© Borgis - Postępy Nauk Medycznych 7/2010, s. 546-549
*Józef Kładny1, Janina Suchy2, Dagmara Dymerska2, Grzegorz Kurzawski2, Tadeusz Dębniak2, Jan Lubiński2
Lynch Syndrome (HNPCC)
Zespół Lyncha (HNPCC)
1Department of General and Oncological Surgery, Pomeranian Medical University, Szczecin, Poland
Head of Department of General and Oncological Surgery: prof. dr hab. med. Józef Kładny
2International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Head of Department of Genetics and Pathology: prof. zw. dr hab. med. Jan Lubiński
Praca jest przeglądem doświadczeń własnych oraz danych z piśmiennictwa na temat diagnostyki, profilaktyki i leczenia nowotworów w przebiegu zespołu Lyncha (HNPCC).
Unikalną wartość wnoszą odmienne od standardowych kryteria rozpoznawania „HNPCC susp”. Taką sytuację kliniczną według własnych badań autorów należy rozpoznawać wówczas, gdy:
1. u probanta lub któregokolwiek z jego krewnych I° lub II° stwierdza się raka jelita grubego;
2. u chorego z rakiem jelita grubego, spełniającego kryterium 1) lub wśród jego krewnych I° stwierdza się raka z tzw. spektrum HNPCC – raka jelita grubego, trzonu macicy, jelita cienkiego lub dróg moczowych;
3. co najmniej jeden z raków spełniających kryteria 1) lub 2) zdiagnozowany został poniżej 50. r.ż.
4. wykluczono polipowatość rodzinną.
Publication is the review based on author's own experience and literature data concerning diagnosis, prevention and treatment of tumors in families with Lynch Syndrome (HNPCC).
The unique value is provided by special, distinct from standard, criteria of diagnosing "HNPCC susp”. According to authors studies such diagnosis can be established when:
1. proband or at least one of his I° or II° relatives is affected by colorectal cancer (CRC);
2. patient with CRC matching criterium 1) or one of his I° relatives is affected by at least one cancer from so called HNPCC spectrum – CRC, cancer of the endometrium or of the small bowel or of the urinary tract;
3. at least one of cancers matching criteria 1) or 2) has been diagnosed under age of 50 years;
4. familial adenomatous polyposis is excluded.
It is estimated that a high genetic predisposition is the cause of 10-20% of all colon cancers (CRC) (1-5).
Among the well known syndromes of inherited predisposition to tumours manifesting with CRC such syndromes showing mendelian pattern of inheritance can be included like: hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome), familial adenomatous polyposis (FAP); Gardner, Zankas, Turcot, Peutz-Jaghers syndromes and juvenile polyposis.
Lynch syndrome (HNPCC)
HNPCC has been described by Lynch (6) in 60's and is the cause of around 5% of all CRC. It has been shown that HNPCC is caused by mutations within several genes such as: MSH2, MLH1, MSH6, EPCAM, PMS2. Mutation within the two first are the most frequent cause of the Lynch syndrome (7-10). Characteristic clinical feature of Lynch syndrome include:
– early age of CRC diagnosis (about 45 yrs),
– more frequent right site tumour localization,
– two and more CRC cases among I° relatives,
– many syn- and meta-chronous CRC tumours
– occurrence of disease in consecutive generations (vertical transmissions)
– increased frequency of occurrence among relatives of cancers of the endometrium, small bowel and urinary tract
According to international group of experts (International Collaborative Group on HNPCC – ICG-HNPCC) Lynch syndrome can be definitively diagnosed, if constitutional mutation within one of genes connected with HNPCC, such as MSH2 or MLH1 is identified or if the following pedigree-clinical criteria are matched (tab. 1) (11, 12).
Table 1. Diagnostic criteria of HNPCC according to ICG-HNPCC (12).
|1.||at least 3 relatives are affected by histologically verified CRC or cancer of the endometrium, small bowel or urinary tract; at least one of them is I° relative to the other two; FAP is excluded*|
|2.||at least 2 of above persons are I° relatives from two different generations|
|3.||at least 1 of above persons with cancer diagnosed at age under 50 yrs|
All other parameters (right site localization, syn- or metachronous tumours) should be treated like non-diagnostic features.*colorectal polyposis, congenital hypertrophy of the retinal pigment epithelium, cysts and osteomas of the mandible/maxilla and desmoids are excluded.
A family matching definitive criteria of HNPCC according to ICG-HNPCC is presented on figure 1.
Fig. 1. Family pedigree matching HNPCC criteria, according to ICG-HNPCC.
Due to incomplete penetrance of genes what is typical for dominant mendelian disorders, deaths caused by various diseases, or due to difficulties in achieving full information about all of relatives, the large proportion – perhaps majority – of families actually with HNPCC, can not be diagnosed using Amsterdam criteria summarized in table 1.
Therefore several authors is using another type of criteria, fulfillment of which is not allowing definitive diagnosis of HNPCC, however it is useful in identification of families with highly increased risk (12-15). According to our experience criteria summarized in table 2 are of a particular value in identification of cases suspected of HNPCC.
Table 2. Diagnostic criteria of "suspected HNPCC” (16).
|1.||among I° relatives of CRC patients (or in himself) at least one cancer of the CRC, endometrium, small bowel or urinary tract|
|2.||at least one of above cancers diagnosed under age of 50 yrs|
|3.||FAP is excluded*|
*see table 1
Examples of families matching criteria of "suspected HNPCC” are presented on figures 2-3.
Fig. 2. Family pedigree "suspected HNPCC”.
Fig. 3. Family pedigree "suspected HNPCC”.
Molecular diagnostics of constitutional mutations in genes associated with HNPCC
DNA testing is recommended in families fulfilling at least "suspected HNPCC” criteria. After exclusion of FAP (characteristic FAP features include polyposis, congenital hypertrophy of the retinal pigment epithelium, cysts and osteomata of bones of the maxilla and mondible desmoid tumors) immunohistochemical analyses (IHC) of MLH1, MSH2, MSH6expression in malignant tissues should be performed (absence of the protein may indicate the mutated gene).
Results of several studies performed in our center characterised the frequencies and spectrum of MSH2 and MLH1 mutations in Poland (16). Similary to other populations, the most frequent causes of HNPCC in Poland are MLH1 and MSH2 mutations, constituting 90% of all mutations associated with this syndrome. MLPA detects 10% of these mutations. In over 60% of all HNPCC families recurrent mutations can be found. Thus, after IHC MLPA, for MSH2 and MLH1 should be performed. Next, with MLPA negative, DNA tests searching for recurrent mutations, characteristic for Polish population, should be applied. Last step should include DHPLC (17) and sequencing of the cases indicated by DHPLC results.
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