Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated

PALB2-mutation carriers not only have an increased risk for breast cancer (BC) but also for pancreatic cancer (PC). Thus far, PALB2 mutations have been mainly found in PC patients from families affected by both PC and BC. As it is well known that the prevalence of gene mutations varies between different populations, we studied the prevalence of PALB2 mutations in a Dutch cohort of non-BRCA1/2 familial PC (FPC) families and in non-BRCA1/2 familial BC (FBC) families with at least one PC case. Mutation analysis included direct sequencing and multiplex ligation-dependent probe amplification (MLPA) and was performed in a total of 64 patients from 56 distinct families (28 FPC families, 28 FBC families). In total, 31 patients (48%) originated from FPC families; 24 were FPC patients (77%), 6 had a personal history of BC (19%) and 1 was a suspected carrier (3.2%). The remaining 33 patients (52%) were all female BC patients of whom 31 (94%) had a family history of PC and 2 (6.1%) had a personal history of PC. In none of these 64 patients a PALB2 mutation was found. Therefore, PALB2 does not have a major causal role in familial clustering of PC and BC in non-BRCA1/2 families in the Dutch population.     

BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland

Sixty high-risk breast and/or ovarian cancer families from North-Eastern Poland were screened for germline mutations in BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), using a combination of protein truncation test, denaturing high-performance liquid chromatography and direct sequencing. Sixteen (27%) of the families were found to carry nine different BRCA mutations, including 14 families with BRCA1 mutation and two families with BRCA2 mutation. The results suggest the presence of two strong BRCA1 founder mutations in the Polish population - 5382insC (6 families) and 300T>G (Cys61Gly; 3 families). The remaining seven mutations were found in single families and included three previously reported BRCA1 mutations (185delAG, 2682C>T [Gln855Ter] and 3819del5), a novel BRCA1 mutation (IVS14+1G>A), as well as two BRCA2 mutations (4088delA and 7985G>A [Trp2586Ter]) not previously observed in Polish families. We confirm the strong influence of two Central-Eastern European BRCA1 founder mutations in familial breast and/or ovarian cancer in Poland. We also conclude that the Polish population has a more dispersed BRCA mutation spectrum than had been earlier thought. This warrants further careful BRCA mutation screening in order to optimise genetic counselling and disease prevention in affected families.     

A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families

The 185delAG and 5382insC founder mutations account for the majority of mutations identified in BRCA1 in Ashkenazi Jewish breast and breast-ovarian cancer families. Few non-founder BRCA1 mutations have been identified to date in these families. We initially screened a panel of 245 Ashkenazi Jewish breast-ovarian cancer families with an affected proband and at least one other case of breast or ovarian cancer for founder mutations in BRCA1 and BRCA2. Founder mutations were identified in 85 families (185delAG in 44 families, 5382insC in 16 families, and the BRCA2 6174delT in 25 families). The 160 negative families were then screened for the entire BRCA1 gene by a combination of DGGE and PTT. We identified one novel frameshift mutation in BRCA1 in exon 14 (4572del22) that truncated the protein at codon 1485. The family contained three cases of early-onset ovarian cancer (41 years, 43 years, and 52 years) and one case of breast cancer (at age 54 years subsequent to an ovarian cancer). In addition, three missense variants of unknown significance (exon 11 C3832T (P1238L), exon 15 G4654T (S1512I), and exon 15 G4755A (D1546N)) were found in single families. These missense variants have been previously identified in other families [BIC Database] and are considered to be "unclassified variants, favoring polymorphism." Non-founder BRCA1 mutations are rare in Ashkenazi Jewish breast/ovarian cancer families.     

Experiences and attitudes of hereditary cancer screening patients in a consumer directed testing model

BackgroundSince 2015, the Information is Power initiative has offered free and reduced cost hereditary cancer screening to the North Alabama population with a consumer-initiated model. Patients received pre-test and post-test education through a genetic counseling video. Positive results also received a call from a genetic counselor.ObjectiveWe surveyed past Information is Power patients to assess if video education and electronic result delivery addressed the needs of a hereditary cancer screening population.MethodsAn electronic survey was sent out to Information is Power patients who opted into research contact. The survey assessed participant knowledge, satisfaction with result delivery, and perceived uncertainty after receiving test results.Results213 participants completed the survey. Eighteen percent of participants would have preferred individual communication with a genetics specialist about their results. Over 99 % of survey participants correctly interpreted a positive result, while 73 % correctly interpreted a negative result. Overall, participants were certain about the impact of their genetic test results.Practice ImplicationsThese findings support a model of population genetic testing and genetic counseling that is sustainable while meeting the educational needs of most participants. Observed misconceptions surrounding a negative result should be highlighted in future population screening patient resources to meet patient needs.     

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor (CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.     

Real-time PCR-based gene dosage assay for detecting BRCA1 rearrangements in breast-ovarian cancer families

BRCA1 and BRCA2 germline mutations, mainly point mutations and other small alterations, are responsible for most hereditary cases of breast-ovarian cancer. However, the observed frequency of BRCA1 alterations is lower than that predicted by linkage analysis. Several large BRCA1 rearrangements have been identified with a variety of technical approaches in some families. We have developed a gene dosage assay based on real-time quantitative PCR and used it to extensively analyze 91 French families of breast-ovarian cancer in which no BRCA1 or BRCA2 point mutations was identified. This gene dosage method calculates the copy number of each BRCA1 exon to readily detect one, two, and three or more copies of BRCA1 target exons. In the series of 91 families at high risk of carrying BRCA1 mutations, we detected seven large rearrangements of the BRCA1 gene by using this real-time PCR approach. This simple, rapid, and semiautomated real-time quantitative polymerase chain reaction (PCR) assay is a promising alternative technique to Southern blot, bar code analysis on combed DNA, quantitative multiplex PCR of short fluorescent fragments, and cDNA length analysis for the detection of large rearrangements. Therefore, this technique should be considered as a powerful diagnostic method for breast/ovarian cancer susceptibility in clinical and research genetic surveys.     

PALB2 mutations in European familial pancreatic cancer families

Slater EP, Langer P, Niemczyk E, Strauch K, Butler J, Habbe N, Neoptolemos JP, Greenhalf W, Bartsch DK. PALB2 mutations in European pancreatic cancer families. Recently, PALB2 was reported to be a new pancreatic cancer susceptibility gene as determined by exomic sequencing, as truncating PALB2 mutations were identified in 3 of 96 American patients with familial pancreatic cancer (FPC). Representing the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) and the German National Case Collection for Familial Pancreatic Cancer (FaPaCa), we evaluated whether truncating mutations could also be detected in European FPC families. We have directly sequenced the 13 exons of the PALB2 gene in affected index patients of 81 FPC families. An index patient was defined as the first medically identified patient, stimulating investigation of other members of the family to discover a possible genetic factor. None of these patients carried a BRCA2 mutation. We identified three (3.7%) truncating PALB2 mutations, each producing different stop codons: R414X, 508‐9delAG and 3116delA. Interestingly, each of these three families also had a history of breast cancer. Therefore, PALB2 mutations might be causative for FPC in a small subset of European families, especially in those with an additional occurrence of breast cancer.     

A computer model for the study of breast cancer

A computer model was designed as a relational database to assess breast cancer screening in a cohort of women where the growth and development of breast cancer originates with the first malignant cell. The concepts of thresholds for growth, axillary spread, and distant sites are integrated. With tumor diagnosis, staging was performed that includes clinical and sub-clinical states. The model was parameterized to have staging characteristics similar to data published by the Surveillance, Epidemiology, and End-Results (SEER) Program. Validation was accomplished by comparing simulated staging results with non-SEER sources, and simulated survival with independent clinical survival data.     

Breast cancer in an MSH2 gene mutation carrier

A 49-year-old woman presented with breast cancer. She is a member of a family with the hereditary nonpolyposis colorectal cancer syndrome for which a 2-base pair deletion in exon 11 of the mismatch repair gene MSH2 (c1705_1706 delGA) had been identified. Breast cancer is rare in the hereditary nonpolyposis colorectal cancer syndrome. Microsatellite analysis of the tumor showed a microsatellite instable pattern for markers Bat25, Bat26, and Bat40, and no changes for markers D2S123 and D5S346, a so-called microsatellite instability-high pattern. Immunohistochemical staining for the mismatch repair enzymes MSH2 and MSH6 was negative, whereas the tumor cells were positive for MLH1, a pattern suggestive for biallelic MSH2 gene inactivation. We tested the tumor for loss of heterozygosity of the MSH2 gene and found loss of the wild-type MSH2 allele. These data strongly suggest that the MSH2 gene was involved in the development of this breast tumor.     

Psychosocial and clinical predictors of continued cancer screening in older adults

ObjectiveMany older adults (aged 75+) continue cancer screening despite guidelines suggesting they should not. Using mixed-methods, we examined psychosocial and clinical factors associated with continued breast/prostate screening.MethodsWe conducted an online, scenario-based, randomized study in Australia with participants aged 65+ years. The primary outcome was screening intention (10-point scale, dichotomized: low (1−5) and high (6−10)). We also measured demographic, psychosocial, and age-related clinical variables. Participants provided reason/s for their screening intentions in free-text.Results271 eligible participants completed the survey (aged 65–90 years, 71% adequate health literacy). Those who reported higher cancer anxiety, were men, screened more recently, had family history of breast/prostate cancer and were independent in activities of daily living, were more likely to intend to continue screening. Commonly reported reasons for intending to continue screening were grouped into six themes: routine adherence, the value of knowing, positive screening attitudes, perceived susceptibility, benefits focus, and needing reassurance.ConclusionsPsychosocial factors may drive continued cancer screening in older adults and undermine efforts to promote informed decision-making.Practice implicationsWhen communicating benefits and harms of cancer screening to older adults, both clinical and psychosocial factors should be discussed to support informed decision-making.     

Communicating polygenic risk scores in the familial breast cancer clinic

ObjectiveTo describe the communication of polygenic risk scores (PRS) in the familial breast cancer setting.MethodsConsultations between genetic healthcare providers (GHP) and female patients who received their PRS for breast cancer risk were recorded (n = 65). GHPs included genetic counselors (n = 8) and medical practitioners (n = 5) (i.e. clinical geneticists and oncologists). A content analysis was conducted and logistic regression was used to assess differences in communication behaviors between genetic counselors (n = 8) and medical practitioners (n = 5).ResultsOf the 65 patients, 31 (47.7 %) had a personal history of breast cancer, 18 of whom received an increased PRS (relative risk >1.2). 25/34 unaffected patients received an increased PRS. Consultations were primarily clinician-driven and focused on biomedical information. There was little difference between the biomedical information provided by genetic counselors and medical practitioners. However, genetic counselors were significantly more likely to utilize strategies to build patient rapport and counseling techniques.ConclusionsOur findings provide one of the earliest reports on how breast cancer PRSs are communicated to women.Practice implicationsKey messages for communicating PRSs were identified, namely: discussing differences between polygenic and monogenic testing, the multifactorial nature of breast cancer risk, polygenic inheritance and current limitation of PRSs.     

A pragmatic clinical trial of cascade testing for familial hypercholesterolemia

PurposeWe compared new cases detected per index case in familial hypercholesterolemia (FH) families with or without an identifiable monogenic etiology.MethodsWe enrolled 52 FH probands with a pathogenic variant (FH^g+) in LDLR, APOB, or PCSK9 and 73 probands without such a variant (FH^g–). After direct contact by the study team, family members (FMs) of FH^g+ probands could opt-in for genetic testing and FMs of FH^g– probands were asked to provide a lipid profile. New cases were defined as presence of a pathogenic variant in FH^g+ families and as low-density lipoprotein cholesterol ≥155 mg/dL in FH^g– families.ResultsOf 71 FH^g+ probands seen by a genetic counselor, 52 consented and identified 253 FMs (111 consented and were tested, yielding 48 new cases). Of 101 FH^g– probands who received counseling, 73 consented and identified 295 FMs (63 consented and were tested, yielding 17 new cases). New case detection per index case was significantly greater in FH^g+ than in FH^g– families (0.92 vs 0.23), a result of higher cascade testing uptake (43.9 vs 21.4%) and yield (43.2 vs 27.0%) in the former.ConclusionNew case detection rate was significantly higher in FH families with a monogenic etiology than in those without such an etiology owing to greater uptake and yield of cascade testing.     

Breast cancer screening in France: results of the EDIFICE survey

Background: The EDIFICE survey aimed to investigate the compliance of the general population to the screening tests available in France for the 4 most common cancers: breast, colorectal, prostate and lung. Implementation of breast cancer screening has been generalized in France since 2003: women aged between 50 and 74 years are systematically invited to perform a mammography every second year. Results pertaining to breast cancer are reported hereafter.     

Mammographic breast cancer screening —a randomized trial in Malmö, Sweden

A randomized trial is presented on the effect of repeated invitation to breast cancer screening with mammography on mortality from breast cancer. The invited group and the control group each consisted of approximately 21,000 women aged 45-69 yr at the start of the screening. The attendance rate was 74% at the first screening and 70% at the two subsequent screening rounds. The cancer detection rate was 7.5 per 1000 women examined in the first screening round and 2.2 and 2.0 per 1000 woman-years in the second and third screenings with an incidence of 0.9 in the intervals. The incidence in the control group was 2.7 per 1000 woman-years. The proportion of positive biopsies was 61% in the first screening round, 33% in the second, and 58% in the third. After the prevalence screening, the stage distribution was more favourable in the invited group (including non-attenders) than in the control group. In the two most recent periods of the programme, 62 out of 160 women with cancer (39%) in the invited group were in stage II-IV compared with 91 out of 159 (57%) in the control group. More than 60% of cancers detected at screening were either non-invasive or invasive with a diameter of 1 cm. The corresponding percentage in the control group was 27%. The importance of sampling bias is discussed. Although data on mortality still have to be awaited, the results so far clearly indicate a positive effect of screening.     

Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments

Recent studies have revealed a significant proportion of BRCA1 exon deletions or duplications in breast-ovarian cancer families with high probability of BRCA1- or BRCA2-linked predisposition, in which mutations of these genes have not been found. The difficulty of detecting such heterozygous rearrangements has stimulated the development of several new screening methods. Quantitative fluorescent multiplex PCR is based on simultaneous amplification of multiple target sequences under conditions that allow rapid and reliable quantitative comparison of the fluorescence of each amplicon in test samples and in controls. The modified method described here, named quantitative multiplex PCR of short fluorescent fragments (QMPSF), is particularly well suited for large genes. All BRCA1 coding exons were analyzed using four multiplexes in 52 families without point mutations in the exons or splice-sites of BRCA1 and BRCA2, and selected because of high probability of a BRCA1- or BRCA2-linked genetic predisposition. Five distinct BRCA1 rearrangements were detected: a deletion of exons 8-13, a duplication of exons 3-8, a duplication of exons 18-20, a deletion of exons 15-16, and a deletion of exons 1-22-which is the largest deletion found so far within the BRCA1 gene. The method described here lends itself to rapid, sensitive, and cost-effective search of BRCA1 rearrangements and may be included into the routine molecular analysis of breast-ovarian cancer predispositions. Hum Mutat 20:218-226, 2002.     

Genetic analysis of familial colorectal cancer in Israeli Arabs

Colorectal cancers (CRC) among Israeli Arabs differ from those diagnosed in Jewish Israeli individuals in two manners: an earlier age of occurrence and a low frequency. These differences are unaccounted for and thus prompted us to perform genetic analysis in Israeli Arab CRC patients. Analysis included the major Hereditary non-polyposis colorectal cancer (HNPCC) genes and the APC I1307K mutation (MIM# 175100.0029). Twenty-five patients and 25 relatives from 24 unrelated families were clinically classified according to personal and familial cancer history. If MSI (microsatellite instability) was displayed in tumor tissue, patients underwent mutation analysis of the MSH2 and MLH1 genes using DGGE (denaturing gradient gel electrophoresis) and sequencing. MSI was detected in 9/21 of the tumors tested (43%). Two novel missense mutations were diagnosed among 11 fully analyzed patients: a change of A to G at position 380 in MSH2 (N127S), and a D601G mutation in MLH1. The I1307K mutation was detected in 8 families (8/24, 33.3%). This is the first report of genetic analysis in familial CRC associated genes among Israeli Arabs. We suggest that the I1307K mutation may contribute to CRC in Israeli Arabs and that inactivating mutations of MSH2 and MLH1 may not be a major cause for early onset CRC.