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Photo Courtesy of Marco Pompei
Medicine is not merely a science but an art. The character of the physician may act more powerfully upon the patient than the drugs employed.
Understanding the busy schedule of the professional, the following pages are quick guides for professionals to acquaint them with the basic knowledge of Lynch syndrome and how to diagnose and manage the disorder.
More detailed information to supplement these pages can be found by clicking on the LSI Library link on the Main Menu, to the left of this page, whereupon selected studies are available as well as clinical trials, registries, patient payment assistance programs, anti-discrimination laws and other resources relative to Lynch syndrome.
Simply follow the links on the top right to review the basic steps toward diagnosis of the Lynch syndrome.
Lynch syndrome is part of a syndrome known as hereditary nonpolyposis colorectal cancer (HNPCC). This syndrome includes half of the individuals individuals having Familial Colorectal Cancer Type X, who display no evidence of DNA mismatch repair gene deficiency and the other half having Lynch syndrome, which is indicated by a defect in mismatch repair genes.
Approximately 10% of all cancers are hereditary. Thirty five percent (35%) of colorectal cancers have been stated to be the result of a familial or hereditary condition.
The American Cancer Society reports about 145,000 people per year contract colorectal cancer and studies conducted by the James Cancer Center at Ohio State University indicate one in every 35 of those persons are affected with Lynch syndrome.
Geneticists preduct approximately 800,000 individuals within the United States, alone, are affected by Lynch syndrome, however it is believed less than 5% of that number have been diagnosed. It is thought one in every 440 to 550 persons is affected by Lynch syndrome.
Relying upon these numbers, it can be reasonably assumed each physician whose practices provides care for 3,000 to 4,000 persons, has five to ten patients affected by Lynch syndrome, and each patient has an average of three to five direct family members and most likely over a dozen second degree family members affected.
The only way to diagnose these patients is either by taking a family history, to assess risk and arrange for the genetic testing of those patients, or when those patients present with colorectal and endometrial tumors, arrange for pathological tesitng of those tumors for the characteristics of Lynch syndrome.
- The only true form of diagnosis of Lynch syndrome is through genetic testing.
- Genetic testing saves lives. During genetic testing, the DNA is sequenced seeking out defects in four primary mismatch repair genes, MLH1, MSH2, MSH6, PMS2 and another gene, TACSTD1 ( Epcam) which sits to the right or to the front of the MSH2 gene. Deletions in the EPCAM gene have been found to silence or turn off the MSH2 gene and in doing so, predisposes the individual to cancers of the Lynch syndrome.
The lifetime risks for the cancers of Lynch syndrome are high:
LYNCH CANCERS LIFETIME RISKS (Source NCCN Guidelines 1.2013)
| || || ||MLH1-MSH2 ||1,2||MSH6||2|| ||PMS2 ||3|
|Cancer||Gen Pop1|| ||Risk||Avg Age|| ||Risk||Avg Age|| ||Risk||Avg Age|
|---------------||------------|| ||-----------||-----|| ||--------------||-----|| ||----------||-----------|
|Colon||5.50%|| ||40%-40%||44-81 yrs|| ||10%-22%||54 yrs|| ||15%-20%||51-66 yrs|
|Endometrium||2.70%|| ||25%-60%||48-62 yrs|| ||16%-28%||55 yrs|| ||15% ||49 yrs|
|Stomach||<1%|| ||1%-13%||56 yrs|| ||<3%||63 yrs|| ||6%*||70-73 yrs|
|Ovaries||1.60%|| ||4%-24%||42.5 yrs|| ||1%-11%||46 yrs|| ||6%*||42 yrs|
|Hepatobiliary Tract||<1%|| ||1.4%-4%||50-57 yrs|| ||Unk||Unk|| ||6%*||Unknown|
|Urinary Tract||<1%|| ||1%-4%||54-60 yrs|| |
|65 yrs|| ||6%*||Unknown|
|Small Bowel||<1%|| ||3%-8%||47-49 yrs|| ||Unk||54 yrs|| ||6%*||59 yrs|
|Brain/CNS||<1%|| ||1%-3%||50 yrs|| ||Unk||Unk|| ||6%*||45 yrs|
|Sebaceous Neoplasms||<1%|| ||1%-9%||Unk|| ||Unk||Unk|| ||Unknown||Unknown|
|Pancreas||<1%|| ||1%-6%||Unk|| ||1%-6%||Unk|| ||Unknown||Unknown|
|1. Kohlman, W Gruber, SB||2012|| ||www.genetests.org|| |
|1,2 Bonatel et al ||Jama 2011|| || || || |
|3 Sentel, et al||Gastroentrology 2008|| || |
|4 Kastrinos et al ||Jama 2009|| || || || |
* Starred Cancers combined = 6% Risk.
More detailed information on the diagnosis and management of Lynch syndrome is below.
The Basics of Identification, Diagnosis and Management of Lynch Syndrome
Identification, Diagnosis and Management - Excellent Immediate Resource Guide for Physicians: Lynch Syndrome by Wendy Kohlman, MS and Stephen B. Gruber, MD, PhD, revised 9/20/2012
Is Breast Cancer A Part of the Lynch Syndrome?
Breast cancer has been identified as an integral component of LS based upon mismatch repair germline mutation factors in breast cancer tissues from family members who are not only at high risk, but, moreover, who had Lynch syndrome cancers, such as involving the colorectum. Breast cancer is exceedingly common in the population and, therein, its occurence in Lynch syndrome families could be due to chance, but importantly, a subset will likely be integrally related to a germline mismatch repair Lynch syndrome mutation in some LS families. Therefore, it would be prudent to mount a screening and management program for Lynch syndrome in those families where breast cancer is believed to be an integral lesion.
What Are Cost Effective Methods Of Tumor Testing?
A detailed cost-effectiveness analysis* of screening for LS was completed after the EGAPP™ recommendation was published. The four testing approaches evaluated were found to be cost effective in the following order, from most to least cost effective:
- Preliminary screening of tumor tissue using IHC, plus BRAF
- Preliminary screening of tumor tissue using IHC only
- Preliminary screening of tumor tissue using MSI
- Genetic sequencing (DNA analysis) for all 4 MMR genes
What Is The Cost Effectiveness Of Genetic Testing?
*The Cost-Effectiveness of Genetic Testing Strategies for Lynch Syndrome Among Newly Diagnosed Patients with Colorectal Cancer, published online on January 15, 2010 in Genetics in Medicine. Authors: Mvundura M, Grosse SD, Hampel H, Palomaki GE.
Widespread Genetic Testing Appears Cost Effective published online on 1/4/2011 in Cancer Prev Res (Phila) Authors: Dinh, TA, Rosner, BL, Atwood, JC, Boland, CR, Syngal S, Vasan, HF, Gruber, SB, Burt, RW
New NCCN guidelines recommend "MMR protein testing should strongly be considered for ALL colon cancer patients <70 years of age based upon an increased likelihood of Lynch syndrome in this population. (NCCN Guidelines for IHC-MSI testing) Some centers, however, now perform IHC (and sometimes MSI) testing on all colorectal tumors to determine which patients should have genetic testing for Lynch syndrome. The cost effectiveness of this so-called " reflex testing" approach has been confirmed for colorectal cancer and this approch was endorsed by the Evaluation of Genomic Applications in Prevention and Practice. (EGAPP) working group at the Centers For Disease Control (CDC)."
LSI recommends germline testing for individuals who meet the Amsterdam criteria or who have a family history of a diagnosis of Lynch syndrome.