© Borgis - Postępy Nauk Medycznych 11/2010, s. 881-885
*Katarzyna Nej-Wołosiak, Tomasz Huzarski, Jan Lubiński
Clinical genetics of pancreatic cancer
Genetyka kliniczna raka trzustki
International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University
Head of the Genetics and Pathology Unit: prof. dr hab. med. Jan Lubiński
Streszczenie
Rak trzustki jest chorobą o agresywnym przebiegu i należy do nowotworów o wysokim wskaźniku śmiertelności. Rak trzustki znalazł się w pierwszej dziesiątce najczęściej występujących w Polsce nowotworów złośliwych. Średni czas przeżycia od rozpoznania choroby wynosi 6 miesięcy. Rak trzustki występuje częściej w starszym wieku. Wczesna diagnoza raka trzustki jest też trudna z uwagi na mało specyficzne objawy kliniczne w początkowym stadium choroby. Rokowanie w raku trzustki jest złe. Mimo rozwoju metod diagnostycznych rak trzustki należy do nowotworów późno wykrywalnych. Etiologia raka trzustki nie jest do końca poznana.
Genetyczne predyspozycje do raka trzustki przejawiają się w trzech formach. Po pierwsze ryzyko rozwoju raka trzustki zwiększone jest w wielu znanych zespołach genetycznych, takich jak np. Zespół Peutz-Jeghersa, FAMMM, zespół HBOC, zespół Lyncha, rodzinna polipowatość gruczolakowata, rodzinna polipowatość młodzieńcza, zespół ataksja-teleangiektazja oraz zespół Wernera. Po drugie zespoły takie jak dziedziczne zapalenie trzustki ( hereditary pancreatitis) oraz cystic fibrosis, znane z wcześnie występujących zmian w obrębie trzustki mogą predysponować do rozwoju raka tego narządu. I w końcu rodzinny rak trzustki ( familial pancreatic cancer) odnosi się do rodzin, w których wystąpiły dwa lub więcej przypadki raka trzustki wśród krewnych pierwszego stopnia a rodziny takie nie spełniają kryteriów dla żadnego innego zespołu genetycznego.
Dotychczasowe algorytmy diagnostyczne raka trzustki dotyczą sytuacji, w której wskazaniem do ich stosowania jest wystąpienie objawów klinicznych. Nieznana jest natomiast ich przydatność w detekcji najwcześniejszych postaci raków u osób z wykrytą testami DNA zwiększoną predyspozycją do raka trzustki. Podobnie jak w przypadku innych nowotworów zakładamy, że poznanie podłoża genetycznego raka trzustki umożliwi również efektywną chemoprewencję oraz chemioterapię.
Summary
Pancreatic cancer is an aggressive disease and the mortality rate is high. Pancreatic cancer is one of the 10 most frequent malignancies in Poland. The average time of a pancreatic cancer patients' survival is 6 months. Pancreatic cancer occurs in older age. Early diagnosis is difficult because of non-specific symptoms in the initial stage of the disease. Pancreatic cancer is a malignancy with poor prognosis. Despite many efforts, little is known about the genetic etiology of pancreatic cancer.
There is no gene identified as specifically predisposing to pancreatic cancer yet. An inherited predisposition to pancreatic cancer is believed to occur in three distinct clinical settings. First, it occurs in hereditary tumor predisposition syndromes that are known to be associated with an increased risk of pancreatic cancer like Peutz-Jeghers syndrome, HBOC syndrome, FAMMM syndrome, Lynch syndrome, juvenile polyposis, familial adenomatous polyposis, ataxia-teleangiectasia and Werner syndrome. The second setting is hereditary pancreatitis and cystic fibrosis, in which genetically determined early age onset changes of the pancreas can predispose to the development of pancreatic cancer. The term familial pancreatic cancer refers to families with two or more first-degree relatives with pancreatic cancer without fulfilling the criteria for another inherited tumor syndrome.
Diagnostic algorithms for pancreatic cancer refer to the situation when clinical symptoms occur. The usefulness of these algorithms in detecting early stages of pancreatic cancer in patients carrying DNA changes predisposing to this malignancy is unknown. It is possible that recognition of the genetic background of pancreatic cancer will enable effective chemoprevention and chemotherapy.
Pancreatic cancer is an aggressive disease with a high mortality rate. The incidence rate is constantly increasing, and currently is at 200,000 new cases per year worldwide (1). According to National Cancer Registry, 3,253 patients was diagnosed with this condition in 2008 in Poland. Incidences of pancreatic cancer ranks in the top ten of all malignancies in Poland, while the mortality rate of the condition is among the highest in all neoplasms. In 2008 there were 93,060 cancer deaths, including 2,253 males and 2,269 females with pancreatic cancer, which puts the disease in seventh place in deaths due to cancer (2). Taking into account this extreme mortality rate in several countries the condition ranks even higher, fourth place on the list of deaths due to cancer, immediately after lung, breast and bowel cancer.
The mortality rate in pancreatic cancer showed an increasing trend in Poland over recent decades (3). The disease progresses rapidly with mean survival time of 6 months. Since the moment of diagnosis <2% of patients survive 5 years, 8% survive 2 years and <50% survive 3 months or more (4). Nearly all patients with pancreatic cancer die of this condition.
Pancreatic cancer is a disease of elderly people. Approximately 80% of diagnosed patients are aged between 60 and 80 (5, 6). Cases of the disease in patients under the age of 40 is extremely rare. Mean age at the time of diagnosis is 65. It was well proven that the disease tends to occur more frequently in man than in women, though the difference is minor (7, 8, 9). Detection of the condition, despite obvious diagnostic advances, remains difficult, leading to a diagnostic delay of 4 to 9 months. Early recognition is hindered by the lack of specific signs at that stage.
Exocrine glandular pancreatic cancer (i.e. adenocarcinoma) constitutes 85-90% of pancreatic neoplasms. Cancer can be localized in the head (60-70%), body (5-10%), or tail of the pancreas (10-15%). In 20% of cases it is diffused and engrosses the entire gland.
Even though the etiology of pancreatic cancer is not fully understood there are many well-known known risk factors for pancreatic cancer. They include environmental risk factors such as smoking, a diet rich in protein and fat (obesity), diabetes, exposure to hydrocarbons and petroleum derivatives, chronic inflammation, infection and previous cholecystectomy.
Genetic predisposition to pancreatic cancer manifests in three forms (10). Firstly, the disease occurs frequently in many genetic syndromes. Secondly, conditions such as hereditary pancreatitis and cystic fibrosis provoking early pancreatic lesions may lead to pancreatic cancer. Lastly, familial pancreatic cancer which is related to families with two or more cases of pancreatic cancer among first-degree relatives, while not meeting criteria of any genetic syndrome.
PANCREATIC CANCER IN GENETIC SYNDROMES WITH HIGH NEOPLASIA RISK
With Peutz-Jeghers Syndrome there is an increased risk of pancreatic, breast, lung, ovarian and endometrial cancer (11). Approximately 50% of patients with the condition will develop cancer (12, 13, 14, 15). Pancreatic cancer is one of the most frequent in Peutz-Jeghers Syndrome. The underlying genetic cause of the disease is germinal mutation within STK11/LKB1 ( serine/threonine kinase 11) suppressor gene.
Many reports underline increased pancreatic cancer risk in families with FAMMM(Familial Atypical Multiple Mole Melanoma Syndrome) (16, 17, 54). Germinal suppressor gene mutation CDKN2A underlies this condition. The simultaneous occurrence of pancreatic cancer and melanoma in one family appears to be a separate genetic syndrome currently known as Melanoma-Pancreatic Cancer Syndrome/Familial Atypical Multiple Mole Melanoma-Pancreatic Carcinoma Syndrome (MPCS/FAMMM-PC; OMIM 606719).
HBOC Syndrome ( Hereditary Breast and Ovarian Cancer) is caused by BRCA1 and BRCA2 gene germline mutation. Increased risk of breast and ovarian cancer as well as prostate, large bowel, pancreas, gastric and cervical cancer is linked with the mutations (18). A large number of authors demonstrated a strict relation between BRCA1 and BRCA2 gene mutation and the increased risk of pancreatic cancer (19, 20, 21, 55).
Lynch Syndrome (HNPCC – Hereditary Non-Polyposis Colorectal Cancer) causes about 5% of all large bowel carcinomas (22, 23). This condition is connected with an increased risk of large bowel, endometrial, small bowel and urinary tract cancer, and, according to some investigators, additionally ovarian, breast and pancreatic cancer (24, 25). Lynch Syndrome is most frequently induced by germinal mutations of DNA repair genes MSH2 and MLH1, also MSH6, PMS1 and PMS2 (26). Despite the rare incidence of pancreatic cancer in patients with HNPCC it was demonstrated that this syndrome may lead to pancreatic cancer (27, 28, 56). The cumulative risk of pancreatic cancer in these families with gene mutations was 1,31% up to age 50 years and 3,68% up to age 70 years, which represents an 8,6-fold increase compared with the general population (56).
FAP ( Familial Adenomatous Polyposis) is responsible for approximately 1% of all large bowel cancers. It is generally caused by APC ( Adenomatous Polyposis Coli) suppressor gene mutation. A few reports show increased incidences of pancreatic cancer in families with FAP (29, 30). However, establishing the relationship between FAP and pancreatic cancer is impossible because of the relatively low number of cases (31).
FJP ( Familial Juvenile Polyposis) is linked with DCP4 ( Deleted in Pancreatic Parcinoma 4) suppressor gene mutation. This syndrome is characterized by the occurrence of numerous benign digestive tract polyps and an increased risk of digestive tract cancer. DCP4 gene mutations are the most frequently observed mutations in patients with pancreatic and large bowel cancer (32).
Ataxia teleangiectasia (AT) is an autoimmune disorder characterized by increased chromosome instability. The condition seems to influence the risk of pancreatic cancer, even though the overall risk remains low (33).
Werner syndrome (WS) is an autosomal recessive genetic disorder characterized by accelerated aging and cancer predisposition (pancreatic cancer), and is caused by loss-of-function mutations in the WS RecQ helicase gene WRN (57).
HEREDITARY PANCREATITIS AND CYSTIC FIBROSIS
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