The history of hereditary nonpolyposis colorectal cancer was first recognized formally in the literature by Henry Lynch in With advances of molecular genetics, there has been a transformation from clinical phenotype to genotype diagnostics. This has led to the ability to diagnose affected patients before they manifest with cancer, and therefore allow preventative surveillance strategies. Genotype diagnostics has shown a difference in penetrance of different cancer risks dependent on the gene containing the mutation.
Surgery is recommended as prevention for some cancers; for others they are reserved for once cancer is noted. Various surveillance strategies are recommended dependent on the relative risk of cancer and the ability to intervene with surgery to impact on survival. Risk reduction through aspirin has shown some recent promise, and continues to be studied.
Association of LS with prostate, breast, and lung cancers has also been reported 6 , 8 , 17 Table 1. The risks of CRC and extracolonic cancer in carriers vary depending on the different germline mutation in the MMR gene. Making the diagnosis of LS is critical because a missed diagnosis means overlooking the dangers of high lifetime cancer risks in mutation carriers.
One of the places in the tumor DNA where such errors become most manifest is at simple repetitive sequences microsatellites. Therefore, identifying disruptions in repetitive sequences in the tumor DNA, but not in the adjacent normal tissue, is the gold-standard method for detecting MSI The most well-known of these is epigenetic silencing of the MLH1 gene caused by hypermethylation of the MLH1 promoter 8. Additionally, this hypermethylation is often associated with a BRAF c. VE mutation Rarely, such hypermethylation can be inherited. In a series of LS-suspected patients, the frequencies of germline MLH1 promoter hypermethylation was 0.
The MMR proteins work to maintain genomic fidelity by identifying and correcting replication errors single nucleotide mismatch or insertion and deletion loops that have escaped the normal editing function of DNA polymerase According to the study of Dr. However, recent publications have indicated that the frequencies of MSH6 and PMS2 gene mutations have likely been underestimated in the past, because affected carriers display less striking phenotypes.
The early identification of LS is critical for effective cancer prevention in probands and their at-risk family members. Historically, the diagnosis of LS relied on pedigree features such as clustering of cancers at early ages. However, diagnostic approaches to LS have significantly evolved over the past years. By , these criteria were replaced by the Amsterdam II criteria Table 2 , to include some extracolonic tumors except gastric and ovarian cancer as qualifying criteria for LS There are several limitations to replying on clinical criteria alone.
A comprehensive family history is often not available for every cancer patient, and family size has decreased over time, making pedigrees less informative. Thus, current guidelines for LS diagnosis utilize not only family history but also molecular testing, germline mutational analysis, and clinical prediction models. We summarized most currently published evidence-based guidelines for LS diagnosis Table 3 , and discuss their differences from the Asian and Western perspectives 6 , 8 , 36 - The guidelines differ depending on whether the individual is clinically affected by CRC or whether a germline mutation is known in the family The remaining discussion pertains to testing of individuals presenting with a CRC without a known family mutation.
Current guidelines around the globe remain divided in terms of selective testing or universal testing of CRC patients for LS. More recent guidelines from Western countries advocate a universal testing approach, while still acknowledging alternative strategies that are more selective. On the other hand, the older European guideline and the available guidelines from Asia have taken the selective testing approach Table 3. Selecting who to test based on clinical criteria outlined in Table 2 has been criticized for low sensitivity and efficiency.
These computational models aim to estimate the probability of finding a pathogenic mutation in a MMR gene. Unfortunately, practical utilization of these models has remained limited by lack of awareness among physicians and lack of compliance by suspected patients. During the Jerusalem workshop organized by Dr. Shike in , selective testing of CRC patients who are younger than 70 years of age was proposed as more cost-effective than universal testing, while missing only 4. A pooled analysis demonstrated that relative to universal testing, the relative sensitivity for selective testing based on the Bethesda guidelines was As more guidelines support universal testing in all newly diagnosed CRC cases regardless of age 8 , 37 , attention should be paid to the impact on healthcare costs, patient anxiety, and the feasibility of widespread adoption.
With advances in genomic medicine and next-generation sequencing NGS , multiple genes can be sequenced using panel testing.
When compared to traditional phenotype-directed germline testing, multi-gene panel testing can identify individuals who have hereditary cancer syndrome with atypical and even no, phenotypes or clinical presentations It can test multiple genes simultaneously and is more efficient when there is a wide differential diagnosis for the potential hereditary syndromes. There is wide variation in the exact nature and composition of the available panels.
Some include not only highly penetrant genes that predispose mutation carriers to CRC e. Therefore, the main challenge of clinical use of these panels is the increased complexity of result interpretation and assessment of the clinical significance of uncertain or unexpected findings. And the need for careful case selection under the direction of a clinician with expertise in genetics is emphasized Germline testing for LS can lead to three categories of results: pathogenic mutation, variant of uncertain significance VUS , and informative negative finding The practice of universal tumor MSI testing followed by confirmatory germline mutation testing has led to identification of a cohort of patients who present with MSI-high CRC, no evidence of MLH1 promoter hypermethylation or BRAF mutation, but have no identified pathogenic mutation on germline testing The use of multiplex gene panel testing is associated with even higher proportions of variants of uncertain significance and uninformative negative results would be observed.
Currently, these variants are thought to potentially represent missense mutations 52 , which would cause unknown or highly variable clinical effects.
There is a significant amount of active research in variant reclassification. These efforts utilize a combination of in silico prediction models, in vitro functional assays, and aggregate clinical data. However, translation of variant reclassification approaches to clinical practice is challenging.
SNIP measures contextual citation impact by wighting citations based on the total number of citations in a subject field. Lynch syndrome was formerly known as Hereditary Nonpolyposis Colorectal Cancer. Currently, these two nomenclatures each have their unique definitions and are no longer used interchangeably. The history of hereditary nonpolyposis colorectal cancer was first recognized formally in the literature by Henry Lynch in With advances of molecular genetics, there has been a transformation from clinical phenotype to genotype diagnostics.
This has led to the ability to diagnose affected patients before they manifest with cancer, and therefore allow preventative surveillance strategies. Genotype diagnostics has shown a difference in penetrance of different cancer risks dependent on the gene containing the mutation. Surgery is recommended as prevention for some cancers; for others they are reserved for once cancer is noted. Various surveillance strategies are recommended dependent on the relative risk of cancer and the ability to intervene with surgery to impact on survival. Risk reduction through aspirin has shown some recent promise, and continues to be studied..
Journal of Coloproctology. ISSN: Open Access Option. Previous article Next article. Issue 2. Pages April - June Download PDF. Andrew I. Wolf a , Adam H.here
Historical review of Lynch syndrome
Buchanan b , Linda M. Farkas c ,. Corresponding author. This item has received. Under a Creative Commons license. Article information.
- Distinguishing clinicopathologic features of LS?
- Midnight Awakening (Midnight Breed Book 3).
- Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI].
Risk reduction through aspirin has shown some recent promise, and continues to be studied. Full text is only aviable in PDF. Lynch, A.
The 150 most important questions in cancer research and clinical oncology series: questions 94–101
Gastroenterology, 53 , pp. Heredity with reference to carcinoma as shown by the studies of cases examined in the pathological laboratory of the University of Michigan, Arch Intern Med, 12 , pp.
Cancer, 27 , pp. Lynch, R. Harris, W. Bardawil, P. Lynch, H. Guirgis, M. Swartz, et al. Management of hereditary site-specific colon cancer. Arch Surg, , pp. Lynch, T. Drouhard, G. Schuelke, K. Biscone, J. Lynch, B. Hereditary nonpolyposis colorectal cancer in a Navajo Indian family. Cancer Genet Cytogenet. Lynch, G.
Schuelke, W. Kimberling, W. Albano, J. Lynch, K. Biscone, et al. Hereditary nonpolyposis colorectal cancer Lynch syndromes I and II. Biomarker studies.
Related Hereditary Colorectal Cancer: 5 (MD Anderson Solid Tumor Oncology Series)
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