© Borgis - Postępy Nauk Medycznych 1/2015, s. 4-10
*Tadeusz Dębniak1, Tomasz Gromowski1, Józef Kładny2, Janina Suchy1, Dagmara Dymerska1, Katarzyna Tutlewska1, Grzegorz Kurzawski1, Jan Lubiński1
Zespół Lyncha (HNPCC)
Lynch syndrome (HNPCC)
1Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin
Head of Department: prof. Jan Lubiński, MD, PhD
2Department of General and Oncological Surgery, Pomeranian Medical University, Szczecin
Head of Department: prof. Józef Kładny, MD, PhD
Streszczenie
Zespół Lyncha, nazywany także dziedzicznym rakiem jelita grubego niezwiązanym z polipowatością (ang. hereditary non-polyposis colorectal cancer – HNPCC), stanowi 2-5% wszystkich raków jelita grubego. Wykazano, że zespół Lyncha jest wynikiem mutacji germinalnych genów biorących udział w naprawie DNA (ang. mismatch repair – MMR): MSH2, MLH1, MSH6 i PMS2, podczas gdy określenie „HNPCC” odnosi się do rodzin, które spełniają kryteria Amsterdamskie. Ostatnie doniesienia sugerują, że utrata genu EPCAM jest związana z zespołem Lyncha poprzez epigenetyczną zmianę statusu regionu promotorowego MSH2. Nosiciele mutacji są narażeni na zwiększone ryzyko rozwoju raka jelita grubego i raka trzonu macicy w młodym wieku. Inne, pozajelitowe nowotwory, jak rak jajnika, jelita cienkiego, dróg moczowych, dróg żółciowych, rak żołądka i nowotwory mózgu również są związane z HNPCC. Ponad połowa zgonów z powodu nowotworów w rodzinach z HNPCC spowodowana jest właśnie nowotworami pozajelitowymi. Korzyści z nadzoru nowotworów ginekologicznych nie są jeszcze udowodnione i nie ma również zgodności co do zaleceń nadzoru dla kobiet z mutacjami w MMR.
Przeprowadzono systematyczny przegląd piśmiennictwa i ocenę ryzyka raka w polskich rodzinach HNPCC, zakwalifikowanych do zespołu Lyncha (wykryte mutacje MMR) lub HNPCC (spełniające kryteria Amsterdamskie lub zmodyfikowane kryteria Amsterdamskie).
Udowodniono skuteczność programu profilaktyczno-diagnostycznego opartego na kolonoskopii w rodzinach z zespołem Lyncha poprzez zmniejszenie śmiertelności z powodu raka jelita grubego. Opublikowane dane wyraźnie wskazują na brak korzyści z badań przesiewowych w kierunku raka jajnika.
Ze względu na wysoce skumulowane ryzyko raka jelita grubego, pełna kolonoskopia jest zalecana w rodzinach HNPCC, począwszy od wieku 20-25 lat, co rok lub co dwa lata. Ze względu na wysokie ryzyko raka trzonu macicy uzasadnione jest proponowanie, po ukończeniu 35. roku życia, badań ginekologicznych z wykorzystaniem USG przezpochwowym z rutynowym pobieraniem próbek endometrium u kobiet z zespołem Lyncha lub rodzin HNPCC. Alternatywną opcją, która mogłaby być wzięta pod uwagę dla kobiet preferujących prewencję chirurgiczną, jest, zmniejszająca ryzyko, całkowita histerektomia (z obustronną resekcją przydatków) u nosicielek po ukończeniu okresu rozrodczego. Ze względu na zwiększone ryzyko raka jajnika i brak korzyści z ginekologicznych badań przesiewowych, według piśmiennictwa zaleca się profilaktyczną adneksektomię u kobiet nosicielek mutacji w MMR po ukończeniu 35. roku życia. Opcja ta powinna być traktowana jako redukująca ryzyko. Coroczne przezpochwowe badanie USG wspierane przez badanie markera CA125 lub HE4 powinny być wykonywane po zabiegu profilaktycznym u tych kobiet.
Summary
Lynch syndrome, also referred to as hereditary non-polyposis colorectal cancer (HNPCC), accounts for somewhere between 2 and 5% of all CRC. It has been shown that Lynch syndrome (LS) is a result of germline mutations in genes involved in DNA mismatch repair (MMR) MSH2, MLH1, MSH6, and PMS2, whereas as HNPCC refers to families that adhere to the Amsterdam criteria or iterations of it. More recently, it has been reported that loss of EPCAM is associated with Lynch syndrome, by virtue of it changing the epigenetic status of the promoter region of MSH2. Mutation carriers are at high risk of developing colorectal cancer (CRC), and endometrial cancer (EC) at unusually young ages. Other, extra-colonic tumor types such as ovarian, small bowel, urinary, biliary tract, gastric, and brain tumors, have also been associated with HNPCC. Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies. The benefit of surveillance for gynecological cancers is not yet proven and there is no consensus on the optimal surveillance recommendations for women with MMR mutations.
We performed a systematic review of the literature and evaluated cancer risk in Polish HNPCC families classified into either Lynch syndrome (LS, MMR mutations detected) or HNPCC (fulfillment of the Amsterdam or modified Amsterdam criteria).
CRC detection screening strategy based upon colonoscopy has been documented to decrease CRC mortality. Published data clearly indicates no benefit for ovarian cancer screening in contrast to risk reducing surgery.
Due to the high cumulative risk of CRC full colonoscopy is recommended in HNPCC families beginning from age of 20-25 yrs every one-two years. Due to the high risk of EC it is reasonable to offer, after the age of 35 years, annual clinical gynecologic examinations with transvaginal ultrasound supported by routine aspiration sampling of the endometrium for women from either LS or HNPCC families. An alternative option, which could be taken into consideration for women preferring surgical prevention, is risk reducing total hysterectomy (with bilateral salpingo-oophorectomy) for carriers after childbearing is complete. Due to the increased risk of OC and absence of any benefit from gynecological screening reported in the literature it is recommended that prophylactic oophorectomy for female carriers of MMR mutations after 35 year of age should be considered as a risk reducing option. Annual transvaginal ultrasound supported by CA125 or HE4 marker testing should be performed after prophylactic surgery in these women.
Publication of this review is based on the authors’ own experience and data from the literature concerning the diagnosis, prevention and treatment of disease in families with Lynch syndrome (HNPCC).
The disease encapsulated by the term is HNPCC is one defined by a definition, known as the Amsterdam criteria. The Amsterdam criteria identify a clinical entity but do not provide information about the genetic predisposition to epithelial malignancies, Lynch syndrome. A unique perspective is provided by special, as distinct from standard, criteria of diagnosing „suspected HNPCC”, according to studies undertaken by the author so that a diagnosis can be established when:
1. The proband or at least one first or second degree relative is affected by colorectal cancer (CRC).
2. A patient with CRC and the matching criteria of 1) or one of his I° relatives is affected by at least one cancer from the HNPCC spectrum of malignancy – that include CRC, endometrial cancer, a small bowel malignancy or a urinary tract tumour.
3. At least one of cancers matching described in criteria 1) or 2) has been diagnosed in a patient who is under 50 years of age.
4. Familial adenomatous polyposis (FAP) is excluded.
It is estimated that a highly penetrant genetic predisposition is associated with the cause of somewhere between 10 and 20% of all colon cancers (1-5).
Among the well recognized inherited syndromes associated with a cancer predisposition that manifestprimarily as familial CRC, they include syndromes demonstrating a Mendelian pattern of inheritance that include hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome), familial adenomatous polyposis (FAP); Gardener, Zankas, Turcot, Peutz-Jaghers syndromes and juvenile polyposis.
Lynch syndrome (HNPCC)
HNPCC was first described by Warthin about 100 years ago and further defined by Lynch (6) in the 1960’s accounts for somewhere between 2 and 5% of all CRC. It has been shown that HNPCC is a result of germline mutations in genes involved in DNA mismatch repair MSH2, MLH1, MSH6, and PMS2. Mutation within MSH2 and MLH1 are the most frequently mutated in Lynch syndrome (7-10). More recently, it has been reported that loss of EPCAM is associate with Lynch syndrome, by virtue of there being a change in epigenetic status of the promoter region of MSH2 (11).
The characteristic clinical feature of Lynch syndrome include:
– early age of CRC diagnosis (about 45 yrs),
– more frequent right sided colonic tumour localization,
– two or more CRC cases among I° relatives,
– synchronous and metachronous CRC tumours,
– occurrence of disease in consecutive generations (vertical transmissions),
– increased frequency of cancers of the endometrium, small bowel and urinary tract in relatives.
According to the international group of experts (International Collaborative Group on HNPCC – ICG-HNPCC) Lynch syndrome can be definitively diagnosed, if constitutional mutations within one of the four genes connected with HNPCC, such as MSH2 or MLH1 is identified or if the following clinical and pedigree criteria are matched (tab. 1) (12, 13).
Due to incomplete disease penetrance (normally typical for dominant Mendelian disorders), deaths caused by various diseases, or due to difficulties in achieving complete clinical information about all relatives, the large proportion – perhaps majority – of families actually with HNPCC, can not be diagnosed using the clinical definition of HNPCC as defined by the Amsterdam criteria (tab. 1). Therefore several centres are using less stringent criteria, the fulfillment of which can not provide a definitive diagnosis of HNPCC, but it is useful for the identification of families who are most likely to be associated with this entity (13-16). According to our experience the criteria summarized in table 2 are of particular value for the identification of cases suspected of HNPCC.
Table 1. Diagnostic criteria of HNPCC according to ICG-HNPCC (13).
| 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
Table 2. Diagnostic criteria of „suspected HNPCC” (20).
| 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
Tumor spectrum
Recent analysis of the cancer spectrum in 368 MMR genes mutation carriers (mainly non-Hispanic white US citizens) from 176 families confirmed that the two most common LS cancers were: CRC (58% of all cancers) in both sexes and EC (14%) followed by ovarian cancer (OC) as the third most common malignancy (3.5%). Cancers of the urogenital tract (kidney/uterus/bladder) constituted 3.1%, stomach/small intestine 2.7%, breast 1.9% and prostate 1.1% of all malignancies in these families (17). Another study from Europe performed on 2118 German and Dutch MMR gene mutation carriers revealed a similar tumor spectrum and a high incidence of gynecological cancers: CRC 50%, EC 16%, OC 4.4%, breast 4.4%, urological 3.6%, stomach 1.6% (18). LS-associated OC has been reported to exhibit a variety of histopathological subtypes, mostly invasive, with 22% presenting with synchronous primary EC (19).
Consistent with reports in the literature, a comparison of the cancer spectrum between 278 LS families and 353 HNPCC families (with no MMR mutations) diagnosed at the International Hereditary Cancer Center (IHCC, Szczecin, Poland) confirmed the high incidence of gynecological cancers in Polish families. There were 21 OCs among 573 tumors (3.6%) in LS families and 18 OCs among 588 tumors (3.1%) in the HNPCC families. EC was more prevalent among LS families (138/573 tumors, 24% of all cancers) compared to HNPCC families (81/588 tumors, 14% of all cancers).
Molecular diagnostics for constitutional mutations in genes associated with HNPCC
DNA testing is recommended for families fulfilling at least the „suspected HNPCC” criteria. After exclusion of FAP (characteristic symptoms that include polyposis, congenital hypertrophy of the retinal pigment epithelium, lipomas and osteomas of bones of the maxilla and mandible and desmoid tumors) immunohistochemical analyses (IHC) of MLH1, MSH2, MSH6 and PMS2 expression in malignant tissues should be performed (where the absence of the immunohistochemical staining for the respective DNA mismatch repair proteins may indicate the mutated gene).
Results of several studies performed in our centre characterized the frequencies and spectrum of MSH2 and MLH1 mutations in Poland (20). Similar to other populations, the most frequent causes of Lynch syndrome in Poland are MLH1 and MSH2 mutations, constituting 90% of all mutations associated with this entity. Partial or whole gene deletions identified by the multiplex ligation probe amplification (MLPA) assay detects 10% of these mutations. In over 60 % of all Lynch syndrome families recurrent mutations can be found. Thus, after IHC, gene sequencing and MLPA analysis for MSH2 and MLH1 should be performed. Once found DNA tests searching for recurrent mutations should be applied so that family members can benefit from this knowledge (21).
Another promising method when there are common founder mutations is the designer iPLEX/TaqMan test plexes, which comprise seven mutations of the APC gene and 29 mutations from three of the mismatch repair genes. This approach appears to be an outstanding tool for the identification of recurrent mutations among hereditary colorectal cancer patients (22).
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