http://www.hccpjournal.com The latest research articles published by Hereditary Cancer in Clinical Practice 2012-01-10T00:00:00Z Lynch syndrome (LS) individuals are predisposed to a variety of cancers, most commonly colorectal, uterine, urinary tract, ovarian, small bowel, stomach and biliary tract cancers. The risk of extracolonic manifestations appears to be highest in MSH2 mutations carriers.We present a carrier case with a novel MSH2 gene mutation that clearly demonstrates the broad extent of LS phenotypic expression and highlights several important clinical aspects. Current evidence suggests that colorectal tumors from LS patients tend to have better prognoses than their sporadic counterparts, however survival benefits for other cancers encountered in LS are unclear.In this article we describe a family with a novel protein truncating mutation of c.2388delT in the MSH2 gene, particularly focusing on one individual carrier affected with multiple primary cancers who is surviving 25 years on. Our report of multiple primary tumors occurring in the 12-25 years interval might suggest these patients do not succumb to other extracolonic cancers, provided they are regularly followed-up. http://www.hccpjournal.com/content/10/1/1 Ramunas Janavicius Pavel Elsakov Hereditary Cancer in Clinical Practice 2012, null:1 2012-01-10T00:00:00Z doi:10.1186/1897-4287-10-1 /content/figures/1897-4287-10-1-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 1 2012-01-10T00:00:00Z PDF About 5-10% of breast and ovarian carcinomas are hereditary and most of these, result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish descent, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations,c.68_69del (185delAG) and c.5266dup (5382insC) in BRCA1 and c.5946del (6174delT) in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer (Gomes et al., 2007).Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for the hereditary breast and ovarian cancer (HBOC) syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%). This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p=0.023). The BRCA1c.68_69del and BRCA2c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1c.68_69del and BRCA2c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. A negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be further assessed in a larger well characterized high-risk cohort. http://www.hccpjournal.com/content/9/1/12 Ingrid Ewald Patricia Izetti Fernando Vargas Miguel Moreira Aline Moreira Carlos Moreira-Filho Danielle Cunha Sara Hamaguchi Suzi Camey Aishameriane Schmidt Maira Caleffi Patricia Koehler-Santos Roberto Giugliani Patricia Ashton-Prolla Hereditary Cancer in Clinical Practice 2011, null:12 2011-12-20T00:00:00Z doi:10.1186/1897-4287-9-12 /content/figures/1897-4287-9-12-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 12 2011-12-20T00:00:00Z PDF Background: We assessed ovarian cancer screening outcomes in women with a positive family history of ovarian cancer divided into a low-, moderate- or high-risk group for development of ovarian cancer. Methods: 545 women with a positive family history of ovarian cancer referred to the Ovarian Screening Service at the Royal Marsden Hospital, London from January 2000- December 2008 were included. They were stratified into three risk-groups according to family history (high-, moderate- and low-risk) of developing ovarian cancer and offered annual serum CA 125 and transvaginal ultrasound screening. The high-risk group was offered genetic testing. Results: The median age at entry was 44 years. The number of women in the high, moderate and low-risk groups was 397, 112, and 36, respectively. During 2266 women years of follow-up two ovarian cancer cases were found: one advanced stage at her fourth annual screening, and one early stage at prophylactic bilateral salpingo-oophorectomy (BSO). Prophylactic BSO was performed in 138 women (25.3%). Forty-three women had an abnormal CA125, resulting in 59 repeat tests. The re-call rate in the high, moderate and low-risk group was 14%, 3% and 6%. Equivocal transvaginal ultrasound results required 108 recalls in 71 women. The re-call rate in the high, moderate, and low-risk group was 25%, 6% and 17%. Conclusion: No early stage ovarian cancer was picked up at annual screening and a significant number of re-calls for repeat screening tests was identified. http://www.hccpjournal.com/content/9/1/11 Marielle Nobbenhuis Elizabeth Bancroft Eleanor Moskovic Fiona Lennard Paul Pharoah Ian Jacobs Ann Ward Desmond Barton Thomas Ind John Shepherd Jane Bridges Martin Gore Chris Haracopos Susan Shanley Audrey Ardern-Jones Sarah Thomas Rosalind Eeles Hereditary Cancer in Clinical Practice 2011, null:11 2011-11-23T00:00:00Z doi:10.1186/1897-4287-9-11 /content/figures/1897-4287-9-11-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 11 2011-11-23T00:00:00Z XML Background: Inheritance of a mutation in either BRCA1 or BRCA2 accounts for approximately 5% of all breast cancer cases, but varies by country. Investigations into the contribution of BRCA mutations to breast cancer incidence in Greece have been, for the most part, limited by small sample sizes and by the use of cases selected for their family history of cancer. The aim of the current study was to estimate BRCA mutation frequencies in breast cancer patients unselected for family history. Methods: To do so, we enrolled 127 unselected women with breast cancer from the Alexandra Hospital in Athens, Greece, a large public hospital in the city. Mutations in BRCA1 and BRCA2 were detected using a combination of techniques and were confirmed by direct sequencing. Two large genomic deletions were sought using mutation-specific assays. A detailed family history of cancer was obtained from each patient. Results: We were able to successfully complete testing on samples from 127 women. Among these, six mutations were identified (four in BRCA1 and two in BRCA2) representing 4.7% of the total or 9.5% of cases diagnosed before age forty. None of the mutation carriers had a family history of breast or ovarian cancer. Three of the four BRCA1 mutations were in exon 20: two were a G5331A mutation and the third was a 3.2 kb deletion. The fourth BRCA1 mutation was the 3819delGTAAA in exon 11. The two BRCA2 mutations were in exon 11 (3782del10 and 4512insT). Conclusions: The G5331A mutation in BRCA1 appears to be a founder mutation in the Greek population. http://www.hccpjournal.com/content/9/1/10 Chrissovaladis Koumpis Constantine Dimitrakakis Aris Antsaklis Robert Royer Shiyu Zhang Steven Narod Joanne Kotsopoulos Hereditary Cancer in Clinical Practice 2011, null:10 2011-11-15T00:00:00Z doi:10.1186/1897-4287-9-10 /content/figures/1897-4287-9-10-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 10 2011-11-15T00:00:00Z XML Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in the PRF1 coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutated PRF1 in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein. http://www.hccpjournal.com/content/9/1/9 Rim El Abed Violaine Bourdon Ilia Voskoboinik Halima Omri Yosra Ben Youssef Mohamed Laatiri Laetitia Huiart Francois Eisinger Laetitia Rabayrol Marc Frenay Paul Gesta Liliane Demange Helene Dreyfus Valerie Bonadona Catherine Dugast Helene Zattara Laurence Faivre Monia Zaier Saloua Yacoub Jemni Tetsuro Noguchi Hagay Sobol Zohra Soua Hereditary Cancer in Clinical Practice 2011, null:9 2011-09-21T00:00:00Z doi:10.1186/1897-4287-9-9 /content/figures/1897-4287-9-9-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 9 2011-09-21T00:00:00Z XML Background: Lynch syndrome is a hereditary cancer with confirmed carriers at high risk for colorectal (CRC) and extracolonic cancers. The purpose of the current study was to develop a greater understanding of the factors influencing decisions about disease management post-genetic testing. Methods: The study used a grounded theory approach to data collection and analysis as part of a multiphase project examining the psychosocial and behavioral impact of predictive DNA testing for Lynch syndrome. Individual and small group interviews were conducted with individuals from 10 families with the MSH2 intron 5 splice site mutation or exon 8 deletion. The data from confirmed carriers (n = 23) were subjected to re-analysis to identify key barriers to and/or facilitators of screening and disease management. Results: Thematic analysis identified personal, health care provider and health care system factors as dominant barriers to and/or facilitators of managing Lynch syndrome. Person-centered factors reflect risk perceptions and decision-making, and enduring screening/disease management. The perceived knowledge and clinical management skills of health care providers also influenced participation in recommended protocols. The health care system barriers/facilitators are defined in terms of continuity of care and coordination of services among providers. Conclusions: Individuals with Lynch syndrome often encounter multiple barriers to and facilitators of disease management that go beyond the individual to the provider and health care system levels. The current organization and implementation of health care services are inadequate. A coordinated system of local services capable of providing integrated, efficient health care and follow-up, populated by providers with knowledge of hereditary cancer, is necessary to maintain optimal health. http://www.hccpjournal.com/content/9/1/8 Kathy Watkins Christine Way Jacqueline Fiander Robert Meadus Mary Jane Esplen Jane Green Valerie Ludlow Holly Etchegary Patrick Parfrey Hereditary Cancer in Clinical Practice 2011, null:8 2011-09-07T00:00:00Z doi:10.1186/1897-4287-9-8 /content/figures/1897-4287-9-8-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 8 2011-09-07T00:00:00Z XML Background: The perception of breast cancer risk held by women who have not had breast cancer, and who are at increased, but unexplained, familial risk of breast cancer is poorly described. This study aims to describe risk perception and how it is related to screening behaviour for these women. Methods: Participants were recruited from a population-based sample (the Australian Breast Cancer Family Study - ABCFS). The ABCFS includes women diagnosed with breast cancer and their relatives. For this study, women without breast cancer with at least one first- or second-degree relative diagnosed with breast cancer before age 50 were eligible unless a BRCA1 or BRCA2 mutation had been identified in their family. Data collection consisted of an audio recorded, semi-structured interview on the topic of breast cancer risk and screening decision-making. Data was analysed thematically. Results: A total of 24 interviews were conducted, and saturation of the main themes was achieved. Women were classified into one of five groups: don't worry about cancer risk, but do screening; concerned about cancer risk, so do something; concerned about cancer risk, so why don't I do anything?; cancer inevitable; cancer unlikely. Conclusions: The language and framework women use to describe their risk of breast cancer must be the starting point in attempts to enhance women's understanding of risk and their prevention behaviour. http://www.hccpjournal.com/content/9/1/7 Louise Keogh Belinda McClaren Carmel Apicella John Hopper Hereditary Cancer in Clinical Practice 2011, null:7 2011-09-06T00:00:00Z doi:10.1186/1897-4287-9-7 How do women at increased risk of familial breast cancer perceive and manage their risk? /content/figures/1897-4287-9-7-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 7 2011-09-06T00:00:00Z XML Background: Neurofibroma occurs as isolated or multiple lesions frequently associated with neurofibromatosis type 1 (NF1), a common autosomal dominant disorder affecting 1 in 3500 individuals. It is caused by mutations in the NF1 gene, which comprises 60 exons and is located on chromosome 17q11.2. NF1 is a fully penetrant gene exhibiting a mutation rate some 10-fold higher compared with most other disease genes. As a consequence, a high number of cases (up to 50%) are sporadic. Mutation detection is complex due to the large size of the NF1 gene, the presence of pseudogenes and the great variety of lesions. Methods: 110 patients with at least two neurofibroma lesions recorded in the files of the Pathology Department of the University of Modena during the period 1999-2010, were included in this study. Through interviews and examination of clinical charts, pedigrees were drawn for all patients who were affected by at least two neurofibromas. We attempted to delineate the clinical features of NF1 and the mutational spectrum in the cohort of 11 NF1 families identified. For each proband, the whole coding sequence and all splice sites were studied for mutations, either by the protein truncation test (PTT), or, more frequently, by denaturing high performance liquid chromatography (DHPLC). Two GIST tumors of NF1 patients were tested for somatic NF1 mutations. Results: NF1 germline mutations were identified in 7 (68%) patients. A novel mutation, c.3457_3460delCTCA in exon 20, was detected in two unrelated patients and was associated with different clinical features. No NF1 somatic mutations were detected in the GIST tumors. A wide phenotypic and genotypic variability was registered, both in the spectrum of skin lesions and visceral neoplasms, even among members of the same family who had different clinical manifestations. A proclivity to multiple tumors arising in the same subject, and a higher tumor burden per family were the most relevant findings observed in patients affected with the NF1 mutation. Conclusions: We report a novel NF1 mutation and we contribute data for the refinement of the NF1 genotype-phenotype spectrum. http://www.hccpjournal.com/content/9/1/6 Giovanni Ponti Lorena Losi Davide Martorana Manuela Priola Elisa Boni Annamaria Pollio Tauro Neri Stefania Seidenari Hereditary Cancer in Clinical Practice 2011, null:6 2011-08-12T00:00:00Z doi:10.1186/1897-4287-9-6 /content/figures/1897-4287-9-6-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 6 2011-08-12T00:00:00Z XML Tumors arising in patients with hereditary cancer syndromes may have distinct drug sensitivity as compared to their sporadic counterparts. Breast and ovarian neoplasms from BRCA1 or BRCA2 mutation carriers are characterized by deficient homologous recombination (HR) of DNA, that makes them particularly sensitive to platinum compounds or inhibitors of poly (ADP-ribose) polymerase (PARP). Outstandingly durable complete responses to high dose chemotherapy have been observed in several cases of BRCA-related metastatic breast cancer (BC). Multiple lines of evidence indicate that women with BRCA1-related BC may derive less benefit from taxane-based treatment than other categories of BC patients. There is virtually no reports directly assessing drug response in hereditary colorectal cancer (CRC) patients; studies involving non-selected (i.e., both sporadic and hereditary) CRC with high-level microsatellite instability (MSI-H) suggest therapeutic advantage of irinotecan. Celecoxib has been approved for the treatment of familial adenomatous polyposis (FAP). Hereditary medullary thyroid cancers (MTC) have been shown to be highly responsive to a multitargeted tyrosine kinase inhibitor vandetanib, which exerts specific activity towards mutated RET receptor. Given the rapidly improving accessibility of DNA analysis, it is foreseen that the potential predictive value of cancer-associated germ-line mutations will be increasingly considered in the future studies. http://www.hccpjournal.com/content/9/1/5 Evgeny Imyanitov Vladimir Moiseyenko Hereditary Cancer in Clinical Practice 2011, null:5 2011-08-06T00:00:00Z doi:10.1186/1897-4287-9-5 Drug therapy for hereditary cancers /content/figures/1897-4287-9-5-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 5 2011-08-06T00:00:00Z XML Background: Risk perception is considered a motivating factor for adopting preventive behaviors. This study aimed to verify the demographic characteristics and cancer family history that are predictors of risk perception and to verify if risk perception is a predictor of colonoscopy adherence. Methods: Individuals with a family colorectal cancer history as indicated by a proband with cancer were interviewed by telephone. They responded to a questionnaire covering demographic characteristics, colonoscopy history and four questions on risk perception. Tests of multiple linear regression and logistic regression were used to identify associations between dependent and independent variables. Results: The 117 participants belonged to 62 families and had a mean age of 45.2 years. The majority of these individuals were female (74.4%) and from families who met the Amsterdam Criteria (54.7%). The average risk perception was 47.6%, with a median of 50%. The average population perception of individual risk was 55.4%, with a median of 50%. Variables associated with a higher risk perception were age, gender, religion, school level, income, and death of a family member. The variable predicting colonoscopy was receiving medical information regarding risk (odds ratio OR 8.40). Conclusions: We found that family cancer history characteristics (number of relatives with cancer, risk classification) are associated with adequate risk perception. Risk perception does not predict colonoscopy in this sample. The only variable that predicted colonoscopy was receiving medical information recommending screening. http://www.hccpjournal.com/content/9/1/4 Erika Santos Maria Teresa Lourenco Benedito Rossi Hereditary Cancer in Clinical Practice 2011, null:4 2011-07-28T00:00:00Z doi:10.1186/1897-4287-9-4 Risk Perception in Brazilians with High Risk for Colorectal Cancer and use of Colonoscopy This study focused on predictors of risk perception, and verified whether risk perception is a predictor of colonoscopy adherence. The authors found that risk perception did not predict use of colonoscopy in their study population. The only variable that predicted use of colonoscopy was receiving medical information recommending such surveillance. /content/figures/1897-4287-9-4-toc.gif Hereditary Cancer in Clinical Practice 1897-4287 ${item.volume} 4 2011-07-28T00:00:00Z XML