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Lynch Syndrome 101: The nuts and bolts of testing for Muir Torre
Lynch Syndrome is one of the most common forms of hereditary cancer. First described by Dr. Warthin in 1913,
the syndrome remained unacknowledged by the medical community for over 60 years, when Dr. Henry Lynch
started exploring pedigrees of his high risk patients. To his surprise, one of his families was the initial family
(Family G) reported by Warthin. Dr. Lynch’s early publications garnered international interest in what appeared
to be a hereditary syndrome associated with increased risk for cancers of the intestines. The syndrome was thus
termed Hereditary Non-Polyposis Colorectal Cancer (HNPCC). It is now known that the syndrome encompasses a
broad spectrum of cancers, including those of the colon, small intestine, endometrium, ureter/renal pelvis,
kidney, bladder, stomach, pancreas, ovary, brain, liver and gall bladder, skin (sebaceous adenomas, sebaceomas,
sebaceous cancers, keratoacanthomas), possibly breast, prostate and sarcomas, and recently, adrenocortical
carcinoma was added to the seemingly ever-growing list. In recognition of Dr. Lynch's contribution, this complex
pattern of familial cancers was renamed Lynch Syndrome. Lynch Syndrome (LS) is caused by a hereditary
mutation in a family of genes known as DNA Mismatch Repair genes.
The Mismatch Repair genes (MMR genes) consist of a family of genes, each of which has a slightly different role in
the DNA repair process. The proteins produced by the genes form a complex which straddles newly synthesized
DNA, trolling for nucleotide mismatches which may have occurred during the process of DNA replication. By
utilizing each of the MMR proteins in this complex, base-pair mismatches are detected, excised and repaired,
leading to maintenance of the genomic integrity. Deleterious genetic mutations in an MMR gene disable the
gene and its protein, which in turn compromises formation of the MMR complex, resulting in the accumulation of
countless, unrepaired sequence changes throughout genome. Many of these somatic mutations undoubtably
occur in gene deserts, or other areas which do not negatively impact cell function. However, unrepaired
mutations occurring in genes which regulate cell growth, angiogenesis, apoptosis or other critical cell functions
can lead to neoplastic transformation. Frequently dividing cells, such as those within the lumen of hollow organs
and in the skin, are at elevated risk for malignancy in individuals who harbor bi-allelic mutations in an MMR gene.
The four genes that contribute to LS in humans are MLH1, MSH2, MSH6, and PMS2. Other MMR genes exist, but
none are believed at this time to play a major role in Lynch Syndrome. The most commonly mutated genes are
MLH1 and MSH2, followed by MSH6 and PMS2. Regardless of which MMR gene is mutated in a Lynch family,
those who inherit the mutated gene are at higher risk for development of cancer, with lifetime risks that can
exceed 80%. Lynch Syndrome mutations are germline, e.g., the mutation is present in either the sperm or the
egg. As the fertilized conceptus divides, each cell will contain one copy of the mutated gene. Although the
mutated allele is unable to produce a normal MMR protein, the level of protein synthesized by the normal (wild
type) allele is sufficient to maintain mismatch repair. Cancers arise when a somatic mutation knocks out the
remaining normal copy of the MMR gene within a given cell. That cell, regardless of type, now has no MMR
defenses against genetic damage or changes in the sequence of the DNA.
The mode of inheritance in Lynch Syndrome is dominant, with each child having a 50% chance of inheriting the
mutated gene and a 50% chance of inheriting a normal allele from the affected parent. Pedigrees observed in
Lynch families are usually checkered with a multi-generational pattern of malignancies, with ages of diagnosis
ranging from early 20's to late 70s or older. Younger diagnosis is commonly observed in LS families. Those
affected with LS are, in addition, at risk for both synchronous and metachronous tumors. Diagnosis of more than
seven primaries has been confirmed in some LS patients. Cancers of the colorectum are the most common,
followed by endometrial carcinoma. For colon, the transition period from polyp to cancer is accelerated (2-3
years, compared to 10-15 years for those with non-hereditary colorectal cancer). Hence, fastidious surveillance
measures are not only required, but have been demonstrated to reduce both morbidity and mortality. For some,
prophylactic surgical procedures might be recommended.
Muir-Torre Syndrome is a variant of Lynch syndrome in which individuals are additionally at risk for skin tumors,
including sebaceous adenomas, sebaceomas, sebaceous epitheliomas, sebaceous adenocarcinomas, and
keratoacanthomas. Not all LS patients develop sebaceous neoplasms, and not all sebaceous neoplasms are the
result of impaired mismatch repair mechanisms. Extra-occular lesions (especially those occurring on the trunk
and extremities) are thought to be more common in LS patients, but futher studies are needed to confirm this and
to fully investigate the spectrum of cutaneous lesions which arise as a result of germline MMR mutations.
Currently, sebaceous hyperplasia is not thought to be associated with LS. Referral of any patient diagnosed with a
sebacous neoplasm to a genetic counselor, or testing of tumor tissue to confirm the presence or absence of MMR
protein expression, can be instrumental in identifying previously undiagnosed LS families.
Two methods are primarily used to test tumor tissue for Lynch Syndrome markers. Immunohistochemistry (IHC)
is used to evaluate tissue for the expression of MMR proteins. Separate slides are stained with antibodies to each
of the four MMR proteins. Positive staining suggests that the MMR gene is not mutated and is able to produce a
normal and functional protein. In most patients with Lynch Syndrome, the mutated MMR gene produces an
abnormal protein that cannot complex with the antibody and as a result, the tissue section will appear pale in
color. IHC is useful because it may indicate which MMR gene is mutated, which can direct subsequent genetic
testing. The second test is evaluation for microsatellite instability, or MSI. This test compares DNA microsatellite
sequences (which are more prone to replication-associated mismatches) in normal tissue to identical sequences in
tumor tissue. In LS mutation carriers, the number of mismatches in tumor tissue will outnumber that of its
normal counterpart. The presence of microsatellite instability suggests that one of the MMR genes is not
functioning properly, but does not indicate which gene might be mutated. MSI requires DNA extraction from both
tumor and normal tissue, and testing is generally done in specialized laboratories. Confirmation of LS is
conducted through genetic testing on genomic DNA. A genetic counselor or MD geneticist is in the best position
to make the determination of which tests should be ordered.
Awareness of Lynch Syndrome in clinicians who assess cutaneous lesions can have far reaching benefits. Querying
a patient about family history or ensuring that paraffin-embedded tumor tissue is available should testing be
warranted are small steps which can ultimately lead to the identification of LS in unsuspecting patients. In turn,
testing of family members can prove to be a life-saving measure for an entire extended family, as screening
procedures in newly identified mutation-positive individuals can begin immediately. For those who are young
adults, this translates into decades of additional screening. Within a matter of months, a family with no
knowledge of Lynch Syndrome can transition into a family with scores of relatives who now are aware of their
mutation status. This cascade brings a cycle of hope to families that have suffered from generations of cancer
diagnoses and deaths.
Terrilea Burnett, PhD
Hawaii Colorectal Cancer Family Registry
University of Hawaii Cancer Center
Honolulu, HI 96813
Familial Cancer (May 2013) vol 12 (entire issue is devoted to Lynch Syndrome)
Orta L, Klimstra DS, Qin J, Mecca P, Tang LH, Busam KJ, Shia J. Towards identification of hereditary DNA mismatch
repair deficiency: sebaceous neoplasm warrants routine immunohistochemical screening regardless of patient’s
age or other clinical characteristics.. Am J Surg Pathol 2009; 33: 934-944.
Shalin SC, Lyle S, Calonje E, Lazar AJF. Sebacaceous neoplasia and the Muir-Torre syndrome:
connections with clinical implications. Histopathology 2010; 56: 133-147.
important
On-line Resources for Lynch Syndrome
National Cancer Institute (NCI): www.cancer.gov (for general information about cancer and amino acids)
NCI : www.cancer.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional/Page3#Section_89
U.S. National Library of Medicine, Genetics Home Reference: www.ghr.nlm.nih.gov/condition/lynch-syndrome
National Library of Medicine, NIH: www.ncbi.nlm.nih.gov/books/NBK1211
Cancer.Net: www.cancer.net/cancer-types/lynch-syndrome
Lynch Syndrome Screening Network: www.lynchscreening.net
Mayo Clinic: www.mayoclinic.com/health/lynch-syndrome
UCSF Medical Center: www.ucsfhealth.org/conditions/lynch_syndrome/
Lynch Syndrome International: www.lynchcancers.com/
Lynch Syndrome Australia: www.lynchsyndrome.org.au/
NCCN: http://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf
LS: explanation for families: http://ghr.nlm.nih.gov/condition/lynch-syndrome/show/Educational+resources