Constitutional MLH1 methylation presenting with colonic polyposis syndrome and not Lynch syndrome
We report the first case of constitutional MLH1 promoter methylation associated with a colonic polyposis syndrome in a 39 year-old man with a family history of colorectal cancer (CRC) and a personal history of 21 polyps identified over 8 years as well as the development of two synchronous CRCs over 16 months who was evaluated for a hereditary cancer syndrome. Immunohistochemistry (IHC) of multiple tumors showed absent MLH1 and PMS2 expression, though germline testing with Sanger sequencing and multiplex ligation-dependent probe amplification of these mismatch repair genes (MMR) genes was negative. A next gen...
Source: Familial Cancer - January 18, 2016 Category: Cancer & Oncology Source Type: research

Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis
Abstract In up to 30 % of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative genes, exome sequencing was performed using DNA from leukocytes and a total of 12 colorectal adenomas from seven unrelated patients with unexplained sporadic adenomatous polyposis. For data analysis and variant filtering, an established bioinformatics pipe...
Source: Familial Cancer - January 16, 2016 Category: Cancer & Oncology Source Type: research

CDH1 germline mutations and hereditary lobular breast cancer
Abstract Hereditary diffuse gastric cancer is an autosomal dominant inherited disease associated of CDH1 germline mutations (that encodes for the E-cadherin protein), and lobular breast cancer is the second most frequent type of neoplasia. Recently, novel E-cadherin constitutional alterations have been identified in pedigree clustering only for lobular breast carcinoma without evidence of diffuse gastric tumors and in absence of BRCA1/2 mutations. This first evidence opens novel questions about the inherited correlation between diffuse gastric and lobular breast cancers. In this brief review we revise the literatu...
Source: Familial Cancer - January 13, 2016 Category: Cancer & Oncology Source Type: research

Developing and assessing the utility of a You-Tube based clinical genetics video channel for families affected by inherited tumours
Abstract We have designed and implemented the first worldwide You Tube channel with 22 videos covering common questions asked in familial cancer susceptibility clinics. We discuss the use of the videos including demographics of registered You Tube users, and what lessons have been learnt about how the general public uses medical information online. The most popular video on inheritance patterns has been watched on average 84 times per month. The mostly highly viewed videos include inheritance patterns, breast cancer screening and hereditary non-polyposis colorectal cancer. Registered viewers were more commonly mal...
Source: Familial Cancer - January 11, 2016 Category: Cancer & Oncology Source Type: research

The impact of an interventional counselling procedure in families with a BRCA1/2 gene mutation: efficacy and safety
Conclusions: A protocol directly informing relatives nearly doubles the number of relatives tested and is psychologically safe. This should lead to a change in counselling guidelines in families with a strong germline predisposition for cancer. (Source: Familial Cancer)
Source: Familial Cancer - January 9, 2016 Category: Cancer & Oncology Source Type: research

Germline BAP1 mutations misreported as somatic based on tumor-only testing
We present three unrelated patients with germline mutations in BAP1 misreported as somatic mutations. All had strong family histories of cancer. One of these patients presented with an invasive breast cancer with the tumor tissue showing partial loss of the mutant rather than the wild type allele, suggesting that the germline BAP1 mutation didn’t contribute to breast cancer development in this patient. This data highlights the importance of sequencing matching germline and tumor DNA for proper assessment of somatic versus germline mutation status. In patients with somatic mutations reported from laboratories carrying...
Source: Familial Cancer - January 9, 2016 Category: Cancer & Oncology Source Type: research

Relationship of immunohistochemistry, copy number aberrations and epigenetic disorders with BRCAness pattern in hereditary and sporadic breast cancer
Abstract The study aims to identify the relevance of immunohistochemistry (IHC), copy number aberrations (CNA) and epigenetic disorders in BRCAness breast cancers (BCs). We studied 95 paraffin included BCs, of which 41 carried BRCA1/BRCA2 germline mutations and 54 were non hereditary (BRCAX/Sporadic). Samples were assessed for BRCA1ness and CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA); promoter methylation (PM) was assessed by methylation-specific-MLPA and the expression of miR-4417, miR-423-3p, miR-590-5p and miR-187-3p by quantitative RT-PCR. IHC markers Ki67, ER, PR, HER2, CK5/6, EGFR and CK1...
Source: Familial Cancer - January 2, 2016 Category: Cancer & Oncology Source Type: research

Initial clinical validation of Health Heritage, a patient-facing tool for personal and family history collection and cancer risk assessment
Abstract Personal and family health histories remain important independent risk factors for cancer; however they are currently not being well collected or used effectively. Health Heritage was designed to address this need. The purpose of this study was to validate the ability of Health Heritage to identify patients appropriate for further genetic evaluation and to accurately stratify cancer risk. A retrospective chart review was conducted on 100 random patients seen at an adult genetics clinic presenting with concern for an inherited predisposition to cancer. Relevant personal and family history obtained from the...
Source: Familial Cancer - December 28, 2015 Category: Cancer & Oncology Source Type: research

Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect
Abstract Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastr...
Source: Familial Cancer - December 23, 2015 Category: Cancer & Oncology Source Type: research

Risk of thyroid cancer among Caribbean Hispanic patients with familial adenomatous polyposis
This study reports the standardized incidence ratio (SIR) of TC in Hispanic FAP patients. TC incidence rates in patients with FAP between the periods of January 1, 2006 to December 31, 2013 were compared with the general population through direct database linkage from the Puerto Rico Central Cancer Registry (PRCCR) and the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). The study population consisted of 51 Hispanic patients with FAP and 3239 with TC from the general population. The SIR was calculated using the Indirect Method, defined as observed TC incidence among patients with FAP in PURIFICAR’s cohort...
Source: Familial Cancer - December 21, 2015 Category: Cancer & Oncology Source Type: research

Gatekeeper role of gastroenterologists and surgeons in recognising and discussing familial colorectal cancer
This study aimed to gain insight into the gatekeeper role of surgeons and gastroenterologists (including residents) during a first consultation at a tertiary gastro-intestinal centre regarding referral for genetic counselling, and to test the feasibility of a checklist for indications for referral. Consecutive patients were invited before and after introduction of a checklist, to complete a questionnaire assessing their perception of discussing cancer genetic topics. Initial consultations were audiotaped to assess the quality of this discussion by gastroenterologists and surgeons. Data on completeness of the checklist and ...
Source: Familial Cancer - December 19, 2015 Category: Cancer & Oncology Source Type: research

Mutation analysis of MUTYH in Japanese colorectal adenomatous polyposis patients
Abstract Germline MUTYH mutations were investigated in 14 Japanese colorectal polyposis patients without germ line adenomatous polyposis coli (APC) gene mutations. Three patients had a heterozygous IVS10-2A>G MUTYH mutation. The onset of MUTYH-associated polyposis (MAP) occurs later than that of familial adenomatous polyposis with germline APC mutation. Thus, we compared the carrier frequency of MUTYH IVS10-2A>G heterozygote in the APC mutation negative cases with that in 115 controls over 70 years of age who showed no apparent clinical manifestations of cancer and claimed that they had no history of ca...
Source: Familial Cancer - December 18, 2015 Category: Cancer & Oncology Source Type: research

Determining the familial risk distribution of colorectal cancer: a data mining approach
This study was aimed to characterize the distribution of colorectal cancer risk using family history of cancers by data mining. Family histories for 10,066 colorectal cancer cases recruited to population cancer registries of the Colon Cancer Family Registry were analyzed using a data mining framework. A novel index was developed to quantify familial cancer aggregation. Artificial neural network was used to identify distinct categories of familial risk. Standardized incidence ratios (SIRs) and corresponding 95 % confidence intervals (CIs) of colorectal cancer were calculated for each category. We identified five major,...
Source: Familial Cancer - December 17, 2015 Category: Cancer & Oncology Source Type: research

Associations between allergic conditions and pediatric brain tumors in Neurofibromatosis type 1
Abstract Individuals with Neurofibromatosis type 1 (NF1) are at increased risk for pediatric brain tumors (PBTs), especially optic gliomas; however, factors influencing their development are largely unknown. Extensive research suggests that allergic conditions protect against brain tumors, particularly gliomas in individuals without NF1. In this large cross-sectional study, we employed two different data sources to evaluate evidence for the hypothesis that allergic conditions (allergies, asthma, and eczema) may protect against PBT development in individuals with NF1. We used self- and parent/legal guardian reporte...
Source: Familial Cancer - December 14, 2015 Category: Cancer & Oncology Source Type: research

Mismatch repair deficiency concordance between primary colorectal cancer and corresponding metastasis
Abstract Universal screening for mismatch repair deficiency (dMMR) in cancer is increasingly being implemented to detect Lynch syndrome and aid in treatment decisions. The mismatch repair (MMR) immunohistochemistry (IHC) concordance rate between primary colorectal cancer (CRC) and metastasis is unknown. At times, only metastatic tumor is available for screening (lymph node, liver, lung etc.) rather than the primary tumor. Therefore, it is important to confirm that tissue from metastases can be used for screening for dMMR. We tested dMMR primary and metastatic tumor to assess concordance between the two. We identif...
Source: Familial Cancer - December 14, 2015 Category: Cancer & Oncology Source Type: research

Screening of the BRCA1 gene in Brazilian patients with breast and/or ovarian cancer via high-resolution melting reaction analysis
Abstract The aim of this study was to evaluate the profile of BRCA1 mutations among cancer-affected Brazilian women from the Midwest region of Minas Gerais state with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. In this Brazilian region, the first Center for Hereditary Cancer Control began operation in 2011, and 90 % of patients receive assistance from the public health service. Eighteen patients at high risk for HBOC were subjected to molecular analysis. Primers were designed for 22 coding exons of the gene; DNA was extracted; and real-time PCR followed by high-resol...
Source: Familial Cancer - December 14, 2015 Category: Cancer & Oncology Source Type: research

Methylation of the miR-126 gene associated with glioma progression
Abstract Gliomas are the most common and the most malignant brain tumors, accouting for 45–55 % of all intracranial tumors. The incidence of glioma worldwide is about 6–12 per 100,000. Recently, several studies showed that the activation of the oncogenes and the inactivation and/or loss of the tumor suppressor genes, especially for miRNA-21, let-7 and so on, are the most primary molecule event in gliomas. MicroRNAs (miRNAs) are a class of endogenously expressed small noncoding RNAs which are usually 21–23 nucleotides long. miRNAs regulate gene expression and play important roles in a var...
Source: Familial Cancer - October 13, 2015 Category: Cancer & Oncology Source Type: research

Diagnostic values of osteopontin combined with CA125 for ovarian cancer: a meta-analysis
Abstract Osteopontin (OPN) is currently one of the most studied serum biomarkers of ovarian cancer (OC). This meta-analysis aims to ascertain whether OPN is a useful diagnostic biomarker for OC and determine the overall diagnostic accuracy of OPN measurement when combined with cancer antigen 125 (CA125). A systematic literature search was conducted in Cochrane Library, PubMed, EMBASE, CBM, and China National Knowledge Infrastructure databases. Information was independently extracted by two investigators. The Quality Assessment for Studies of Diagnostic Accuracy tool was applied to examine the quality of eligible s...
Source: Familial Cancer - October 12, 2015 Category: Cancer & Oncology Source Type: research

Surveillance using capsule endoscopy is safe in post-colectomy patients with familial adenomatous polyposis: a prospective Japanese study
Abstract The utility of capsule endoscopy (CE) for the surveillance of small intestinal lesions in familial adenomatous polyposis (FAP) patients has been reported. However, few studies have investigated the safety of CE in FAP patients who have undergone colon surgery. We aimed to assess the safety of surveillance CE in post-colectomy FAP patients and the endoscopic findings associated with small intestinal lesions. We assessed the safety of CE surveillance of small intestinal lesions in 41 FAP patients who had undergone colectomies. Forty-two CEs were performed in 41 patients at our facility from April 2012 to Ju...
Source: Familial Cancer - October 8, 2015 Category: Cancer & Oncology Source Type: research

Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary
Abstract Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome with considerable genetic and phenotypic heterogeneity, defined by the development of multiple adenomas throughout the colorectum. FAP is caused either by monoallelic mutations in the adenomatous polyposis coli gene APC, or by biallelic germline mutations of MUTYH, this latter usually presenting with milder phenotype. The aim of the present study was to characterize the genotype and phenotype of Hungarian FAP patients. Mutation screening of 87 unrelated probands from FAP families (21 of them presented as the attenuated var...
Source: Familial Cancer - October 7, 2015 Category: Cancer & Oncology Source Type: research

Genetic testing for Lynch syndrome: family communication and motivation
In conclusion, the majority of respondents consider the current family-mediated information procedure acceptable, although the provision of information on LS by relatives may be burdensome. Special attention should be paid to communication of LS to more distant relatives. (Source: Familial Cancer)
Source: Familial Cancer - October 7, 2015 Category: Cancer & Oncology Source Type: research

Germline TERT promoter mutations are rare in familial melanoma
Abstract Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.−57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated...
Source: Familial Cancer - October 3, 2015 Category: Cancer & Oncology Source Type: research

Association between the FTOrs8050136 polymorphism and cancer risk: a meta-analysis
Abstract A meta-analysis on cancer risk relevant to FTOrs8050136 polymorphism. To investigate the comprehensive effect of FTOrs8050136 polymorphism on cancer risk based on a pooled result. Carcinogenesis is closely related to obesity. Both obesity and cancer share common pathogenic factors such as hereditary susceptibility and environmental predisposition. Recently, several studies had reported that the FTOrs8050136 polymorphism, a genetic variation highly associated with obesity, can be a potential cancer risk factor, while these results were inconsistent. With the help of PubMed, EMBASE, Chinese National Knowled...
Source: Familial Cancer - October 1, 2015 Category: Cancer & Oncology Source Type: research

Aortopulmonary window parathyroid gland causing primary hyperparathyroidism in men type 1 syndrome
Abstract Primary hyperparathyroidism (HPT) is the most common endocrinopathy in Multiple Endocrine Neoplasia type 1 (MEN1) syndrome. Supernumerary and/or ectopic parathyroid glands, potentially causes of persistent or recurrent HPT after surgery, have been previously described. However, this is the first ever described case of ectopic parathyroid gland localized in the aortopulmunary window causing HPT in MEN1. After a consistent concordant pre-operative imaging assessment the patient, a 16 years old male affected by a severe hypercalcemia, underwent surgery. The parathyroid was found very deeply near the tra...
Source: Familial Cancer - September 22, 2015 Category: Cancer & Oncology Source Type: research

First report of somatic mosaicism for mutations in STK11 in four patients with Peutz–Jeghers syndrome
This report details the first four reported cases of somatic mosaicism for STK11 associated with PJS. This shows that techniques in addition to direct sequencing such as MLPA must be used to assess for large scale genomic deletions in patients meeting clinical diagnostic criteria for PJS. This also adds further weight to the hypothesis of a single genetic locus for PJS. (Source: Familial Cancer)
Source: Familial Cancer - September 19, 2015 Category: Cancer & Oncology Source Type: research

Is there an association between invasive lobular carcinoma of the breast and a family history of gastric cancer?
Abstract CDH1 gene mutations have been found to be associated with diffuse type gastric cancer and invasive lobular carcinoma (ILC) of the breast. To the best of our knowledge, this is the only study relating a family history of gastric cancer to ILC of the breast. We conducted a retrospective study comparing the family history of malignancies in patients with invasive ductal carcinoma (IDC) of the breast and ILC treated in our Medical Center. The comparison was evaluated in both types of breast cancer groups, dividing the patients into two age groups,
Source: Familial Cancer - September 10, 2015 Category: Cancer & Oncology Source Type: research

Screening of HELQ in breast and ovarian cancer families
Abstract Several high and moderate risk alleles have been identified for breast and ovarian cancer predisposition and most of them encode proteins that function in DNA repair. A prospective candidate for breast and ovarian cancer susceptibility is the HELQ helicase that has a role in the resolution of DNA interstrand cross-links. HELQ interacts with the RAD51 paralog complex BCDX2. Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk. To investigate the role of HELQ in cancer predisposition...
Source: Familial Cancer - September 8, 2015 Category: Cancer & Oncology Source Type: research

Birt–Hogg–Dubé syndrome: novel FLCN frameshift deletion in daughter and father with renal cell carcinomas
Abstract Germline mutation of the FLCN gene causes Birt–Hogg–Dubé syndrome (BHD), a rare autosomal dominant condition characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal tumours. We identified a hitherto unreported pathogenic FLCN frameshift deletion c.563delT (p.Phe188Serfs*35) in a family of a 46-year-old woman presented with macrohematuria due to bilateral chromophobe renal carcinomas. A heritable renal cancer was suspected due to the bilaterality of the tumour and as the father of this woman had suffered from renal cancer. Initially, however, BHD was overl...
Source: Familial Cancer - September 5, 2015 Category: Cancer & Oncology Source Type: research

Rhabdoid tumor predisposition syndrome caused by SMARCB1 constitutional deletion: prenatal detection of new case of recurrence in siblings due to gonadal mosaicism
Abstract Rhabdoid tumors are aggressive malignancies that show loss-of-function mutations of SMARCB1 gene, a member of the SWI/SNF chromatin-remodeling complex controlling gene transcription. One-third of patients affected by rhabdoid tumor harbor a germ-line mutation of SMARCB1 defining a rhabdoid tumor predisposition syndrome. The occurrence of a second somatic mutation determines the development of neoplasia in a two-hit model. Most germ-line mutations occur de novo, and few cases of recurrence in a sibship have been described. Here we report on a new Italian family with recurrence of SMARCB1 germ-line deletion...
Source: Familial Cancer - September 5, 2015 Category: Cancer & Oncology Source Type: research

The knowledge value-chain of genetic counseling for breast cancer: an empirical assessment of prediction and communication processes
Abstract The aim of this paper is twofold: to analyze the genetic counseling process for breast cancer with a theoretical knowledge transfer lens and to compare generalists, medical specialists, and genetic counselors with regards to their genetic counseling practices. This paper presents the genetic counseling process occurring within a chain of value-adding activities of four main stages describing health professionals’ clinical practices: (1) evaluation, (2) investigation, (3) information, and (4) decision. It also presents the results of a cross-sectional study based on a Canadian medical doctors and gen...
Source: Familial Cancer - September 3, 2015 Category: Cancer & Oncology Source Type: research

Association of APC I1307K and E1317Q polymorphisms with colorectal cancer among Egyptian subjects
This study included 120 unrelated CRC Egyptian patients who were compared to 100 healthy controls from the same locality. For all subjects, DNA was genotyped for APC I1307K and E1317Q polymorphisms using the PCR-ARMS technique. The frequency of APC I1307K carrier (TA+AA genotypes) was noted to be significantly higher among cases with CRC compared to controls (18.3 vs. 9.0 %, OR 2.58, 95 % CI 1.09–6.09, p = 0.03). Also the frequency of the APC I1307K A allele was significantly higher among cases compared to controls (10.4 vs. 4.5 %, OR 2.47; 95 % CI 1.12–5.42, p = 0.03). O...
Source: Familial Cancer - August 28, 2015 Category: Cancer & Oncology Source Type: research

The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer
Abstract Prostate cancer (PrCa) is one of the most common cancers diagnosed worldwide and 5–10 % of all cases are estimated to be associated with inherited predisposition. Even though there is strong evidence that the genetic component is significant in PrCa, the genetic etiology of familial and early-onset disease is largely unknown. Although it has been suggested that men from families with hereditary breast/ovarian cancer (HBOC) and, more recently, with Lynch syndrome may have an increased risk for PrCa, the contribution of these syndromes to PrCa predisposition in families ascertained for early-...
Source: Familial Cancer - August 20, 2015 Category: Cancer & Oncology Source Type: research

Ovarian tumors related to intronic mutations in DICER1 : a report from the international ovarian and testicular stromal tumor registry
In this report, a young woman presented with ovarian undifferentiated sarcoma. Four years later, she presented with SLCT. She was successfully treated for both malignancies. Sequence results showed a germline intronic mutation in DICER1. This mutation results in an exact duplication of the six bases at the splice site at the intron 23 and exon 24 junction. Predicted improper splicing leads to inclusion of 10 bases of intronic sequence, frameshift and premature truncation of the protein disrupting the RNase IIIb domain. A second individual with SLCT was found to have an identical germline mutation. In each of the ovarian tu...
Source: Familial Cancer - August 20, 2015 Category: Cancer & Oncology Source Type: research

Long-term outcome of sporadic and FAP-associated desmoid tumors treated with high-dose selective estrogen receptor modulators and sulindac: a single-center long-term observational study in 134 patients
This study included all desmoid patients that were treated and followed at our institution and had completed at least 1 year of treatment. Response was defined as stable size or regression of desmoid size between two CT or MRI scans. A total of 134 patients were included. 64 (47.8 %) patients had a confirmed diagnosis of FAP, 69 (51.5 %) patients were sporadic. Overall 114 (85.1 %) patients showed regressive or stable desmoid size. Patients with previous history of multiple desmoid-related surgeries showed less-favorable response. The mean time to reach at least stable size was 14.9 (±9.1) months...
Source: Familial Cancer - August 14, 2015 Category: Cancer & Oncology Source Type: research

Incidental diagnosis of HLRCC following investigation for Asperger Syndrome: actionable and actioned
Abstract Incidental findings are inevitable as clinical research and practice transitions from a single gene approach to a genomic approach. A novel deletion of the Fumarate Hydratase (FH) gene was identified in a 22 year old male who underwent a molecular karyotype as part of an autism spectrum disorder research project. This unexpected result implies a predisposition to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a rare, autosomal dominant condition and has unforeseen implications for him and his family. We review the typical features and management of HLRCC and discuss the challenges that face...
Source: Familial Cancer - August 14, 2015 Category: Cancer & Oncology Source Type: research

The effect of personal medical history and family history of cancer on the uptake of risk-reducing salpingo-oophorectomy
Abstract Women with an increased lifetime risk of ovarian cancer are advised to undergo risk-reducing salpingo-oophorectomy (RRSO) to reduce risk of adnexal cancer. We investigated the uptake of RRSO and evaluated the influence of personal medical history of (breast) cancer, risk-reducing mastectomy (RRM) and family history of ovarian and/or breast cancer on the RRSO decision. This single center retrospective observational cohort study was performed in a tertiary multidisciplinary clinic for hereditary cancer of the University Medical Centre Utrecht, the Netherlands. Women ≥35 years old with an estimated l...
Source: Familial Cancer - August 12, 2015 Category: Cancer & Oncology Source Type: research

Screening of RET gene mutations in Chinese patients with medullary thyroid carcinoma and their relatives
This study investigated the spectrum of germline RET mutations and clinical features in Chinese hereditary MTC patients. A total of 53 family members from 11 different hereditary MTC families were recruited for detection of RET exon 8, 10, 11, 13, 14, 15, and 16 mutations, in genomic DNA from peripheral blood leucocytes using polymerase chain reaction (PCR) and direct DNA sequencing. Of the 53 participants, eight different germline RET mutations were detected in 37 individuals. These RET mutations were distributed in exons 10, 11, 13, and 16. The most frequent RET mutation was localized at exon 11 codon 634 (67.6 %; 2...
Source: Familial Cancer - August 9, 2015 Category: Cancer & Oncology Source Type: research

POLE mutations in families predisposed to cutaneous melanoma
Abstract Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in ...
Source: Familial Cancer - August 7, 2015 Category: Cancer & Oncology Source Type: research

Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30-year semi-prospective analysis
Abstract BRCA1 and BRCA2 mutation carriers have an increased risk of contralateral breast cancer after primary breast cancer. Risk reduction strategies are discussed after assessment of risk factors for developing contralateral breast cancer. We assessed potential risk factors that could be of use in clinical practice, including the novel use of single nucleotide polymorphisms (SNP) testing. 506 BRCA1 and 505 BRCA2 mutation carriers with a diagnosis of breast cancer were observed for up to 30 years. The risk of a contralateral breast cancer is approximately 2–3 % per year, remaining ...
Source: Familial Cancer - August 4, 2015 Category: Cancer & Oncology Source Type: research

Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene
Abstract The base excision repair protein, MUTYH, functionally interacts with the DNA mismatch repair (MMR) system. As genetic testing moves from testing one gene at a time, to gene panel and whole exome next generation sequencing approaches, understandin g the risk associated with co-existence of germline mutations in these genes will be important for clinical interpretation and management. From the Colon Cancer Family Registry, we identified 10 carriers who had both a MUTYH mutation (6 with c.1187G>A p.(Gly396Asp), 3 with c.821G>A p.(Arg274Gln), and 1 with c.536A>G p.(Tyr179Cys)) and a MMR gene mut...
Source: Familial Cancer - July 23, 2015 Category: Cancer & Oncology Source Type: research

Risk reducing salpingectomy and delayed oophorectomy in high risk women: views of cancer geneticists, genetic counsellors and gynaecological oncologists in the UK
We report on the acceptability/attitude of UK health professionals towards RRSDO. An anonymised web-based survey was sent to UK Cancer Genetics Group (CGG) and British Gynaecological Cancer Society (BGCS) members to assess attitudes towards RRSDO. Baseline characteristics were described using descriptive statistics. A Chi square test was used to compare categorical, Kendal-tau-b test for ordinal and Mann–Whitney test for continuous variables between two groups. 173/708 (24.4 %) of invitees responded. 71 % respondents (CGG = 57 %/BGCS = 83 %, p = 0.005) agreed with the...
Source: Familial Cancer - July 16, 2015 Category: Cancer & Oncology Source Type: research

Metastatic sympathetic paraganglioma in a patient with loss of the SDHC gene
Abstract Mutation of the genes encoding the succinate dehydrogenase (SDH) subunits A, B, C, or D, or the SDHAF2 protein, cause the SDHx-hereditary paraganglioma syndromes. Hereditary susceptibility to metastatic sympathetic pheochromocytomas and paragangliomas is most commonly due to germline mutations in the SDHB gene. Individuals with SDHD mutations occasionally present with metastatic disease, while conversely malignant paragangliomas are rarely observed in SDHC carriers. A 43 year-old woman presented with an abdominal paraganglioma metastatic to the skeleton and multiple lymph nodes. The tumor produced ex...
Source: Familial Cancer - July 11, 2015 Category: Cancer & Oncology Source Type: research

Massive gastric polyposis associated with a germline SMAD4 gene mutation
Abstract Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by the development of multiple hamartomatous polyps in the gastrointestinal tract. Polyps are most common in the colorectum (98 % of patients) and the stomach (14 %). Causative mutations for JPS have been identified in two genes to date, SMAD4 and BMPR1A. SMAD4 mutations are associated with a higher incidence of gastric polyposis. In this case report, we describe two patients with massive gastric polyposis associated with a SMAD4 mutation. Both presented with anaemia and both had colonic polyps. Initial endosco...
Source: Familial Cancer - July 10, 2015 Category: Cancer & Oncology Source Type: research

Challenges to clinical utilization of hereditary cancer gene panel testing: perspectives from the front lines
Abstract Next generation sequencing (NGS) technology is rapidly being implemented into clinical practice. Qualitative research was performed to gain an improved understanding of the landscape surrounding the use of NGS in cancer genetics. A focus group was conducted at the Wisconsin Cancer Risk Programs Network biannual meeting. Free flowing discussion with occasional open-ended questions provided insights into the use of NGS. 19 genetic counselors and medical professionals participated. Three major themes were identified with respect to NGS and its use in cancer genetics: knowledge gaps, the evolving clinician ro...
Source: Familial Cancer - June 25, 2015 Category: Cancer & Oncology Source Type: research

High accuracy of family history of melanoma in Danish melanoma cases
We examined the family history of 181 melanoma probands who reported 199 cases of melanoma in relatives, of which 135 cases where in first degree relatives. We confirmed the diagnosis of melanoma in 77 % of all relatives, and in 83 % of first degree relatives. In 181 probands we validated the negative family history of melanoma in 748 first degree relatives and found only 1 case of melanoma which was not reported in a 3 case melanoma family. Melanoma patients in Denmark report family history of melanoma in first and second degree relatives with a high level of accuracy with a true positive predictive value betwee...
Source: Familial Cancer - June 21, 2015 Category: Cancer & Oncology Source Type: research

BRCA1 gene variant p.P142H associated with male breast cancer: a two-generation genealogic study and literature review
Abstract Breast cancer occurs rarely in male patient. BRCA1 gene mutation seems to be related to male breast cancer, but its role is not clearly defined. We have identified in a male patient affected by breast cancer the BRCA1 gene variant p.P142H. We performed a literature research using the keywords “male breast cancer”, “male breast cancer mutations” and “BRCA” and we reviewed the cases. We found ew other studies regarding BRCA1 variant p.P142H, about female subjects. At the moment, BRCA1 gene variant p.P142H is not certainly classified as neutral or deleterious. Genetic test...
Source: Familial Cancer - June 18, 2015 Category: Cancer & Oncology Source Type: research

Supporting families with Cancer: A patient centred survivorship model of care
Abstract In 2011, the Leicestershire Clinical Genetics Department in collaboration with Macmillan Cancer Support initiated a project called Supporting Families with Cancer (SFWC). The project aimed to raise awareness of inherited cancers amongst both healthcare professionals and the general public and develop a patient-centred collaborative approach to cancer treatment and support services. This paper describes the project’s development of a range of community outreach events and a training scheme for primary healthcare professionals designed to improve familial cancer referral rates in Leicester. Follow...
Source: Familial Cancer - June 16, 2015 Category: Cancer & Oncology Source Type: research

Coexistence of paraganglioma/pheochromocytoma and papillary thyroid carcinoma: a four-case series analysis
Abstract The paraganglioma (PGL)/pheochromocytoma (PHEO)—papillary thyroid carcinoma (PTC) dyad has been reported rarely. Whether the association is coincidental or results from an underlying genetic predisposition is difficult to ascertain. We analyzed clinical and molecular data on four unrelated patients identified and treated by one of us (MJB) at a tertiary center. Patients were screened for germline variants in a panel of candidate genes: RET, VHL, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, PTEN, CDKN1B. All patients were female; median age at diagnosis of PGL/PHEO was 45 years and at diagnosis of PT...
Source: Familial Cancer - June 14, 2015 Category: Cancer & Oncology Source Type: research

Follicular variant of papillary thyroid cancer in Alström syndrome
We report a 35-year-old woman with known history of AS, who developed a follicular variant of papillary thyroid carcinoma. To our knowledge this is the first association of AS with thyroid malignancy, among the approximately 450 cases reported since the first description of the syndrome. We conclude that papillary thyroid carcinoma should be considered in the differential diagnosis of thyroid nodules in patients with AS. (Source: Familial Cancer)
Source: Familial Cancer - June 6, 2015 Category: Cancer & Oncology Source Type: research

BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study
Abstract Male breast cancer (MBC) is a rare disease that represents
Source: Familial Cancer - May 31, 2015 Category: Cancer & Oncology Source Type: research