Should unaffected female BRCA2 pathogenic variant carriers be told there is little or no advantage from risk reducing mastectomy?
(Source: Familial Cancer)
Source: Familial Cancer - August 23, 2019 Category: Cancer & Oncology Source Type: research

Population frequencies of pathogenic alleles of BRCA1 and BRCA2 : analysis of 173 Danish breast cancer pedigrees using the BOADICEA model
AbstractThe Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) calculates the probability that a woman carries a pathogenic variant inBRCA1 orBRCA2 based on her pedigree and the population frequencies of pathogenic alleles ofBRCA1 (0.0006394) andBRCA2 (0.00102) in the United Kingdom (UK). BOADICEA allows the clinician to define the population frequencies of pathogenic alleles ofBRCA1 andBRCA2 for other populations but only includes preset values for the Ashkenazy Jewish and Icelandic populations. Among 173 early-onset breast cancer pedigrees in Denmark, BOADICEA discriminated well ...
Source: Familial Cancer - August 21, 2019 Category: Cancer & Oncology Source Type: research

TP53 variants of uncertain significance: increasing challenges in variant interpretation and genetic counseling
This report cases highlights the challenges and impact ofTP53 variant interpretation especially when there is no clear LFS/LFL phenotype. (Source: Familial Cancer)
Source: Familial Cancer - July 18, 2019 Category: Cancer & Oncology Source Type: research

Lynch syndrome with exclusive skin involvement: time to consider a molecular definition?
AbstractMuir –Torre syndrome (MTS) is clinically characterized by the occurrence of skin, usually sebaceous, and visceral tumors in the same individual. The most common underlying mechanism is a constitutional defect of the mismatch repair (MMR) genes that cause Lynch syndrome (LS). Herewithin we report on a 7 6 years-old male patient heterozygous for a pathogenicMSH2 missense substitution who presented with a striking cutaneous phenotype in the absence of typical LS visceral tumors. The patient developed 20 skin tumors, including sebaceous adenomas/carcinomas and keratoacanthomas. Two skin tumors showed immunoh...
Source: Familial Cancer - July 10, 2019 Category: Cancer & Oncology Source Type: research

Hereditary diffuse gastric cancer: cancer risk and the personal cost of preventive surgery
The objective of this research was to examine post-surgical clinical outcomes and to identify which of the domains/symptoms from the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30) were determinants of overall quality of life (QOL) in individuals undergoing PTG. Participants were recruited through multiple sources. Postsurgical clinical outcomes were obtained from hospital records. Participants completed validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point in time. The mean QOL in this cohort was 70.6 (SD  =...
Source: Familial Cancer - July 4, 2019 Category: Cancer & Oncology Source Type: research

Multiple primary malignancies associated with a germline SMARCB1 pathogenic variant
AbstractA 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes of anorexia and vomiting. Examination revealed right torticollis and Horner ’s syndrome, and a large abdominal mass arising from the pelvis. Magnetic resonance and positron emission tomography imaging revealed (A) a 14 cm heterogeneous enhancing mass, abutting the left kidney with standardised uptake value max = 2.9, (B) a large heterogeneous enhancing pelvic mass (C ) mesenteric adenopathy standardised uptake value max = 10.3 and (D) 6 cm right lung apex...
Source: Familial Cancer - June 25, 2019 Category: Cancer & Oncology Source Type: research

Energy balance related lifestyle factors and risk of endometrial and colorectal cancer among individuals with lynch syndrome: a systematic review
AbstractLifestyle factors related to energy balance, such as excess body weight, poor diet, and physical inactivity, are associated with risk of sporadic endometrial cancer (EC) and colorectal cancer (CRC). There are limited data on energy balance-related lifestyle factors and EC or CRC risk among individuals with lynch syndrome, who are at extraordinarily higher risk of developing EC or CRC. We conducted a systematic review of evidence related to weight status, weight change, dietary habits, and physical activity on EC and CRC risk among individuals with lynch syndrome. Findings are reported narratively. We searched Medli...
Source: Familial Cancer - June 24, 2019 Category: Cancer & Oncology Source Type: research

Ability of known susceptibility SNPs to predict colorectal cancer risk for persons with and without a family history
AbstractBefore SNP-based risk can be incorporated in colorectal cancer (CRC) screening, the ability of these SNPs to estimate CRC risk for persons with and without a family history of CRC, and the screening implications need to be determined. We estimated the association with CRC of a 45 SNP-based risk using 1181 cases and 999 controls, and its correlation with CRC risk predicted from detailed family history. We estimated the predicted change in the distribution across predefined risk categories, and implications for recommended screening commencement age, from adding SNP-based risk to family history. The inter-quintile ri...
Source: Familial Cancer - June 17, 2019 Category: Cancer & Oncology Source Type: research

Assessing a single SNP located at TERT/CLPTM1L multi-cancer risk region as a genetic modifier for risk of pancreatic cancer and melanoma in Dutch CDKN2A mutation carriers
AbstractCarriers of pathogenic variants inCDKN2A have a 70% life-time risk of developing melanoma and 15 –20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 ofCDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC inp16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients ’ surveillance. In a recent genome-wide association study (GWAS),...
Source: Familial Cancer - June 15, 2019 Category: Cancer & Oncology Source Type: research

Targeted next generation sequencing screening of Lynch syndrome in Tunisian population
In this study we aimed to identify the underlying genetic cause in 32 patients with early onset CRC and/or a positive family history. Of twenty-four patients ’ tumor or biopsies could be analyzed with immunohistochemical staining to detect loss of expression of one of the MMR proteins. Ten tumors showed loss of expression, of which one tumor was from a patient where a germline pathogenicMSH2 variant was detected previously with Sanger sequencing. Next generation sequencing of the MMR,POLE andPOLD1 genes was performed in leukocyte and tumor DNA of the remaining nine patients, as well as in two patients with MMR-profic...
Source: Familial Cancer - May 21, 2019 Category: Cancer & Oncology Source Type: research

Endoscopic full thickness resection for early colon cancer in Lynch syndrome
We report a case of a 62 year old man, diagnosed with MSH2-Lynch syndrome, who underwent successful eFTR treatment of an early (pT1) colon cancer located in the ascending colon, with no signs of recurrence 12 months after treatment. We discuss the pros and cons of endoscopic re section of early colorectal carcinoma in Lynch syndrome patients. (Source: Familial Cancer)
Source: Familial Cancer - May 20, 2019 Category: Cancer & Oncology Source Type: research

The incidence of consecutive manifestations in Von Hippel-Lindau disease
In this study we aimed to gain insight into the development of subsequent manifestations in VHL disease. We retrospectively scored each new VHL-related manifestation as detected by standard follow-up (retina, central nervous system, kidneys and pancreas, excluding adrenal and endolymfatic sac manifestations) in 75VHL mutation carriers. The Kaplan –Meier method was used to plot the cumulative proportions of all consecutive manifestations in each organ against age. The cumulative average number of manifestations in all organs during life was calculated by summating these cumulative proportions. Poisson model parameters...
Source: Familial Cancer - May 13, 2019 Category: Cancer & Oncology Source Type: research

Genetic counseling referral for ovarian cancer patients: a call to action
The objective of the study was to determine if disparities exist in genetic referrals and characterize referral patterns over time. A retrospective cohort study included all women diagnosed with invasive epithelial ovarian cancer at the University of Virginia from 2004 to 2015. Clinicopathologic data were abstracted from the electronic medical record and analyzed for association with genetic referral and testing. We identified 696 cases, with a median age of 62  years and a median follow up of 25.2 months (range 1–115). Thirty-four percent were referred for genetic counseling with an 80% genetic testing rat...
Source: Familial Cancer - April 16, 2019 Category: Cancer & Oncology Source Type: research

Implication of DNA repair genes in Lynch-like syndrome
AbstractMany colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained byMLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor ’s mutational profiles using FFPE DNA. Six hundred and fifty-four consecutive CRC patients were screened for suspected LS using MS...
Source: Familial Cancer - April 15, 2019 Category: Cancer & Oncology Source Type: research

Hereditary gastric cancer: what ’s new? Update 2013–2018
AbstractAround 10 –20% of gastric cancer patients have relatives with a diagnosis of GC and in 1–3% of patients a genetic cause can be confirmed. Histopathologically, GC is classified into intestinal-type, with glandular growth, and diffuse-type with poorly cohesive growth pattern often with signet ring cells. Fa milial or hereditary GC is classified into hereditary diffuse GC (HDGC), familial intestinal GC (FIGC) and polyposis forms. This review focuses on recent research findings and new concepts of hereditary GC. (Source: Familial Cancer)
Source: Familial Cancer - April 15, 2019 Category: Cancer & Oncology Source Type: research

Development and pilot testing of a leaflet informing women with breast cancer about genomic testing for polygenic risk
This study aimed to develop, and pilot test a leaflet with a sample of women participating in a large prospective cohort study. The leaflet aimed to provide information about polygenic risk to assist women to decide whether or not to learn results from genomic testing for common risk variants associated with breast cancer risk. A prototype of the leaflet was developed based on published literature and with the expertise from a multidisciplinary team. The acceptability of the leaflet was assessed by self-report questionnaire among 29 women participating in the prospective cohort study. More than 80% participants stated that...
Source: Familial Cancer - April 1, 2019 Category: Cancer & Oncology Source Type: research

Referral frequency, attrition rate, and outcomes of germline testing in patients with pancreatic adenocarcinoma
AbstractHereditary predisposition is estimated to account for 10% of all pancreatic cancer cases. However, referral patterns and clinical workflow for germline testing in this disease differ significantly by institution, and many at-risk patients may not undergo appropriate counseling and testing. We undertook an analysis of patients diagnosed with pancreatic cancer (PDAC) who were referred to the Clinical Genetics program of a high-volume academic center over a 3-year period to assess referral frequency, evaluate the yield of germline testing in this selected patient cohort, and elucidate the reasons individuals did not u...
Source: Familial Cancer - April 1, 2019 Category: Cancer & Oncology Source Type: research

Electronically ascertained extended pedigrees in breast cancer genetic counseling
AbstractA comprehensive pedigree, usually provided by the counselee and verified by medical records, is essential for risk assessment in cancer genetic counseling. Collecting the relevant information is time-consuming and sometimes impossible. We studied the use of electronically ascertained pedigrees (EGP). The study group comprised women (n  = 1352) receiving HBOC genetic counseling between December 2006 and December 2016 at Landspitali in Iceland. EGP’s were ascertained using information from the population-based Genealogy Database and Icelandic Cancer Registry. The likelihood of being positive ...
Source: Familial Cancer - April 1, 2019 Category: Cancer & Oncology Source Type: research

Pediatric craniopharyngioma in association with familial adenomatous polyposis
We report the first case of craniopharyngioma associated with FAP in a pediatric patient. A seven-year-old girl who presented with headache and vomiting was found on magnetic resonance imaging to have a suprasellar mass with cystic extension to the pre-pontine space. The tumor represented an adamantinomatous craniopharyngioma (aCP) with nuclear β-catenin expression. Whole exome sequencing confirmed aCTNNB1 activating point mutation and a germlineAPC frameshift variant. This case represents the first FAP-associated craniopharyngioma in childhood …. expanding our understanding of the molecular underpinnings drivi...
Source: Familial Cancer - March 27, 2019 Category: Cancer & Oncology Source Type: research

NTHL1 -associate polyposis: first Australian case report
AbstractWhile familial adenomatous polyposis accounts for approximately 1% of all colorectal cancer, the genetic cause underlying the development of multiple colonic adenomas remains unsolved in many patients. Adenomatous polyposis syndromes can be divided into: familial adenomatous polyposis,MUTYH-associated polyposis, polymerase proofreading associated polyposis and the recently describedNTHL1-associated polyposis (NAP). NAP is characterised by recessive inheritance, attenuated adenomatous polyposis, colonic cancer(s) and possible extracolonic malignancies. To date, 11 cases have been reported as having germline homozygo...
Source: Familial Cancer - March 11, 2019 Category: Cancer & Oncology Source Type: research

International society for gastrointestinal hereditary tumours —InSiGHT
(Source: Familial Cancer)
Source: Familial Cancer - March 4, 2019 Category: Cancer & Oncology Source Type: research

Progress report: familial pancreatic cancer
AbstractA hereditary predisposition to pancreatic ductal adenocarcinoma (PDAC) is reported in approximately 5% of patients. Familial pancreatic cancer (FPC) accounts for the vast majority of hereditary PDAC cases. FPC defines families with two or more affected first-degree relatives with PDAC that do not fulfil the criteria of any other inherited tumor syndrome or families with PDAC in three or more relatives of any degree. The current progress report focuses on the knowledge of FPC with regard to molecular pathogenesis, clinical and molecular diagnosis, surveillance and novel treatment options reported in the last 5  ...
Source: Familial Cancer - February 22, 2019 Category: Cancer & Oncology Source Type: research

Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting
AbstractA subset of colorectal cancer (CRC) cases are attributable to Lynch syndrome (LS), a hereditary form of CRC. Effective evaluation for LS can be done on CRC tumors to guide diagnostic testing. Increased diagnosis of LS allows for surveillance and risk reduction, which can mitigate CRC-related burden and prevent cancer-related deaths. We evaluated participation in LS screening among newly diagnosed adult CRC patients. Some cases were referred for genetics evaluation prior to study recruitment (selective screening). Those not referred directly were randomized to the intervention or control (usual care) arms. Control c...
Source: Familial Cancer - February 7, 2019 Category: Cancer & Oncology Source Type: research

Moving into the mainstream: healthcare professionals ’ views of implementing treatment focussed genetic testing in breast cancer care
This study sought to determine genetics and non-genetics specialists’ views of a proposal to mainstreamBRCA1 and2 testing in newly diagnosed breast cancer patients. Qualitative interview study. Nineteen healthcare professionals currently responsible for offering TFGT in a standard (triage  + referral) pathway (breast surgeons + clinical genetics team) and oncologists preparing to offer TFGT to breast cancer patients in a mainstreamed pathway participated in in-depth interviews. Genetics and non-genetics professionals’ perceptions of mainstreaming are influenced by their vie ws of: th...
Source: Familial Cancer - January 28, 2019 Category: Cancer & Oncology Source Type: research

Mutated SON putatively causes a cancer syndrome comprising high-risk medulloblastoma combined with caf é-au-lait spots
We report the case of a boy, who was born to consanguineous parents. Prominently, he had multiple café-au-lait spots. At the age of 3 years he was diagnosed with a high-risk metastatic medulloblastoma. The patient died only 11 months after diagnosis of a fulminant relapse presenting as meningeal and spinal dissemination. Whole-exome sequencing of germline DNA was employed to detect the underlying mutation for this putative cancer syndrome presenting with the combination of medulloblastoma and skin alterations. After screening all possible homozygous gene SNVs, we identified a mutation ofSON, an essential p...
Source: Familial Cancer - January 24, 2019 Category: Cancer & Oncology Source Type: research

Phenotypic confirmation of oligodontia, colorectal polyposis and cancer in a family carrying an exon 7 nonsense variant in the AXIN2 gene
AbstractTheAXIN2 gene, likeAPC, plays a role in the Wnt signalling pathway involved in colorectal tumour formation. Heterozygous mutations inAXIN2 have been shown to cause ectodermal dysplasia (including tooth agenesis, or more specifically, oligodontia), and, in some carriers, colorectal cancer and/or adenomatous polyposis develops. There is a paucity of publishedAXIN2 families making genotype-phenotype (polyposis, colorectal cancer and oligodontia) correlations challenging. In this case report we describe a family with c.1972delA, p.Ser658Alafs*31 nonsense variant inAXIN2 where the three confirmed carriers presented with...
Source: Familial Cancer - January 22, 2019 Category: Cancer & Oncology Source Type: research

Progress report on the major clinical advances in patient-oriented research into familial melanoma (2013 –2018)
(Source: Familial Cancer)
Source: Familial Cancer - January 18, 2019 Category: Cancer & Oncology Source Type: research

Exploring the preferences of involved health professionals regarding the implementation of an online decision aid to support couples during reproductive decision-making in hereditary cancer: a mixed methods approach
AbstractTo support persons having a genetic predisposition to cancer and their partners during reproductive decision-making, an online decision aid was developed and evaluated. To maximize the impact of the support tool, this mixed methods study aims at developing the optimal implementation strategy for the decision aid. A questionnaire to assess the critical determinants that may affect this implementation was completed by health professionals involved in oncogenetic counselling (N  = 46). Subsequently, semi-structured focus groups (N = 19) and individual telephonic interviews (N =&thins...
Source: Familial Cancer - January 17, 2019 Category: Cancer & Oncology Source Type: research

Recent advances in Lynch syndrome
AbstractLynch syndrome is one of the most common hereditary cancer predisposition syndromes and is associated with increased risks of colorectal and endometrial cancer, as well as multiple other cancer types. While the mechanism of mismatch repair deficiency and microsatellite instability and its role in Lynch-associated carcinogenesis has been known for some time, there have been significant advances recently in diagnostic testing and the understanding of the molecular pathogenesis of Lynch tumors. There is also an increased awareness that the clinical phenotype and cancer risk varies by specific mismatch repair mutation,...
Source: Familial Cancer - January 9, 2019 Category: Cancer & Oncology Source Type: research

TP53 germline mutation testing in early-onset breast cancer: findings from a nationwide cohort
AbstractEarly-onset breast cancer may be due to Li –Fraumeni Syndrome (LFS). Current national and international guidelines recommend thatTP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31  years. However, large studies investigatingTP53 mutation prevalence in this population are scarce. We collected nationwide laboratory records for all young breast cancer patients tested forTP53 mutations in the Netherlands. Between 2005 and 2016, 370 women diagnosed with breast cancer younger than 30  years of age were tested forTP53 germline mutations, and eight (2.2%) w...
Source: Familial Cancer - January 3, 2019 Category: Cancer & Oncology Source Type: research

Multi-gene panel testing confirms phenotypic variability in MUTYH -Associated Polyposis
We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelicMUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. BiallelicMUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; ...
Source: Familial Cancer - January 2, 2019 Category: Cancer & Oncology Source Type: research

Low-level parental mosaicism in an apparent de novo case of Peutz –Jeghers syndrome
We report the case of a female found to have mosaicism for mutation in theSTK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in her gastrointestinal tract demonstrated on an excised polyp analysed for diagnosis. Mosaicism for Peutz –Jeghers syndrome (PJS) has been reported in a small number of cases previously but a clinical presentation such as this has not previously been described. This finding of mosaicism was several years after initial investigations failed to identify the sameSTK11 mutation in this woman whose son was diagnosed with PJS at a young age. This case...
Source: Familial Cancer - January 1, 2019 Category: Cancer & Oncology Source Type: research

Capillary electrophoresis as alternative method to detect tumor genetic mutations: the model built on the founder BRCA1 c.4964_4982del19 variant
In this study, we developed a rapid and reliable PCR method, coupled with capillary electrophoresis (CE) for genotyping the Italian founderBRCA1 c.4964_4982del19 (rs80359876) variant. In addition, we compared the performance of two CE platforms: (Agilent 2100 Bioanalyzer and the Experion Automated Electrophoresis system) to identify this variant. Our findings suggest that CE represents a simple and standardized diagnostic strategy for the unambiguously identification of theBRCA1 c.4964_4982del19 variant, on both germline and somatic DNA samples. The results and performance obtained by two platforms are absolutely superimpo...
Source: Familial Cancer - January 1, 2019 Category: Cancer & Oncology Source Type: research

Monoallelic MUTYH carrier status is not associated with increased breast cancer risk in a multigene panel cohort
This study aimed to determine if monoallelicMUTYH mutations are associated with increased breast cancer risk in women undergoing multigene panel testing (MGPT). The prevalence of monoallelicMUTYH mutations was compared between Non-Hispanic white female breast cancer cases (n  = 30,456) and cancer-free controls (n = 12,289), all of whom underwent MGPT that includedMUTYH. We tested breast cancer associations withMUTYH alleles using Fisher ’s exact test, followed by multivariate logistic regression adjusted for age at testing and MGPT type ordered. Frequencies of the two most commonMUTYH foun...
Source: Familial Cancer - December 23, 2018 Category: Cancer & Oncology Source Type: research

A squamous cell carcinoma in a young woman with Lynch syndrome
AbstractLynch syndrome (LS) is an autosomal-dominant inherited disorder characterized by a predisposition to colorectal cancer and extracolonic cancers (particularly endometrium, ovary, stomach, small bowel, hepatobiliary tract, pancreas, urothelial tract, brain, and skin). Muir –Torre syndrome (MTS) is considered a phenotypical variant of LS, where patients develop sebaceous neoplasms and keratoacanthomas. Currently, only few studies and case reports suggest an association between LS and other skin cancers, such as Bowens’ disease, melanoma and squamous cell carcinoma (SCC). In this case-report we describe the...
Source: Familial Cancer - December 17, 2018 Category: Cancer & Oncology Source Type: research

Hereditary brain tumor with a homozygous germline mutation in PMS2 : pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome
AbstractPrecise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of thePMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test ...
Source: Familial Cancer - November 26, 2018 Category: Cancer & Oncology Source Type: research

Germline mutation p.N363K in POLE is associated with an increased risk of colorectal cancer and giant cell glioblastoma
We report a family with an autosomal dominant inheritance of PPAP due to a c.1089C>A; p.Asn363Lys mutation in the proofreading exonuclease domain ofPOLE. Ten patients presenting a history of colorectal tumours and three patients with polyposis are indexed in this family. Three carriers (including siblings and a distant cousin at 30, 45 and 52 respectively) and another member (at 37 not tested) presented glioblastoma. This is the second family reported to carry this mutation. Among the four glioblastomas in the family that we report, both show similar pathology: giant cell glioblastoma. These cases suggest that the c.108...
Source: Familial Cancer - October 27, 2018 Category: Cancer & Oncology Source Type: research

Cleft lip/palate and hereditary diffuse gastric cancer: report of a family harboring a CDH1 c.687  + 1G  & gt;  A germline mutation and review of the literature
This study highlights that CLP represents an important phenotypic feature ofCDH1 germline mutation carriers and emphasizes the inclusion of CLP in the HDGC testing criteria. The underlying causes for the appearance of variable phenotypes inCDH1 mutation carriers could include genetic variation, epigenetic changes and environmental factors and should be investigated in future studies. (Source: Familial Cancer)
Source: Familial Cancer - October 10, 2018 Category: Cancer & Oncology Source Type: research

Risk of multiple colorectal cancer development depends on age and subgroup in individuals with hereditary predisposition
AbstractDevelopment of multiple colorectal cancers (CRCs), synchronously or metachronously, is associated with hereditary predisposition for cancer and accurate risk estimates of multiple tumour development are relevant to recommend rational surveillance programs. A cross-sectional study design was used to estimate the risks of synchronous CRC (SCRC) and metachronous CRC (MCRC) based on data from the National Danish Hereditary Nonpolyposis Register. In total, 7100 individuals from families within the subgroups Lynch syndrome, familial CRC (FCC) and moderate risk were used with estimates relative to a non-hereditary populat...
Source: Familial Cancer - October 9, 2018 Category: Cancer & Oncology Source Type: research

Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes
AbstractApproximately 27 –36 million patients in Europe have one of the ~ 5.000–8.000 known rare diseases. These patients often do not receive the care they need or they have a substantial delay from diagnosis to treatment. In March 2017, twenty-four European Reference Networks (ERNs) were launched with the aim to im prove the care for these patients through cross border healthcare, in a way that the medical knowledge and expertise travels across the borders, rather than the patients. It is expected that through the ERNs, European patients with a rare disease get access to expert care more often and...
Source: Familial Cancer - October 9, 2018 Category: Cancer & Oncology Source Type: research

Ovarian small cell carcinoma in one of a  pair of monozygous twins
AbstractOne of a pair of monozygous twins was diagnosed and died of small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) at the age of 30  years. Her sister remained unaffected and was very concerned about her risk for developing SCCOHT. By performing comprehensive molecular analysis using whole exome sequencing (WES) approach, we showed that the deceased twin’s tumour has bi-allelic somatic genetic defects (a pathogenic frameshift deletion inSMARCA4 and LOH on chr19p). Results of WES of constitutional DNA from her unaffected sister were confirmatory. Based on our findings, we concluded that the livi...
Source: Familial Cancer - October 4, 2018 Category: Cancer & Oncology Source Type: research

Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma
In this study, we report a previously undescribed Belgian family, in which BAP1 was found to be absent in the epithelial malignant mesothelial cells of the index patient. Whole exome analysis did not reveal a germline or somaticBAP1 variant. Also, no germline or somatic copy number changes in theBAP1 region could be identified. However, germline variants, predicted to be damaging, were detected in 11 other ‘Cancer census genes’ (i.e.MPL, RBM15, TET2, FAT1, HLA-A, EGFR, KMT2C, BRD3, NOTCH1, RB1 andMYO5A). Of these, the one inRBM15 seems to be the most interesting given its low minor allele frequency and absence ...
Source: Familial Cancer - October 1, 2018 Category: Cancer & Oncology Source Type: research

Clinical interpretation of pathogenic ATM and CHEK2 variants on multigene panel tests: navigating moderate risk
AbstractComprehensive genomic cancer risk assessment (GCRA) helps patients, family members, and providers make informed choices about cancer screening, surgical and chemotherapeutic risk reduction, and genetically targeted cancer therapies. The increasing availability of multigene panel tests for clinical applications allows testing of well-defined high-risk genes, as well as moderate-risk genes, for which the penetrance and spectrum of cancer risk are less well characterized. Moderate-risk genes are defined as genes that, when altered by a pathogenic variant, confer a 2 to fivefold relative risk of cancer. Two such genes ...
Source: Familial Cancer - October 1, 2018 Category: Cancer & Oncology Source Type: research

Gene expression analysis in peripheral blood cells of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC): identification of NRF2 pathway activation
AbstractHereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare disease that is inherited in an autosomal dominant manner. Affected patients may develop from cutaneous and uterine leiomyomas to type 2 papillary renal cell carcinoma (Schmidt and Linehan, Int J Nephrol Renovasc Dis 7:253 –260, 2014). HLRCC is caused by germline mutations in theFH gene, which produces the fumarate hydratase protein that participates in the tricarboxylic acid cycle during the conversion of fumarate to malate. InFH-deficient cells, high concentrations of fumarate lead to a series of intricate events, which seem to ...
Source: Familial Cancer - October 1, 2018 Category: Cancer & Oncology Source Type: research

Discussions about predictive genetic testing for Lynch syndrome: the role of health professionals and families in decisions to decline
AbstractUnaffected relatives of individuals with Lynch syndrome can be offered predictive genetic testing to guide surveillance recommendations. The decision-making process of those who decline testing, particularly those who do not attend a clinical genetics service, is poorly understood. We have addressed this gap by interviewing 33 individuals from Lynch syndrome mutation-carrying families, unaffected by cancer, who declined predictive genetic testing. Here, we analyse the data provided by 20 participants who unequivocally declined testing. Those who indicated they did not have enough information to make a decision or i...
Source: Familial Cancer - October 1, 2018 Category: Cancer & Oncology Source Type: research

Urological sequelae of desmoids associated with familial adenomatous polyposis
AbstractThe aim of this retrospective cohort study was to review urological complication rates arising from familial adenomatous polyposis associated desmoid tumours and their management. All patients over a 35-year period were identified from a prospectively maintained polyposis registry database and had an intra-abdominal desmoid tumour. Those without ureteric complications (n  = 118, group A) were compared to those that developed ureteric obstruction (n = 40, group B) for demographics, treatment interventions and survival outcomes. 158 (56% female) patients were identified. Median age at diag...
Source: Familial Cancer - October 1, 2018 Category: Cancer & Oncology Source Type: research

APC mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis
AbstractFamilial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15 –20% of theAPC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposi...
Source: Familial Cancer - October 1, 2018 Category: Cancer & Oncology Source Type: research

SNP association study in PMS2-associated Lynch syndrome
AbstractLynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly onMLH1, MSH2 andMSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs inPMS2 mutation carriers. A cohort study was performed in 507PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. ...
Source: Familial Cancer - October 1, 2018 Category: Cancer & Oncology Source Type: research

Feasibility of endoscopic resection using bipolar snare for nonampullary duodenal tumours in familial adenomatous polyposis patients
AbstractThe management of duodenal and colorectal tumours is important in patients with familial adenomatous polyposis (FAP). Endoscopic resection (ER) should be carefully performed because the risk of complications during or after (ER) of nonampullary duodenal tumours is higher than that of stomach or colorectal lesions in general. Thus, we evaluated the feasibility of endoscopic resection using bipolar snare (ERB) for nonampullary duodenal tumours in FAP patients. Eleven FAP patients who underwent ERB for nonampullary duodenal tumours at our hospital between October 2013 and December 2016 were retrospectively analysed ba...
Source: Familial Cancer - October 1, 2018 Category: Cancer & Oncology Source Type: research