurrent, albeit rare, mutation (G84E) in HOXB13 was recently identified by Ewing et al. (2012) in a previously recognized region of linkage at 17q21-22 as harboring an increased risk for familial prostate cancer. Once confirmed and further clarified, this observation will have the potential to be clinically translatable. Xu et al. (2012) have utilized a large international sample of prostate cancer-prone families who were recruited by the International Consortium for Prostate Cancer Genetics (ICPCG) in order to confirm the findings of Ewing et al. (2012) that the G84E mutation is rare, but that it is significantly associated with predisposition to prostate cancer. In the Xu et al. cohort, at least one mutation carrier was identified in each of 112 prostate cancer families (4.6 % of all 2,443 prostate cancer families studied), all of whom were of European descent. The G84E mutation was more frequently encountered in males Invited editorial on Xu et al. (2012).

Commentary on Almassalha Et Al., "the Greater Genomic Landscape: The Heterogeneous Evolution of Cancer"

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.