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© Borgis - Postępy Nauk Medycznych 1/2015, s. 47-56
*Jacek Gronwald1, Tomasz Byrski1, Tomasz Huzarski1, Oleg Oszurek1, Jolanta Szymańska-Pasternak1, Bohdan Górski1, Paulina Tarnowska2, Janusz Menkiszak2, Izabella Rzepka-Górska2, Jan Lubiński1
Dziedziczny rak piersi i jajnika
Hereditary breast and ovarian cancer
1International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin
Head of Department: prof. Jan Lubiński, MD, PhD
2Pomeranian Medical University, Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents, Szczecin
Head of Department: prof. Janusz Menkiszak, MD, PhD
Streszczenie
W ostatnich latach udało się wykazać u niemal wszystkich pacjentek z rakami piersi lub jajnika charakterystyczne podłoże konstytucyjne sprzyjające rozwojowi tych nowotworów. Stwierdzono, że nosicielstwo mutacji w genach BRCA1, BRCA2, CHEK2, NBS1, NOD2, CDKN2A, CYP1B1, jak i rzadziej występujących zmian w genach takich jak ATM, PTEN, STK11 wiąże się z podwyższonym ryzykiem raka piersi. Zaburzenia w genach BRCA1, BRCA2, NOD2, CHEK2, DHCR7 predysponują do rozwoju raka jajnika. W niektórych przypadkach zmiany genetyczne wiążą się z bardzo wysokim ryzykiem nowotworowym, w innych przypadkach wykrywane zaburzenia predysponują do rozwoju raka w mniejszym stopniu. Zdiagnozowanie podwyższonego ryzyka raka umożliwia wdrożenie programu profilaktycznego umożliwiającego zapobieżenie nowotworowi, a tam gdzie to się nie udaje, pozwala na wykrycie raka we wczesnym stadium. Dodatkowo zdiagnozowanie nosicielstwa odpowiednich mutacji pozwala na dobór najefektywniejszego, zindywidualizowanego sposobu leczenia związanego z uwarunkowaniami konstytucjonalnymi pacjenta. Dużym problemem diagnostycznym są pacjentki, u których nie udało się znaleźć zmian molekularnych, ale dane rodowodowo-kliniczne wskazują na silne podłoże genetyczne nowotworu.
W niniejszym opracowaniu przedstawiono podłoże genetyczne rozwoju raka piersi i jajnika, uwzględniając wpływ genów wysokiego oraz umiarkowanie zwiększonego ryzyka oraz zasady interpretacji danych rodowodowych. Omówiono obecnie obowiązujące zasady diagnozowania grup ryzyka, profilaktyki oraz leczenia raka u pacjentek ze zmianami w genach BRCA1, BRCA2 oraz innymi zespołami wysokiego ryzyka, jak również ze zmianami w genach umiarkowanie zwiększonego ryzyka.
Summary
Recently, it is possible to show a constitutional genetic background in almost all patients with breast or ovarian cancer. It has been recognized that increased risk of breast cancers occurs in carriers of mutations in BRCA1, BRCA2, PALB2, RAD51, RAD51C, TP53, MSH6, MRE11A, CDH1, CHEK2, NBS1, NOD2, CDKN2A, CYP1B1 and less frequently of genes such as ATM, PTEN, STK11. Abnormalities in BRCA1, BRCA2, NOD2, CHEK2, DHCR7 genes are predisposing factors also for development of ovarian cancer. In some cases, characteristic gene mutations are related to a very high risk of cancer, in other cases detected genetic changes predispose to cancer at lower degree. Diagnosis of increased risk of cancer allows introduction of prophylactic programs which make possible to avoid cancer, or diagnose it in early stages. Additionaly, the most effective method of treatment can be chosenfor carriers of some mutations. Significant diagnostic problem constitute patients in whom molecular abnormality was not detected but pedigree-clinical data indicate strong genetic background of cancer.
In the review we show the genetic background of breast and ovarian cancer taking into consideration contribution of high and moderate penetrance genes as well as importance of pedigree data. We discuss rules of diagnosis, prophylactics, the most sensitive methods of early detection and treatment in patients with BRCA1, BRCA2 and other high risk syndromes as well as in patients with abnormalities in moderate penetrance genes.
Słowa kluczowe: rak piersi, BRCA1, genetyka.



Familial breast cancer was first recognized in the Roman medical literature of 100 AD (1). The first documentation of familial clustering of breast cancer in modern times was published by Broca, who reported 10 cases of breast cancer in 4 generations of his wife’s family (2). In the middle of nineties it was proven at molecular level that substantial number of breast and ovarian cancers has hereditary monogenic etiology (3, 4). Evaluation of frequency of pedigree-clinical signs characteristic for strong aggregations of breast/ovarian cancers among consecutive cases of cancers of these organs as well as analyses of cancer incidence in monozygotic tweens indicate that about 30% of breast and ovarian cancers develop because of strong genetic predisposition (5). In other breast/ovarian cancers significance of genetic factors was underestimated. However, recently it was possible to show characteristic constitutional baground influencing development of cancer also in patients with sporadic neoplasms. Therefore now, scientists think that in almost all patients with cancer a certain genetic backgroung should be detectable although influencing cancer risk with different degree. Genetic abnormalities strongly related with cancer are called high risk changes (genes) and abnormalities influencing cancer development with lower degree are called moderate risk changes (genes). In Polish population most frequently strong genetic predisposition to breast/ovarian cancers are related to mutations in BRCA1, CHEK2 or PALB2 genes. Mutations in BRCA2 gene are observed relatively rare. Mutations in these genes most often apeare as syndromes of hereditary breast cancer – site specific (HBC-ss), hereditary breast-ovarian cancer (HBOC) and hereditary ovarian cancer (HOC). In family members of families with HBC-ss syndrome only breast cancers but not ovarian cancers are observed. In HBOC syndrome families with both – breast and ovarian cancers are diagnosed and in HOC syndrome only ovarian but not breast cancers are detected. Operational clinical-pedigree criteria which we use in order to diagnose the discussed syndromes are summarized in table 1. In vast majority of cancer cases related to moderate risk genes family history is negative. HBC-ss, HBOC, HOC syndromes are clinically and molecullary heterogenous. Mutations in BRCA1 and BRCA2 genes are the most frequent cause of these syndromes. Recently, it was shown that in substantial number of such families, the syndrome develop because of truncating mutations in CHEK2 gene or PALB2 genes (6, 7).
Table 1. Pedigree-clinical diagnostic criteria of HBC-ss, HBOC and HOC syndromes.
Number of breast or ovarian cancer cases in family
A – 3 (definitive diagnosis)
1. At least 3 relatives affected with breast or ovarian cancer diagnosed at any age
B – 2 (highly probable diagnosis)
1. 2 breast or ovarian cancer cases among I° relatives (or II° through male line)
2. 1 breast cancer and 1 ovarian cancer diagnosed at any age among I° relatives (or II° through male line)
C – 1 (highly probable diagnosis)
1. Breast cancer diagnosed below 40 years of age
2. Bilateral breast cancer
3. Medullary or atypical medullary breast cancer
4. Triple negative breast cancer
5. Breast and ovarian cancer in the same person
6. Breast cancer in male
BRCA1 syndrome
In this syndrome women carry a germline mutation in the BRCA1 gene. Carriers of a BRCA1 mutation have approximately 50-80% life-time risk of breast cancer and 40% risk of ovarian cancer (8). We estimate that these risks are 66% for breast cancer and 44% for ovarian cancer in the Polish population (tab. 2). Both risks appear to be dependent on the type and localization of the mutation (9-11). Our findings suggest that the risk of breast cancer in women with 5382insC is two times higher than in women with 4153delA (9). Another factor affecting the level of risk is the degree of burden of family history. It was found that the risk of breast cancer increases by a further 20% with development of breast cancer before the age of 50 in each I° relative. In contrast, the occurrence of ovarian cancer each I° or II° relative is associated with an increased risk of ovarian cancer by a further 60% (12). Also the place of residence affect the level of the risk. In a recent prospective study found differences in penetration depending on place of residence. And so, the likelihood of developing breast cancer up to 70 years of age for the BRCA1 gene mutation carriers in North America set at 72%, and for the Polish carriers to 49%, indicating the importance of environmental factors (13).
Table 2. Risk of breast and ovarian cancer in BRCA1 mutation carriers in Poland (8).
A: Cumulated risk of breast cancerAgeCumulated risk (%)
< 301.6
406.5
5030
6040.5
7050.5
7566
B: Cumulated risk of ovarian cancer< 301
403.5
5012
6030
7041
7544
Incomplete penetrance of BRCA1 suggests that other factors, genetic and non-genetic modifiers are important in carcinogenesis in the mutation carriers.
So far, several changes with potential significance in modification of the cancer risk have been identified. Multicenter study of CIMBA consortium suggest that these changes alone are weak and likely the effect is variable in different populations (14-29).
Characteristic for BRCA1 carriers is, that except ovarian cancer, it is also also heightened risk of the fallopian tube and peritoneal cancers, estimated at about 10%. The above data on the incidence of ovarian cancer is likely to relate to the incidence of cancers of the ovary, fallopian tube, and peritoneal because these tumors were in the past, the most frequently diagnosed as ovarian cancers due to the similar morphology and the accompanying increase in the level of the marker CA 125.
The risk of cancer to other organs in some types of BRCA1 is also increased, but the effect of carrying a BRCA1 dysfunction has not yet been definitively proven.
Breast and ovarian cancer in BRCA1 carriers have particular clinical characteristics. The mean age at onset of breast cancer is about 42-45 years (30, 31) and of ovarian cancer is about 54 years (32, 33). 18-32% of breast cancers are bilateral (34, 35). These are rapidly growing tumors: > 90% of cases have G3 grade at the time of diagnosis and almost all ovarian cancers in women with a BRCA1 mutation are diagnosed in FIGO stage III°/IV°. Medullar, atypical medullar, ducal and estrogen receptor negative (ER-) breast tumors are common in BRCA1 carriers. BRCA1-dependent breast cancers account for about 25-30% of all cancers triple-negative (ER-, PGR-, HER2-), however in BRCA1-dependent tumors positive ER is observed in 10-15% of cases (34-36). Most carriers of a BRCA1 mutation report a positive family history of breast or ovarian cancer (fig. 1). However, 45% of BRCA1 carriers report a negative family history, mainly because of paternal inheritance and incomplete penetrance (fig. 2) (35).
Fig. 1. Family with HOC syndrome and diagnosed constitutional 4153delA BRCA1 gene mutation.
Fig. 2. Patent with ovarian cancer and detected 5382insC BRCA1 mutation from family with negative family history.
BRCA2 syndrome
Patients with this syndrome have constitutional mutation in BRCA2 gene (5). According to literature data life time risk for BRCA2 carries from families with definitive HBC-ss and HBOC is estimated on 31-56% for breast cancer and 11-27% for ovarian cancer (10, 39-43). Studies performed in 200 Polish families with strong aggregation of breast and/or ovarian cancers proved that mutations in BRCA2 gene are rare with the frequency of 4%. There are no studies on cumulated cancer risk in BRCA2 mutation carriers form Polish population. Most BRCA2 mutations from Polish population most probably slightly increase breast cancer risk. Studies performed in our center showed that in families with aggregation of breast cancer diagnosed before age of 50 and stomach cancer diagnosed in males before age of 55 frequency of BRCA2 carriers is about 10-20% (44). BRCA2 mutations are related also with significantly increased however not precisly estimated risk of ovarian cancer and cancers of digestive tract as stomach, colon, pancreas both in females and males. Studies performd in our center showed BRCA2 mutation are detected with frequency of 30% in families without breast cancer but with aggregation of ovarian cancer with stomach, colon or pancreatic cancer between first and second degree relatives (45). BRCA2 studies performed on male breast cancer patients from Poznań population showed that 15% of patients from this group are mutation carriers (46).
Breast and ovarian cancers in families with BRCA2 mutations have characteristic features. Medium age of breast cancer is 52 and 53 in females and males, respectively and 62 of ovarian cancer (46, 47).
Other high risk breast cancer syndromes
In Poland in about 30% of families with definitively diagnosed HBC-ss and HBOC syndromes and in about 40% of families with HOC syndrome, BRCA1 or BRCA2 mutations are not detected. In rare cases it is possible to diagnose one of rare syndromes listed in table 3. In these syndromes breast/ovarian cancers are observed with higher frequency. Many groups in the world try to identify new genes related to high breast cancer risk.
Table 3. Selected rare syndromes with increased risk of breast and/or ovarian cancer.
DiseaseClinicsGene mutation/inheritanceReferencer
Li-Fraumeni syndromeBreast cancers, sarcomas, brain tumours, leukemia, arenal gland cancerp53, high penetrance;
AD
47, 48
Cowden diseaseMultifocal mucoid skin abnormalities, benign proliferative abnormalities of different organs, thyroid cancers, breast/ovarian cancersPTEN AD49, 50
HNPCCColon cancers, endometrial cancers, other organ cancers including breast and ovaryMSH2, MLH1; AD51
Peutz-Jeghers syndromeHyperpigmentation of the mouth, bowel polyps, colorectal cancers, small bowel cancers, gonadal tumors, breast cancersSTK11; AD52
Ruvalcaba-Myhre-Smith (Bannayan-Riley-Ruvalcaba) syndromeMacrocephaly, bowel polyps, „cafè-au-lait” on penis, lyphomas, thyroid cancers, breast cancersPTEN AD53
Heterozygotic carrier status of „ataxia telangiectasia” geneAtaxia of cerebellum, ocular and skin, hypersensitivity for radiation, different site neoplasm including breast/ovarian cancerATM
penetrance 20-40%
AD
54, 55
Klinefelter syndromeGynecomastia, cryptorchidism, extragonadal germ cell tumors, male breast cancer47, XXY; low penetrance < 10%56
Androgene receptor gene mutationFamilial male breast cancerAndrogene
receptor
57
PALB2 gene mutationHigh risk of brest cancerPALB2
penetrance ~30%
7
Coexistence of CHEK2 gene mutation and polymorphism B2P1High risk of developing breast cancer, and moderately increased risk of cancer of the colon, kidney, thyroid, prostateCHEK2/B2P1
penetrance ~30-40%
58
CHEK2 gene mutation in patients with a family history of breast cancerHigh risk of developing breast cancer, and moderately increased risk of cancer of the colon, kidney, thyroid, prostateCHEK2
penetrance ~30-40%
59, 60
Homozygous mutation in the gene CHEK2High risk of developing breast cancer, and moderately increased risk of cancer of the colon, kidney, thyroid, prostateCHEK2
penetrance ~30-40%
60
Inheritance: AD – autosomal dominant; AR – autosomal recessive
Clinical management in families with high risk of breast/ovarian cancer
Special management should be applied for:
– carriers of mutations of high breast/ovarian cancer risk; usually around 50% of female family members shoud be included into program,

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otrzymano: 2014-12-10
zaakceptowano do druku: 2015-01-05

Adres do korespondencji:
*Jacek Gronwald
International Hereditary Cancer Center
Department of Genetics and Pathology
Pomeranin Medical University
ul. Połabska 4, 70-115 Szczecin
tel. +48 (91) 466-15-33
jgron@pum.edu.pl

Postępy Nauk Medycznych 1/2015
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