Breast-ovarian Cancer Syndrome Research Articles

Guidelines for complex genetic analysis of hereditary breast ovarian cancer syndrome in slovak population

AbstractGenetic diagnostics of hereditary breast and ovarian cancer (HBOC) has been performed in Slovakia in many different forms before the year 2000. Complex HBOC genetic analysis consists of many steps, including the initial genetic consultation, laboratory testing of genes associated with HBOC, interpretation and report of DNA analysis results, secondary explanatory genetic consultation and recommendation of clinical management for pathological mutation carriers. Many clinicians are participating on this workflow, such as clinical geneticists, laboratory diagnosticians as well as gynaecologists, oncologists or radio-diagnosticians. Currently, genetic testing is still technically and financially demanding and aimed only at selected families or patients who fulfil the defined clinical indication criteria.Positive result of DNA analysis, that is, detection of pathological mutation in genes associated with HBOC syndrome means that the risk of breast/ovarian cancer onset in mutation carriers is amplified. This predisposition markedly affects the clinical management and treatment of patient and other members of the family, thus creating the demand to establish widely accepted specific recommendations for genetic diagnostics of HBOC. In the past, the analysis of HBOC in Slovakia followed various technical approaches and indication criteria depending on the workflow of specific laboratory. The guidelines reported below adhere to the current trends in DNA analysis and clinical healthcare, define the criteria for diagnostic laboratories, conditions for genetic testing and determine indications for selection of HBOC families and further clinical management of mutation carriers.

278P Characteristics of endometrial and ovarian cancers in Lynch syndrome and hereditary breast ovarian cancer syndrome

278P Characteristics of endometrial and ovarian cancers in Lynch syndrome and hereditary breast ovarian cancer syndrome

Do hereditary syndrome-related gynecologic cancers have any specific features?

Hereditary syndromes are responsible for 10 % of gynaecologic cancers, among which hereditary breast-ovarian cancer and hereditary non-polyposis colon cancer syndromes, known as HBOC and Lynch syndromes respectively, present the highest relative risk. The latter predisposes to endometrial cancer and both contribute to ovarian cancer. Cowden syndrome-related endometrial cancer and the increased risk of ovarian, uterine and cervical cancers associated with Peutz-Jeghers syndrome, are also demonstrated, while Li-Fraumeni syndrome patients are prone to develop ovarian and endometrial cancers. Despite these syndromes’ susceptibility to gynaecologic cancers being consensual, it is still not clear whether these tumours have any epidemiologic, clinical, pathologic or imaging specific features that could allow any of the intervening physicians to raise suspicion of a hereditary syndrome in patients without known genetic risk. Moreover, controversy exists regarding both screening and surveillance schemes. Our literature review provides an updated perspective on the evidence-based specific features of tumours related to each of these syndromes as well as on the most accepted screening and surveillance guidelines. In addition, some illustrative cases are presented.Teaching Points• HBOC syndrome is mainly associated with ovarian HGSC, which arises in fallopian fimbriae.• LS-related endometrial tumours show histological diversity and predilection for lower uterine segment.• LS and CS-related ovarian cancers are mostly of non-serous type, usually endometrioid.• Ovarian SCTAT and cervical adenoma malignum are strongly associated with PJS.• Unfortunately, hereditary gynaecologic cancers do not seem to have distinctive imaging features.

Deleterious BRCA1/2 mutations in an urban population of Black women.

Information on the prevalence of deleterious BRCA1 and BRCA2 (BRCA1/2) mutations in clinic-based populations of Black women is limited. In order to address this gap, we performed a retrospective study to determine the prevalence of deleterious BRCA1/2 mutations, predictors of having a mutation, and acceptance of risk-reducing surgeries in Black women. In an urban unselected clinic-based population, we evaluated 211 self-identified Black women who underwent genetic counseling for hereditary breast-ovarian cancer syndrome. BRCA1/2 mutations were identified in 13.4% of the participants who received genetic testing. Younger age at diagnosis, higher BRCAPRO score, significant family history, and diagnosis of triple-negative breast cancer were associated with identification of a BRCA1/2 mutation. Of the affected patients found to have a deleterious mutation, almost half underwent prophylactic measures. In our study population, 1 in 7 Black women who underwent genetic testing harbored a deleterious BRCA1/2 mutation independent of age at diagnosis or family history.

El cáncer hereditario en mujeres

Most cases of cancer are sporadic, whereas 5-10% are hereditary and about 20-30% of cancers tend to cluster in families. Families and individuals who are suspected of suffering from hereditary cancer need to undergo a process known as genetic counseling, which is of considerable importance in the prevention and early detection of malignant tumours. The most common hereditary cancer syndromes are: hereditary breast-ovarian cancer syndrome, familial adenomatous polyposis and Lynch syndrome. Genetic diagnosis allows clinicians to estimate the risks of developing different cancers in order to make decisions over surveillance and prophylactic surgery to reduce these risks. The ultimate goal is to reduce cancer mortality through early diagnosis and prevention.

Endometrial cancers in mutation carriers from hereditary breast ovarian cancer syndrome kindreds: report from the Creighton University Hereditary Cancer Registry with review of the implications.

The aim of this study was to categorize and report endometrial cancers in mutation carriers from hereditary breast ovarian cancer families. Our Hereditary Cancer Registry was searched for gynecologic and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified. Eight malignancies were classified as primary endometrial cancers. Five of these were low- or intermediate-grade endometrioid carcinomas, and 3 were pure serous carcinomas or contained serous carcinoma elements mixed with high-grade endometrioid carcinoma. Breast cancers were diagnosed in 5 patients before and in 1 patient after endometrial carcinoma. Three endometrioid carcinomas were preceded by estrogen treatment, 2 for many years and the other for only 2 months, and 2 of the patients with serous carcinoma had been treated with tamoxifen. The finding that 8 of gynecologic and peritoneal cancers in 101 mutation carriers were endometrial cancers with a smaller proportion of endometrioid carcinomas than reported in general populations is added to the current controversial literature on endometrial cancer, particularly regarding serous carcinomas, in hereditary breast ovarian cancer syndrome. Well-designed prospective programs for standardized surgical and pathologic handling, processing, and reporting are essential for working out the pathogenesis, true risks, and best management of this disease in carriers of deleterious BRCA1 and BRCA2 germline mutations.

Double PALB2 and BRCA1/BRCA2 mutation carriers are rare in breast cancer and breast-ovarian cancer syndrome families from the French Canadian founder population

French Canadian families with breast cancer and breast-ovarian cancer syndrome harbor specific BRCA1, BRCA2 and PALB2 germline mutations, which have been attributed to common founders. Mutations in these genes confer an increased risk to breast and ovarian cancers, and have been identified to play a role in and directly interact with the common homologous recombination DNA repair pathways. Our previous study described the case of a female diagnosed with breast cancer at 45 years old, who harbored the PALB2:c.2323C>T [p.Q775X] and BRCA2:c.9004G>A [p.E3002K] germline mutations, which have been found to recur in the French Canadian cancer families. As the frequency of double heterozygous carriers of breast-ovarian cancer susceptibility alleles is unknown, and due to the possibility that there may be implications for genetic counseling and management for these carriers, the present study investigated the co-occurrence of BRCA1/BRCA2 and PALB2 mutations in the French Canadian cancer families. The PALB2:c.2323C>T [p.Q775X] mutation, which is the only PALB2 mutation to have been identified in French Canadian cancer families, was screened in 214 breast cancer cases and 22 breast-ovarian cancer cases from 114 BRCA1/BRCA2 mutation-positive French Canadian breast cancer (n=61) and breast-ovarian cancer (n=53) families using a tailored polymerase chain reaction-based TaqMan® SNP Genotyping Assay. No additional PALB2:c.2323C>T [p.Q775X] mutation carriers were identified among the BRCA1/BRCA2 mutation carriers. The results suggest that carriers of the PALB2:c.2323C>T [p.Q775X] mutation rarely co-occur in French Canadian breast cancer and breast-ovarian cancer families harboring BRCA1 or BRCA2 mutations.

Survival outcome in endometrial cancer patients according to hereditary predisposition

ObjectiveA familial history of ovarian cancer/breast cancer is considered a significant prognostic factor for ovarian cancer. We investigated hereditary factors by examining the incidence of synchronous malignancy in patients with endometrial cancer, and assessed the prognostic role of heredity in endometrial cancer. MethodsWe retrospectively evaluated patients with endometrial cancer who underwent surgery from January 2001 to April 2011. A hereditary background in this study was defined as double primary cancer, that is, endometrial cancer accompanied by colon, ovarian, or breast cancer suggestive of Lynch syndrome, hereditary breast ovarian cancer syndrome, or Cowden syndrome, respectively. ResultsAmong 282 patients with endometrial cancer in the study population, 20 patients (7.1%) had a hereditary predisposition: 10 patients (3.5%) had ovarian cancer, six patients (2.1%) had breast cancer, and four patients (1.4%) had colon cancer. Age and lower uterine segment involvement were not statistically different between the hereditary and nonhereditary groups. The majority of the women in the hereditary group presented with Stage I cancer; however, there were no significant differences in Stage I cancer between the hereditary group and the sporadic endometrial cancer group (85% and 77%, respectively, p = 0.561). The median follow-up period was 60 months. A 5-year overall survival rate was not different between the two groups (95% and 95%, respectively, p = 0.659). Among a subgroup of patients with Stage I endometrial cancer, the 5-year overall survival rate was lower in the endometrial cancer with a hereditary predisposition group compared with the sporadic endometrial cancer group (94% and 98%, respectively, p = 0.027). ConclusionSeven percent of the women with endometrial cancer in our study had other malignancies such as ovarian, colon, or breast cancer synchronously. Among a subgroup of patients with Stage I cancer in the endometrial cancer with a hereditary predisposition group, the 5-year overall survival rate was significantly lower (94%). This finding should be confirmed in a larger population.

Risk factors for pancreatic cancer: underlying mechanisms and potential targets.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths among both men and women in the United States and remains essentially without effective therapies. The 5-year survival of patients with pancreatic cancer is a dismal 6% or less. Environmental risk factors such as smoking, diabetes, obesity, and alcoholism play major roles in the promotion of PDAC. However, currently we have limited understanding of how these risk factors promote the disease. The papers presented in this topic illustrate the latest knowledge regarding the mechanisms of pancreatic cancer induction and promotion by major risk factors such as smoking, pancreatitis, alcohol abuse, obesity and diabetes (Kolodecik et al., 2013), and less studied factors such blood group types (Pelzer et al., 2013) and the genetic mutations (Kong et al., 2013; Reznik et al., 2014; Weiss, 2014). Indeed, an inherited predisposition to PDAC is believed to present in familial cancer syndromes such as the Peutz-Jeghers Syndrome, which is associated with germline mutations in the STK11/LKB1 gene, Familial Atypical Multiple Mole Melanoma syndrome, which results due to germline mutations in the p16/CDKN2A gene, Hereditary Breast-Ovarian Cancer syndrome (BRCA1/2 genes), Hereditary Non-polyposis Colorectal Cancer (mismatch repair genes), and Familial Adenomatous Polyposis syndrome (Reznik et al., 2014). Hereditary causes of pancreatitis, such as the autosomal dominant form caused by germline mutations of the cationic trypsinogen gene, PRSS1, have been indirectly linked to PDAC through early onset chronic pancreatitis with an associated 53-fold increased incidence and approximately 40% of hereditary pancreatitis patients noted to develop pancreatic cancer by age 70 (Weiss, 2014). Finally, more patients with blood group A suffer from PDAC whereas blood group O was less frequent in patients with PDAC (Pelzer et al., 2013). Kras mutations remain the most abundant genetic alteration found in pancreatic cancer patients. Kras mutations may lead to reducing power for ROS detoxification, leading to low ROS levels in pancreatic pre-neoplastic cells and in cancer cells. In adult stem cells and cancer stem cells, low ROS levels have been associated with the formation of a proliferation-permissive intracellular environment and with perseverance of self-renewal capacities. Therefore, it is conceivable that low intracellular ROS levels may contribute significantly to oncogenic Kras-mediated PDAC formation (Kong et al., 2013). Specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. Today, the role of stromal cells is highly appreciated for pancreatic cancer development. Immune cell infiltration into the tumor not only fail to contribute to disease eradication but rather due to exhibiting a Th2-type inflammation and immunosuppression is associated with more rapid disease progression, cachexia induction, and reduced survival. Polarization of macrophages toward M2-type correlates with a poor prognosis after surgery in resected patients. High CD163+ and CD204+ cell counts correlate with metastasis and poor prognosis in PDAC patients (Protti and De Monte, 2013; Tan et al., 2014). Src kinase might serve as a critical mechanistic link between inflammation and cancer, mediating and propagating a cycle between immune and tissue cells that can ultimately lead to the development and progression of cancer (Liu et al., 2013). In addition, there is now compelling evidence that pancreatic stellate cells interact not only with cancer cells themselves, but with several other cell types in the stroma (endothelial cells, immune cells, and possibly neuronal cells) to promote cancer progression. Strategies to target the tumor microenvironment cells are proposed (Wilson et al., 2014). The central role of the mammalian target of rapamycin (mTOR) in mediating a crosstalk between the insulin/IGF-1 and GPCR signaling in pancreatic cancer cells is discussed in depth and strategies, including the use of metformin, to target this signaling pathway in PDAC cells are proposed (Rozengurt, 2014). Finally, a comprehensive review of the latest animal models of pancreatic cancer are discussed, proposing novel tools to study the mechanism of pancreatic cancer initiation and promotion by major risk factors.

The molecular genetics of hereditary and sporadic ovarian cancer: implications for the future.

Epithelial ovarian cancer (EOC) is a heterogeneous condition with poor survival outcomes. The genetics of hereditary and sporadic ovarian cancers will be covered and its implications to management and future research are discussed. Key recent published literature. Both genetic and environmental factors play a role in the development of EOC. Most EOCs develop sporadically and are divided into low-grade/genetically stable type I tumours and high-grade/genetically unstable type II tumours. The commonest hereditary syndromes are hereditary breast ovarian cancer syndrome (HBOC-BRCA mutations) and Lynch syndrome (DNA mismatch repair mutations). The different histological types of EOC may not solely originate from the ovary but from the fallopian tube and endometriosis deposits; there is increasing evidence to support this. Our understanding of the genetics and frequencies of mutations in ovarian cancer is expanding. The proportion of heritable EOC is larger than previously estimated and not all patients have a clear family history for this. Mutations in genes involving the downstream BRCA signalling pathway have recently been implicated in HBOC. TP53 mutations are the single most commonly identified mutations in aggressive sporadic high-grade serous carcinomas, affecting essentially 100% of such tumours. Furthermore, there is increasing recognition that the different histological sub-types need to be treated as separate entities. Given how heterogeneous 'ovarian' cancer is, trials into new drugs should report responses for the different histo-/geno-types rather than simply using staging. Although the effect of new drugs such as poly(ADP-ribose) polymerase inhibitors are being investigated in ovarian cancer, there is still a need to develop targeted therapies-especially to tackle mutations in PI3 K pathway, RAS pathway and TP53.

Are bilateral breast cancers and breast cancers coexisting with ovarian cancer different from solitary tumors? A pair-matched immunohistochemical analysis aimed at intrinsic tumor phenotype.

Patients with bilateral breast cancer (BBC) and breast-ovarian cancer syndrome (BOCS) constitute populations potentially enriched for molecular defects involved in the pathomechanisms of these malignancies. The aim of our study was to compare tumor morphology and expression of estrogen and progesterone receptor, HER2, Ki67, cytokeratin 5/6, E-cadherin, vimentin and epidermal growth factor receptor in tissue microarrays from 199 tumors from BBC or BOCS patients and 199 age-matched solitary tumors. Compared to controls, BBC and BOCS considered jointly had lower incidence of DCIS, lower expression of PgR and HER2, and higher expression of Ki67 and vimentin. BOCS tumors were of higher grade, had lower expression of ER and PgR and higher expression of Ki67, CK5/6, vimentin and EGFR. BBC had less DCIS component, lower HER2 expression and higher Ki67 expression. Metachronous BBC (mBBC) had lower expression of ER, PgR and HER2, and higher expression of Ki67 and vimentin. Synchronous BBC (sBBC) had less DCIS component, higher expression of ER, and lower expression of CK5/6, EGFR and E-cadherin. BBC and breast cancers in BOCS differ in many aspects from solitary tumors. BBC are a heterogeneous group of tumors, differing between sBBC and mBBC. mBBC phenotype shares many features with BOCS tumors.

Are Bilateral Breast Cancers and Breast Cancers Coexisting with Ovarian Cancer Different from Solitary Tumors? a Pair-Matched Immunohistochemical Analysis Aimed at Intrinsic Tumor Phenotype

ABSTRACT Aim: Patients with bilateral breast cancer (BBC) and breast-ovarian cancer syndrome (BOCS) constitute populations potentially enriched for molecular defects involved in the pathomechanisms of these malignancies. We compared the morphological and immunohistochemical characteristics of primary tumors in BBC and BOCS patients with age-matched solitary breast cancers, with particular focus on intrinsic tumor phenotype. Methods: Tumor morphology and expression of 8 immunohistochemical markers were assessed in tissue microarrays from 199 tumors from the multiple tumor group (BBC+BOCS) and 199 age-matched solitary tumors. Analyzed markers included estrogen and progesterone receptor, HER2, Ki67, cytokeratin 5/6, E-cadherin, vimentin and epidermal growth factor receptor. Results: Compared to controls, BBC and BOCS considered jointly had lower incidence of DCIS (p=0.0003), lower expression of PgR (p=0.02) and HER2 (p=0.0004), and higher expression of Ki67 (p=0.007) and vimentin (p=0.036). BOCS tumors were of higher grade (p=0.004), had lower expression of ER (p=0.004) and PgR (p=0.03) and higher expression of Ki67 (p=0.05), CK5/6 (p=0.017), vimentin (p=0.01) and EGFR (p=0.009). BBC had less DCIS component (p=0.001), lower HER2 expression (p=0.002) and higher Ki67 expression (p=0.05). Metachronous BBC (mBBC) had lower expression of ER (p=0.036), PgR (p=0.006) and HER2 (p=0.00009), and higher expression of Ki67 (p=0.0009) and vimentin (p=0.01).Synchronous BBC (sBBC) had less DCIS component (p=0.004), higher expression of ER (p=0.005), and lower expression of CK5/6 (p=0.038), EGFR (p=0.016) and E-cadherin (p=0.03). Conclusions: BBC are a heterogeneous group of tumors, different from solitary cases and differing between sBBC and mBBC. mBBC phenotype shares many features with BOCS tumors. Disclosure: All authors have declared no conflicts of interest.

Multiple primary cancers as a guide to heritability.

There are approximately 100 genes which when mutated are known to predispose to one or more forms of cancer. Currently, genetic testing is offered for many of these, either as single genes or as multi-gene panels. Features of hereditary cancer include a positive family history of cancer, early age of onset and the appearance of multiple primary cancers in one individual. In some cases multiple cancers may be of the same site (e.g., bilateral breast cancer) and in other cases they may be at different sites. Various combinations of cancer sites may be indicative of specific cancer syndromes such as the breast ovarian cancer syndrome. Genetic testing should be offered to individuals who have experienced multiple primary cancers in some circumstances, the genetic counselor should review the ages of sites of cancer, their pathologic features and the family history of cancer as part of the pre-test evaluation.

Les formes héréditaires du cancer de l’ovaire : particularités clinico-biologiques et thérapeutiques

Hereditary ovarian cancers account for 10% of all cases. Two major syndromes with dominant autosomal transmission are identified. The most common one is breast-ovarian cancer syndrome due to BRCA1 and BRCA2 genes mutations, and the Lynch syndrome with mutated MMR genes is the other. Alterations in homologous recombination specifically observed in ovarian cancer with BRCA defects associated to Parp inhibition create a synthetic lethality of special interest. Numerous studies are in progress to explore this promising new approach. Furthermore, it seems that carcinogenesis of these two syndromes are different, suggesting alternative therapeutic options in the near future in order to improve prognosis of ovarian carcinomas.

Familial pancreatic cancer: genetic advances

Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.

Development of an integrated support system for hereditary cancer and its impact on gynecologic services

Patients with hereditary cancer need an integrated support system. A recently launched project was evaluated in terms of its efficacy in screening patients with hereditary cancer at the gynecologic service. The project team comprised gynecologists, surgeons, medical geneticists, and certified genetic counselors (CGCs) in our hospital. At the gynecologic service, a newly developed self-administered family history questionnaire (SAFHQ) was given to patients with ovarian, endometrial, or breast cancer as well as a history of multiple cancers. After an interview, a CGC constructed a pedigree and evaluated the risk for hereditary cancer. Patients at risk were recommended by a gynecologist to receive further genetic counseling at the Department of Genetics according to the modified Bethesda criteria, Amsterdam II criteria, and National Comprehensive Cancer Network (NCCN) guidelines 2012 for breast-ovarian cancer syndrome (HBOC). The numbers of newly screened patients were compared before and after the project launch. The SAFHQ was administered to 131 patients and 106 (81 %) pedigrees were constructed between August 2012 and July 2013. The number of newly screened patients according to the Bethesda criteria was 4 and 8 at 10 years before and 1 year after the project launch, respectively. Two and 31 patients met the NCCN criteria for HBOC excluding ovarian cancer alone, respectively, at these 2 time points. Of 54 patients who were recommended to undergo further counseling, 10 (19 %) visited the Department of Genetics. After the launch of an integrated support system, the number of patients with hereditary cancers who were screened increased. The gynecologic service played a pivotal role in patient and family care.

Abstract P2-14-06: Characterization of risk factors in breast cancer young adult patients

Abstract Background: Breast cancer diagnosis in the age group of 20-34 years represents 4% of breast cancer cases diagnosed at all ages in São Paulo state, Brazil. Risk factors in this age group of patients are little understood, especially in those not reporting familial history of breast/ovarian cancer syndrome (BOCS). Identification of predisposing factors and BRCA1/2 mutations (mut) in young Brazilian patients may contribute to characterize women with increased risk of breast cancer. Objective: Characterize familial history and risk factors for breast cancer in young adult Brazilian patients and germline mutations in BRCA1/2 genes. Methodology: Forty-five patients diagnosed with breast cancer at ages 18-35 years were interviewed using a comprehensive questionnaire. Genomic DNA was extracted from peripheral blood and BRCA1/2 mut were screened by Sanger sequencing of coding sequences, analyzed through Mutation Surveyor v.3.20 and searched in BIC Database, LOVD, LOVD-IARC and UMD. Results: Mean age of patients at time of diagnosis was 33 y (24-35y); mean age of menarche was 13 y (8-19y); 32 (71.1%) patients had at least one born child, median age of first pregnancy was 22 years; 86.7% never smoked; 71.1% were no regular alcoholic drinkers; mean of body mass index was 27.14 (overweight). Most patients were diagnosed with invasive ductal carcinoma (91.1%); grades II or III (95.5%); ER/PR positive (57.8%); triple-negative (TN: 31.1%) or HER2 positive (17.8%). Among them, 22.2% reported positive familial history (NCCN criteria for BOCS). Deleterious mutation in BRCA1/2 genes was found in 17.8% of the patients (BRCA1, n = 3; BRCA2, n = 5). Among 10 and 35 patients reporting or not BOCS familial history, 3 (30%) and 5 (14.3%) respectively, had BRCA1/2mut. All BRCA1mut patients had TN tumors; BRCA2mut patients had ER/PR positive (60%), HER2 positive (20%) or TN tumors (20%). Most patients reported one or two of the following risk factors: early menarche (<12y); current/previous use of oral contraceptive; no breast feeding and no parities. Among 30 patients reporting no familial history and presenting BRCA1/2 wild type, six (20%) and four (13.3%) reported three or four of these risk factors, respectively. Considering breast cancer protective factors, 17.8% of the patients breast fed >16 months and 24.4% were aged <20y at birth of first child. Diet habits are being analyzed. Conclusion: In young adults with breast cancer there is a trend towards a higher rate of positive familial history among whom there is a trend towards a higher chance of BRCA1/2 mutation. A better characterization of patients reporting no familial history is urgently needed. Financial Support: FAPESP. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-06.

Evaluation after five years of the cancer genetic counselling programme of Valencian Community (Eastern Spain)

To evaluate the cancer genetic counselling programme in Valencian Community using intermediate indicators. Descriptive analysis of organisational and effectiveness indicators from the start in 2005 until December 2010: correct referral of patients according to the area from where they were referred (primary or hospital-based care) and syndrome; families identified as having each syndrome; suitability of the genetic testing for individuals with a cancer diagnosis (index cases, IC) and relatives of ICs with mutations; family size; and results of genetic testing on genes, ICs and relatives. 9,942 individuals attended, 87.7 % were referred by hospital-based care and 8.4 % by primary care. 7,516 patients (79 %) fulfilled cancer genetic counselling criteria (82 % from hospital-based care and 46 % from primary care). Amongst those who fulfilled the criteria, 59 % of referrals were related to hereditary breast ovarian cancer syndrome and 32 % to hereditary non-polyposis colorectal cancer. ICs were found in 3,082 families (78.7 %) and genetic testing was carried out on 91.3 % of them. Pathogenic mutations were detected in 21.8 % of the ICs and the testing was then offered to their relatives (an average of 3 per IC). Pathogenic mutations were found in 54 % of the assessed relatives. Results in 5 years confirm the appropriateness of these facilities, as part of an integrated health service, to identify families and individuals with genetic risk to offer them personalized counselling. Improvements have to be made with regard to the information given to both health professionals and patients about the risk criteria for various syndromes.

Family History and BRCA1/BRCA2 Status Among Japanese Ovarian Cancer Patients and Occult Cancer in a BRCA1 Mutant Case

This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer. One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer. Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case. Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

Germline NF1 Mutation Carriers, Neurofibromatosis Type 1 Patients May Be Predisposed to the Development of Barrettʼs Esophagus

Purpose: One of the common genomic alterations of Barrett's esophagus (BE) is somatic loss of the q11 region of chromosome 17. This region of chromosome 17 is known to contain the tumor suppression gene NF1. Germline NF1 mutations are the cause of neurofibromatosis type 1 (NF type 1). Our aims were (1) to determine the prevalence of BE in patients with NF type 1 and (2) compare it to the prevalence in patients with cancer syndromes whose causative genes are not reported to be altered in initial development of BE. Methods: Patients with one of four cancer syndrome diagnoses were studied: NF type 1, Lynch syndrome, familial adenomatous polyposis, and hereditary breast ovarian cancer. Records were reviewed from Mayo Clinic Arizona, Florida and Rochester. Cancer syndrome patients who had had an upper endoscopy or documented history of BE were included in the data set. Results: BE was more common in the NF type 1 group than in other cancer syndrome groups. 30% of NF type 1 patients had BE (7 of 23), compared to 11% for Lynch syndrome (6 of 53, odds ratio [OR] 3.43; 95% CI 1.00-11.7), 6% for familial adenomatous polyposis (9 of 162, OR 7.44; 95% CI 2.44-22.7), and 0% for hereditary breast ovarian cancer syndrome (0 of 48). Five of 7 NF type 1 patients with BE were male. The mean age at diagnosis of BE was 52 years (range 19-71 years). Five patients had non-dysplastic BE, while one patient had low grade dysplasia and one high grade dysplasia. None of the seven patients had progression of their BE while under observation, however, only two patients had the results of more than one upper endoscopy recorded. Conclusion: BE was commonly found in NF type 1 patients who underwent endoscopy, compared with other cancer syndromes. The association is plausible as both BE and NF type 1 are associated with loss of NF1 function. Molecular studies and higher quality clinical studies are needed to confirm this association.Table: Table. Comparison of patients with eosinophilic infiltration with and without refluxTable: Table. Sensitivity, specificity, and predictive values of different maximum esophageal diameters