Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions

Women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with Hereditary Breast/Ovarian Cancer syndrome, have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk ovarian cancer. Similarly, women with mutations in the DNA mismatch repair genes, MLH1, MSH2 or MSH6, associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, have up to a 40-60% lifetime risk of both endometrial and colorectal cancer as well as a 9-12% lifetime risk of ovarian cancer. Genetic risk assessment enables physicians to provide individualized evaluation of the likelihood of having one of these gynecologic cancer predisposition syndromes, as well the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Hereditary cancer risk assessment is a process that includes assessment of risk, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained. This commentary provides guidance on identification of patients who may benefit from hereditary cancer risk assessment for Hereditary Breast/Ovarian Cancer and the Lynch/Hereditary Non-Polyposis Colorectal Cancer syndrome.     

Ovarian cancer at young age: the contribution of mismatch-repair defects in a population-based series of epithelial ovarian cancer before age 40

At least one of ten patients with ovarian cancer is estimated to develop their tumor because of heredity with the breast and ovarian cancer syndrome due to mutations in the BRCA1 and BRCA2 genes and hereditary nonpolyposis colorectal cancer (HNPCC) being the major genetic causes. Cancer at young age is a hallmark of heredity, and ovarian cancers associated with HNPCC have been demonstrated to develop at a particularly early age. We used the Swedish Cancer Registry to identify a population-based series of 98 invasive epithelial ovarian cancers that developed before 40 years. Mucinous and endometrioid cancers were overrepresented and were diagnosed in 27% and 16% of the tumors, respectively. Immunostaining using antibodies against MLH1, PMS2, MSH2, and MSH6 was used to assess the mismatch-repair status and revealed loss of expression of MLH1/PMS2 in two cases, loss of MSH2/MSH6 in one case, and loss of MSH6 only in three tumors. A microsatellite instability-high phenotype was verified in five of six tumors. Based on the identified mutations and family history of cancer, several of these individuals are likely to be affected by HNPCC. We conclude that although the causes of the vast majority of epithelial ovarian cancer at young age are unknown, HNPCC should be considered because of the high risk of metachronous colorectal cancer in the individual and the possibility of preventing additional cancers in the family through control programs.     

The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer

OBJECTIVE: Ovarian cancer has one of the highest fractions of hereditary cases. The hereditary breast and ovarian cancer syndrome, primarily due to mutations in BRCA1 and BRCA2, is the main cause of heredity, but also the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome confers an increased risk of ovarian cancer. In order to clarify the contribution of HNPCC to the development of ovarian cancer, we collected data on family history of cancer and characterized MMR function in a consecutive series of 128 tumors unselected for age at diagnosis and previously characterized for BRCA gene mutations. METHODS: Expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry using tissue microarray sections. Tumors with reduced staining or loss of staining were also analyzed for microsatellite instability (MSI). RESULTS: Loss of MMR protein expression was identified in 3 ovarian cancers, all of which had a MSI-high phenotype. DNA sequence analysis revealed disease-causing germline mutations (deletions of exons 4-6 in MLH1 and a 1-nucleotide deletion in exon 5 of MSH6) in two patients diagnosed at ages 40 and 49 years, both of whom had family histories suggestive of HNPCC. The genetic defect in the third case, which was a 47-year old woman without knowledge about her family history with loss of MLH1/PMS2 expression in the tumor tissue, remains elusive. A family history suggestive of HNPCC was identified in an additional case, but this tumor showed normal, retained MMR protein expression and a microsatellite stable phenotype. CONCLUSIONS: About 2% of ovarian cancer is caused by germline mutations in the MMR-genes, a minor proportion as compared to the contribution of the BRCA-genes (11% in the present series). However, identification of HNPCC patients is important since it allows inclusion of high-risk individuals into control programs aimed at preventing the more frequent colorectal and endometrial cancers. Tumors within the HNPCC-spectrum should therefore be included when recording a family history of cancer among patients diagnosed with ovarian cancer.     

Genetik des Ovarialkarzinoms

Characteristic genetic aberration can be identified in hereditary as well as in sporadic ovarian cancer (OC). Whole genome sequencing revolutionizes the discovery of gene mutations. Goals of such endeavors are personalized cancer risk assessment and therapy. Forty to 50 mutations or aberrations are found in an ovarian cancer; only 2 to eight are“driver mutations” conveying a selective growth advantage. Less aggressive type-1 OC contain mutations in KRAS, BRAF and PIK3CA, type-2 OC carry p53 and BRCA1/2 mutations with high frequency. Hereditary OC are associated with germ-line mutations in BRCA1/2 causing the hereditary breast and ovarian cancer syndrome, in mismatch repair genes in Lynch syndrome or in p53 in the Li-Fraumeni syndrome 1. For individual OC risk assessment, computer models can be used based on family history, germ-line mutations and DNA variations.     

Hereditary predispositions to gynaecological cancers

The breast, ovary and endometrial cancers are hereditary in 5 to 10% of the cases. These genetic predisposition syndromes can be classified into two major classes: ovarian cancer and breast cancer predisposition family cases (genes BRCA1 and BRCA2) and family cases of colon cancer, endometrial cancer and ovarian cancer (Lynch syndrome or HNPCC) (genes hMLH1, hMSH2, hMLH6). The estimate of the family and individual risk can contribute in a determining manner to the management of these patients, by the practice of screening or an adapted prevention. Indeed, the risk of cancer of an individual having a positive test for a gene of predisposition to breast cancer (BRCA1, BRCA2) or to the colon cancer (hMLH1, hMSH2, hMLH6) lies between 50 and 70% at the age of 70 years. The indication of a genetic test must be discussed within the framework of an oncogenetic consultation. An individual and family medical management ranging from simple monitoring to prophylactic surgery is proposed to these predisposed people.     

Ovarian cancer and genetic susceptibility in relation to the BRCA1 and BRCA2 genes. Occurrence, clinical importance and intervention

The Nordic countries have the highest incidences of ovarian cancer in the world (around 15 cases per 100,000 women). We have conducted a review of the recent literature with focus on the Nordic countries, on genetic susceptibility to ovarian cancer, and the clinical implications in relation to the BRCAI and BRCA2 genes. One of the strongest risk factors for ovarian cancer is a family history of ovarian and/or early-onset breast cancer. It is thought that germline mutations in BRCA1/2 might be responsible for as much as 10% of all ovarian cancer cases and all families containing either multiple case, site-specific ovarian cancer cases or breast and ovarian cancers together. Data from several international studies suggest that the lifetime risk of ovarian cancer in a BRCA 1 mutation carrier can vary from 18 to 56% and from 14 to 27% in a BRCA2 carrier, depending on the presence/absence of a family history of the disease. Genetic evaluation and testing is used in many countries to identify families with BRCA1/2 mutations. Once a mutation has been identified, genetic counseling and testing can be offered to unaffected family members. Prophylactic oophorectomy in unaffected mutation carriers will eliminate the risk of ovarian cancer, although there is a slight residual risk of peritoneal cancer. During oophorectomy, the Fallopian tube should also be removed. If a woman does not want prophylactic oophorectomy, then tubal ligation or oral contraceptive use can be considered as these have been shown to reduce ovarian cancer risk also in mutation carriers.     

遗传性卵巢癌综合征相关易感基因的研究进展

卵巢癌是妇科常见的三大恶性肿瘤之一,病死率居妇科肿瘤的首位。由于缺乏敏感度和特异度高的早期筛查手段,多数患者（60%~65%）诊断时已为晚期。在卵巢癌中遗传性卵巢癌综合征（HOCS）占有一定的比例,HOCS的发生常与易感基因的突变有关。目前至少有16个基因已被确定与HOCS有关,其中乳腺癌易感基因1（BRCA1）和BRCA2的突变与HOCS关系最为密切,而限制性内切酶位点相关DNA（RAD51C）、RAD51D和BRCA1相关的羧基端解旋酶基因1（BRIP1）为近期新发现的与HOCS相关的3个基因,对相关易感基因突变进行检测并对高危人群进行监测可能成为早期卵巢癌诊断的有效手段。综述HOCS相关的易感基因。     

Germline BRCA1-2 mutations in non-Ashkenazi families with double primary breast and ovarian cancer

OBJECTIVE: Ashkenazi women with double primary breast and ovarian cancer have a high prevalence (57%) of germline Jewish founder mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes. The purpose of this study was to determine the frequency and type of BRCA1-2 mutations in non-Ashkenazi families with at least one member having double primary breast and ovarian cancer. METHODS: Women at increased risk for cancer based upon their family history were enrolled at the University of Texas Southwestern Familial Cancer Registry between 1992 and 2000. Blood samples from patients desiring genetic testing were sent for complete DNA sequencing of the BRCA1 and BRCA2 genes. Families with a member having both breast and ovarian cancer were identified and clinical data were obtained. RESULTS: Sixty-two (7%) of 900 enrolled families were non-Ashkenazi and had at least one member with double primary breast and ovarian cancer. Twenty-one families had members who underwent genetic testing; 41 did not. Thirteen (62%) families had a germline BRCA1 (n = 11) or BRCA2 (n = 2) mutation; only one Jewish founder mutation (185delAG) was detected. Eight (38%) families tested negative. Six (86%) of seven women undergoing genetic testing who themselves had double primary breast and ovarian cancer were BRCA1-2 mutation carriers. CONCLUSIONS: Germline BRCA1-2 mutations are common in non-Ashkenazi families with a member having double primary breast and ovarian cancer. These mutations occurred throughout both genes, emphasizing the need for comprehensive sequencing. One family had the BRCA2 6985delCT mutation, which lies beyond the "ovarian cancer cluster" region.     

Hereditary breast and ovarian cancer: what the primary care physician should know

In recent years, testing for cancer susceptibility genes has entered the clinical setting. The practicing physician needs to be familiar with this evolving area of medicine to be able to counsel and/or refer high-risk patients such as those with a strong personal or family history of cancer. The following is a review of the clinically pertinent information regarding hereditary breast and ovarian cancers resulting from mutations in BRCA genes. A special emphasis is placed on the different options available for BRCA mutation carriers, because many interventions have already proven to be highly efficacious. The increased risk of cancer seen in hereditary nonpolyposis colorectal cancer (HNPCC) is not part of this review but is mentioned briefly.     

Molecular aspects of ovarian cancer

Ovarian cancer is caused by genetic alterations that disrupt proliferation, apoptosis, senescence and DNA repair. Approximately 10% of ovarian cancers arise in women who have inherited mutations in cancer susceptibility genes (BRCA1 or BRCA2). The ability to perform genetic testing allows identification of women at increased risk who can be offered prophylactic oophorectomy or other interventions aimed at preventing ovarian cancer. The vast majority of ovarian cancers are sporadic, resulting from the accumulation of genetic damage over a lifetime. Several specific genes involved in ovarian carcinogenesis have been identified, including the p53 tumour suppressor gene and HER2/ neu andPIC3KA oncogenes. The recent availability of expression microarrays has facilitated the simultaneous examination of thousands of genes, and this promises to extend further our understanding of the molecular events involved in the development of ovarian cancers. Hopefully, this knowledge can be translated into effective screening, treatment, surveillance, and prevention strategies in the future.     

Family history of gynaecological cancers

Women are presenting to primary and secondary care with concerns about a family history of ovarian and breast cancer, or ovarian, endometrial and bowel cancer. Although most ovarian and endometrial cancer is sporadic, about 5−10% is due to mutations in genes which predispose to breast/ovarian cancers, BRCA1 and BRCA2, and ovarian/endometrial and bowel cancer, the mismatch repair genes of hereditary non-polyposis colon cancer (HNPCC). This review considers different scenarios in women presenting with a family history of ovarian and endometrial cancer. It uses these family histories to illustrate the ways in which families at high risk of ovarian and endometrial cancer can be identified by pedigree analysis. There will be further discussion about these genes and the different management options available to families, including surveillance, chemoprevention and prophylactic surgery.     

Genetik und Prävention des Ovarialkarzinoms

Ovarian cancer has the poorest prognosis of all gynaecological neoplasia. Germline mutations of the genes BRCA1 and BRCA2 are considered to be of substantial relevance in hereditary ovarian cancer. The multifactorial aetiology of this phenomenon accounts for the various phenotypes which are not only relevant in ovarian cancer. The clinical relevance of these syndromes increases with the option of predictive genetic testing for the predisposing genes. The lifetime-risk for ovarian cancer in women with mutations of the BRCA1 and/or BRCA2 genes is increased by upto 60%. The clinical implications of identifying patients at high risk necessitates the optimal use of primary or secondary prevention as proposed by the federally funded “Project for Familiar Breast and Ovarian Cancer”.     

BRCA基因突变女性携带者生育力保存研究进展

长期以来,乳腺癌易感基因1（BRCA1）和BRCA2突变被认为是乳腺癌及卵巢癌的独立危险因素。针对肿瘤的任何治疗方式（如双侧输卵管切除术等）都不可避免地对患者生育力带来破坏或丢失。随着女性生育年龄的普遍推迟和癌症发病年龄的年轻化,生育力保护已成为肿瘤治疗决策时经常需要面临的问题。同时,一些研究表明BRCA基因突变也可导致卵巢功能障碍,尤其是卵巢储备能力的下降。就BRCA1/2基因突变携带者可能面临的生育力问题及目前已有的保存生育力技术进行综述为临床提供参考。     

Is Uterine Papillary Serous Adenocarcinoma a Manifestation of the Hereditary Breast–Ovarian Cancer Syndrome?

Background. Uterine papillary serous carcinoma (UPSC) shares common pathologic, genetic, and clinical features with other serous cancers of müllerian origin. The most common histologic type of ovarian tumor associated with BRCA mutations is papillary serous. Because of these histologic similarities, we postulated that, in some cases, UPSC may be a manifestation of a field defect in BRCA1 carriers, which also includes ovarian carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma.Methods. Fifty-six living patients with UPSC were contacted through their treating physicians and agreed to a family history interview and to provide a blood specimen for BRCA testing. The protein truncation test was used to detect mutations in exons 10 and 11 of BRCA1 and in exon 11 of BRCA2. The presence of four common mutations was assessed by PCR-based specific assays.Results. A high proportion of patients had a past history of breast cancer (11%) or a first-degree relative with breast cancer (29%). Four patients were from families with site-specific hereditary breast cancer. However, there was no clear example of the hereditary breast–ovarian cancer syndrome, and none of the 56 patients was found to carry a BRCA1 or BRCA2 mutation.Conclusions. BRCA mutations do not appear to predispose to UPSC and this type of cancer does not appear to be a manifestation of the classical hereditary breast–ovarian cancer syndrome. The observed association between UPSC and breast cancer may be due to the presence of mutations in other cancer predisposing genes.     

Germline mutations of BRCA1 and BRCA2 in Korean sporadic ovarian carcinoma

OBJECTIVES: Mutations in the BRCA1 and BRCA2 genes predispose women to ovarian and/or breast cancer. The contribution of BRCA1 and BRCA2 mutations to ovarian cancer in Korean women remains to be elucidated. In addition, genetic polymorphisms may affect not only cancer development but also cancer progression and, as a result, could influence cancer phenotypes. The purposes of this study were, first, to investigate the presence of BRCA1 and BRCA2 mutations in women with ovarian cancer who were unselected for family history and, second, to evaluate the relationship between ovarian cancer susceptibility gene polymorphisms and clinicopathological features. METHODS: We studied 37 women who were diagnosed with epithelial ovarian cancer and treated at the Yonsei University Hospital between August 2002 and March 2004. Genomic DNA was analyzed for BRCA mutations using a PCR-DHPLC-sequencing method. The relationship between ovarian cancer susceptibility gene polymorphisms and clinicopathological features was examined. RESULTS: Most mutations of BRCA1 and BRCA2 associated with ovarian and/or breast cancer result in truncated proteins. We found one frameshift mutation in BRCA1 (3746insA) that led to premature termination. The patient had no family history of breast or ovarian cancer. There was no relationship between ovarian cancer susceptibility gene polymorphisms and clinicopathological features. CONCLUSION: Our results were consistent with the hypothesis that BRCA1 and BRCA2 mutations have a limited role in sporadic ovarian carcinogenesis in the Korean population. Furthermore, polymorphisms of certain, selected ovarian cancer susceptibility genes were not associated with the clinicopathological phenotypes of ovarian cancer.     

A genetic epidemiological study of carcinoma of the fallopian tube

OBJECTIVE: The goal of this work was to evaluate the importance of genetic factors in the etiology of fallopian tube cancer. METHODS: All pathologically confirmed cases of fallopian tube cancer diagnosed in Ontario from 1990 to 1998 were identified from the records of the Ontario Cancer Registry. Living patients were approached to provide information about their family history and to provide a blood sample for testing for mutations in BRCA1 and BRCA2. RESULTS: A modest increase in the risk of ovarian cancer (relative risk (RR) = 2.2; 95% confidence interval (CI) = 0.4, 6.3) and of early-onset breast cancer (RR = 2.4; 95% CI = 0.6, 6.1) was observed in the first-degree relatives of the fallopian cancer cases. Five of the forty-four cases were positive for a mutation in BRCA1 (11%) and two were positive for a BRCA2 mutation (5%). Five of eighteen women diagnosed at or before age 55 were positive (28%). Two of the seven mutation carriers had a strong family history of breast and ovarian cancer, and three carriers had a modest family history. Three of the forty-four cases were Jewish, and of these, two carried a founder mutation characteristic of this population. CONCLUSIONS: Fallopian tube carcinoma should be considered to be a clinical component of the hereditary breast-ovarian cancer syndrome, and may be associated with BRCA1 and BRCA2 mutations. Genetic evaluation should be offered to women who present with fallopian tube carcinoma. It is important to consider the risk of fallopian tube carcinoma when prophylactic oophorectomy is performed in high-risk women.     

卵巢癌与基因检测的规范化

随着卵巢癌精准治疗的全面推广,肿瘤易感基因检测的需求日益增长。国内外指南均建议卵巢癌患者在初次病理确诊时进行BRCA1/2胚系基因检测,以确定是否为遗传性上皮性卵巢癌,同时可预测患者对聚腺苷二磷酸核糖聚合酶（poly ADP-ribose polymerase,PARP）抑制剂的获益。准确识别遗传性上皮性卵巢癌,可使患者从个体化治疗中获益,同时对其一级和二级亲属的肿瘤防治意义重大。其他易感基因,例如错配修复（mismatch repair,MMR）基因和同源重组缺陷（homologous recombination deficiency,HRD）相关基因,也在卵巢癌发生中起到关键作用,同时也对卵巢癌患者的治疗决策起到关键作用。文章就卵巢癌基因检测的规范化进行综合探讨分析,以期为卵巢癌个体化诊疗策略提供更具指导性的基因检测依据。     

Das familiäre Mammakarzinom

The majority of breast carcinomas occur sporadically, while about 5–10% are of familial origin. These are associated with mutations in the breast cancer genes BRCA1 and BRCA2. Mutation carriers have a life-time risk of 60–80% for breast cancer and 20–40% for ovarian cancer. Molecular genetic analysis allows identifying women with higher risk. Since 1996 the German consortium “Hereditary Breast and Ovarian Cancer” has provided an interdisciplinary approach to genetic counseling and testing. It also offers preventive and therapeutic strategies such as intensified surveillance, prophylactic surgery, and new tailored therapeutic techniques.     

Problems raised by the gynaecologic management of women with BRCA 1 & 2 mutations

Breast and ovarian cancer occur more frequently in young women with BRCA 1 &2 mutations (respective cumulative risks from 37 to 85% and 10 to 20%), and raise specific gynaecologic problems as prophylactic surgery and hormonal treatments. Two medical files from 2 sisters with BRCA 1 mutation (exon 11) are presented and the authors discuss the therapeutic options chosen. BRCA 1 & 2 tumour suppressor genes seem to play a major role in the repair of cellular damages inducing by the estrogenic proliferative signal. The prophylactic mastectomy is effective for the breast cancer prevention but its acceptance is low. The oophorectomydecreases the ovarian risk (knowing the occurrence of peritoneal carcinomatosis in 1.8% of cases) and currently the breast cancer risk (RR = 0.47) by the hormonal privation: the hormone replacement therapy does not seem to increase the breast cancer risk in the small series published. The HRT is possible in women with BRCA mutation under medical supervision and if the doses of hormones are light. The first results concerning the chemoprevention by Tamoxifen are encouraging (RR = 0.38) in these patients, but more studies are needed. The oral contraception exerts an uncertain effect against ovarian cancer, but possibly enhances the breast cancer risk in this group of women (RR = 3.3).The management of women with BRCA mutation is varying according to their own priorities, which can change during their life.     

Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome?

BACKGROUND: Uterine papillary serous carcinoma (UPSC) shares common pathologic, genetic, and clinical features with other serous cancers of müllerian origin. The most common histologic type of ovarian tumor associated with BRCA mutations is papillary serous. Because of these histologic similarities, we postulated that, in some cases, UPSC may be a manifestation of a field defect in BRCA1 carriers, which also includes ovarian carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. METHODS: Fifty-six living patients with UPSC were contacted through their treating physicians and agreed to a family history interview and to provide a blood specimen for BRCA testing. The protein truncation test was used to detect mutations in exons 10 and 11 of BRCA1 and in exon 11 of BRCA2. The presence of four common mutations was assessed by PCR-based specific assays. RESULTS: A high proportion of patients had a past history of breast cancer (11%) or a first-degree relative with breast cancer (29%). Four patients were from families with site-specific hereditary breast cancer. However, there was no clear example of the hereditary breast-ovarian cancer syndrome, and none of the 56 patients was found to carry a BRCA1 or BRCA2 mutation. CONCLUSIONS: BRCA mutations do not appear to predispose to UPSC and this type of cancer does not appear to be a manifestation of the classical hereditary breast-ovarian cancer syndrome. The observed association between UPSC and breast cancer may be due to the presence of mutations in other cancer predisposing genes.