FaCD Online Syndrome Fact Sheet

Last updated: 24 Oct 2012

Name: Lynch syndrome

Synonym: Hereditary Non-Polyposis Colorectal Cancer, HNPCC, Lynch syndromes 1 and 2 (= Cancer Family Syndrome), Hereditary Mismatch Repair Deficiency syndrome, HMRDS

Mode of Inheritance: AD

OMIM number: 114500 114400 120435 120436 600678 600259

Genes

EPCAM/TACSTD1, mapped to 2p21
MLH1, mapped to 3p21.3
MSH2, mapped to 2p21-p22
MSH6, mapped to 2p16
PMS2, mapped to 7p22

Tumor features

adenomatous polyps in the small intestine
astrocytoma
biliary tract cancer (incl. gallbladder)
colorectal adenomas
endometrial cancer
ependymoma
gastric cancer, intestinal type
gastrointestinal adenomas
gastrointestinal cancer
gastrointestinal polyps
glioblastoma (multiforme)
glioma of the brain
keratoacanthoma
ovarian cancer (i.e. epithelial origin)
pancreatic adenocarcinoma
prostate cancer
renal pyelum cancer
sebaceous adenoma
sebaceous carcinoma
sebaceous epithelioma
ureter cancer

Tumor features (possible)

breast cancer
breast cancer, male
chondrosarcoma
gliosarcoma
hemangiopericytoma, malignant
Hodgkin disease (Hodgkin's lymphoma)
laryngeal cancer
leiomyosarcoma
liposarcoma
lung/bronchial cancer
malignant fibrous histiocytoma
melanoma, cutaneous
non-Hodgkin lymphoma
osteosarcoma
primitive neuroectodermal tumor (PNET)
sarcoma
testicular germ cell tumor
urinary bladder cancer
uterus, sarcoma of the

Comment

Lynch syndrome, the name referring to oncologist Henry Lynch who contributed greatly to our knowledge of this disorder, is an autosomal dominant disorder[1]. It is characterized by a 25-70% cumulative life-time risk of colorectal cancer, often with an early onset (average 40-50 years) and proximal location. Number of adenomatous colorectal polyps is generally small, <5-10. There is an increased risk to develop extra-colorectal cancer, including endometrial cancer, with a cumulative life-time risk of 25-70%, ovarian cancer (3-10%, possibly higher for MSH6), gastric cancer (2-4%), cancer of the small intestine (4-7%), upper urinary tract (1-12%), brain (1%?), hepatobiliary tract (?%), pancreas(3,7%[37]), brain and sebaceous glands (?%, see also the Muir-Torre variant of Lynch syndrome).[2-9,20].

With the exception of endometrial cancer, MSH2 mutation carriers appear to have a higher risk to develop extra-intestinal cancer than MLH1 and MSH6 mutation carriers[20]. For carriers of germline MSH6 mutations the age at diagnosis of endometrial cancer is lower and the age at diagnosis of colorectal cancer higher than for MLH1 and MSH2 mutation carriers[5-7,10,38]. Quehenberger et al[9] and Carayol et al[11] demonstrated a large overestimation of colorectal cancer risk in Lynch syndrome (20+% rather than 70-90%). A recent study suggested approximately 50% risk of colorectal cancer by the age of 70 years[21]. Tumor risk appears to be modified by a CA repeat in the IGF1 gene[24] and presence of CHEK2 1100delC[25]. Senter et al[26] recently published the first risk estimates for carriers of PMS2 mutations. For North America, cumulative cancer risk to age 70 years was estimated at 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. Survival in women with ovarian cancer caused by Lynch syndrome appears to be much better than in women with BRCA1/2 mutations[35].

Incidental cases of other tumor types have been reported in which tumor findings pointed to a causal role of the Lynch syndrome gene mutations: male and female breast cancer[29-32], testicular germ cell tumors[23], sarcoma[27,28], thyroid cancer[12], lymphoma[12,19], melanoma[22], lung cancer[34] and a cerebral primitive neuroectodermal tumor (PNET)[36]. There is no proof yet that Lynch syndrome families have a strongly increased risk to develop these tumor types. Their is evidence for an increased prostate cancer risk[23,40-43],

At the molecular level, Lynch syndrome is characterized by germline mutations in genes responsible for the repair of DNA replication errors, the mismatch repair (MMR) genes, in particular MLH1, MSH2, MSH6 and PMS2. Germline deletion of the 3' exons of TACSTD1/EPCAM can cause heritable somatic methylation and inactivation of MSH2 and thus Lynch syndrome[33] . De novo mutations are very rare[13,14]. Deficiency of MMR genes causes replication errors (mismatches) in repetitive DNA segments, known as microsatellites. Microsatellite instability (MSI) is not a unique feature of Lynch syndrome and therefore no proof of this syndrome, but occurs in different percentages in the majority of solid neoplasms[15].

Clinical criteria =Amsterdam criteria II)[16]:

a) the presence of at least 3 relatives with histologically verified
colorectal cancer,
endometrial cancer,
small bowel cancer,
ureter cancer or
renal pelvis cancer;
and one of these relatives should be a first-degree relative of the other two,
(b) at least 2 successive generations should be affected,
(c) at least one case of these cancers diagnosed before age 50 and
(d) exclusion (on clinical grounds) of Familial Adenomatous Polyposis.

Families that meet these criteria, but do not show signs of mismatch repair deficiency in their tumors are considered not to have Lynch syndrome. Some authors refer to these families as Familial Colorectal Cancer type X[17].

The Revised Bethesda guidelines try to incorporate insights based on the molecular studies of patients and families with colorectal cancer and other HNPCC associated tumors, and aim at providing clinicians with practical criteria to select patients and their families for tumor MSI testing[18]

CRC diagnosed in a patient aged <50 years
Presence of synchronous, metachronous colorectal or other Lynch syndrome-related tumours*, regardless of age
CRC with MSI-H phenotype diagnosed in a patient aged <60 years
Patient with CRC and a first-degree relative with a Lynch syndrome-related tumour, with one of the cancers diagnosed at age <50 years
Patient with CRC with two or more first-degree or second-degree relatives with a Lynch syndrome-related tumour, regardless of age

Links

International Society for Gastrointestinal Hereditary Tumours (InSiGHT) 18 1 08

References