Objective: Patients diagnosed with colorectal cancer before the age of 50 years are recommended for Lynch syndrome (LS) testing according to current clinical guid

/pdf/lynch-syndrome-patients-with-limited-family-history-1pccp2hzs4.pdf

Lynch Syndrome Patients with Limited Family History Identified in a Laboratory Setting: A Descriptive Study

Purpose Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups.

/pdf/feasibility-of-screening-for-lynch-syndrome-among-patients-4uxejch1mi.pdf

Feasibility of screening for Lynch syndrome among patients with colorectal cancer.

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.

Milestones of Lynch syndrome: 1895-2015

High-penetrance mutations in several genes have been identified that contribute to hereditary colorectal cancer. The role of these mutations in cancer pathogenesis is well understood and their detection is successfully used in clinical diagnosis. In stark contrast, our understanding of the influence of low-penetrance mutations that account for most of the remaining familial cases of colorectal cancer, as well as an unknown proportion of sporadic cases, is far less advanced. Extensive ongoing research into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease aetiology and developing new diagnostic, preventive and therapeutic strategies.

Genetic predisposition to colorectal cancer

[Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer].

ContextHereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch
syndrome, is caused by mutations in the mismatch repair genes and confers
an extraordinarily high risk of colorectal, endometrial, and other cancers.
However, while carriers of these mutations should be identified, counseled,
and offered clinical surveillance, at present the mutations are not tested
for in mutation analyses.ObjectiveTo describe the prevalence of a large genomic deletion encompassing
exons 1 to 6 of the MSH2 gene that is widespread
in the US population as a result of a founder effect.Design, Setting, and PatientsOngoing genealogical and historical study conducted to assess the origin
and spread of an MSH2 mutation previously identified
in 9 apparently unrelated families with putative HNPCC and living in widely
different geographic locations in the United States.Main Outcome MeasuresClassification of family members as carriers or noncarriers of the MSH2 mutation; spread of the mutation across the continental
United States.ResultsTo date, 566 family members of the 9 probands have been identified to
be at risk and counseled; 137 of these have been tested, and 61 carry the
founder mutation. Three families have been genealogically shown to descend
from a German immigrant family that arrived and first settled in Pennsylvania
in the early 1700s. Movements of branches of the family from Pennsylvania
through North Carolina, Alabama, Kentucky, Missouri, Iowa, Nebraska, Utah,
Texas, and California have been documented, and carriers of the mutation have
already been diagnosed in 14 states. In contrast, the deletion was not found
among 407 European and Australian families with HNPCC.ConclusionThe postulated high frequency and continent-wide geographic distribution
of a cancer-predisposing founder mutation of the MSH2 gene
in a large, outbred (as opposed to genetically isolated) population, and the
ease with which the mutation can be detected, suggest that the routine testing
of individuals at risk for HNPCC in the United States should include an assay
for this mutation until more is learned about its occurrence.

https://jamanetwork.com/journals/jama/articlepdf/198184/joc32630_718_724.pdf

A Founder Mutation of the MSH2 Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States

Multiple primary cancer, including transitional cell carcinoma of the upper uroepithelial tract in a multigeneration HNPCC family: molecular genetic, diagnostic, and management implications.

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A Founder Mutation of the MSH2 Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States

Multiple primary cancer, including transitional cell carcinoma of the upper uroepithelial tract in a multigeneration HNPCC family: molecular genetic, diagnostic, and management implications.