Bernd Auber

Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer

Purpose To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. Patients and methods Data from 21 401 families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. Results The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). Conclusions Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.

Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer

The prevalence of germ line mutations in non‐BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple‐negative breast cancer (TNBC) and estrogen receptor (ER)‐negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)‐positive tumors.

MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies

Genetic predisposition due to germline mutations in a number of genes (e.g., ETV6 , GATA2 , and RUNX1 ) has been recognized as an important cause of myeloid malignancies. In the 2016 update of the World Health Organization classification of hematological malignancies, a new section, ‘myeloid

BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer

BackgroundGermline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial.MethodsTo assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants.ResultsBRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99–59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00–3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70–2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43–9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients.ConclusionsTo avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded.

Two cancer-predisposing variants in one family: Incidental finding of a fumarate hydrogenase (FH) germline variant in a family with Li-Fraumeni syndrome

About 5–10% of all cancer diagnoses are due to hereditary cancer predisposition. The identification of causative gene variants is highly important as it can provide clinically actionable information and enables genetic counseling as well as appropriate cancer surveillance. Currently, the analysis of candidate gene(s)most consistentwith a suspected clinical diagnosis is often replaced by next-generation sequencing (NGS) analysis of a preset gene panel, whole exome or genome. However, NGS analysis has been considered controversial, as it may provide challenging data.1 Here, we report a family with suspected Li–Fraumeni syndrome (LFS, OMIM: 151623), a cancer predisposition syndrome due to TP53 variants, that illustrates how careful cancer risk prediction has to be done in a way to avoid wrong conclusions due to limited knowledge. Genetic evaluation was initiated in this family when the index patient received treatment for hypodiploid pre-B cell acute lymphoblastic leukemia (ALL; treatment according to ALL-BFM 2009) at the age of 14 years. The patients mother had been diagnosed with cervical cancer and several maternal relatives have had cancers of different entities. LFS was suspected due to fulfilled Chompret criteria2 and—after informed consent—genetic testing was performed. Instead of targeted TP53 sequencing, targeted gene panel sequencing (TruSight Cancer Sequencing Panel was conducted using the Illumina sequencing platform NextSeq500). Since the index patient had undergone stem cell transplantation (according to the PedForum ALL-SCT treatment protocol) and germline DNA from fibroblasts was limited, the mother was tested first. Surprisingly, two pathogenic variants were detected and confirmed by Sanger sequencing. Consistent with the suspected diagnosis of LFS, we identified the very rare deleterious TP53 missense variant c.455C > T (p.Pro152Leu) that has an allele frequency of 0.003%. It is located in the DNA-binding domain (rs587782705) and has been described in LFS (clinvar/variation/142766/)[2, 3]. In addition, the variant c.1431_1433dupAAA (p.Lys477_Asn478insLys) in the FH gene (fumarate hydratase, MIM: 150800) was detected in the mother as well as in the healthy daughter, but excluded in the patient with ALL. Fumarate hydratase deficiency is inherited in an autosomal recessive manner. The detected variant has strong evidence for risk toward fumarate hydratase deficiency when occurring in trans with a second variant in the FH gene.3 In addition, heterozygous FH gene variants confer a risk for the autosomal dominant hereditary leiomyomatosis

Diagnosis of monogenic liver diseases in childhood by Next-Generation Sequencing

Next‐generation sequencing (NGS) has opened up novel diagnostic opportunities for children with unidentified, but suspected inherited diseases. We describe our single‐center experience with NGS diagnostics in standard clinical scenarios in pediatric hepatology. We investigated 135 children with suspected inherited hepatopathies, where initially no causative pathogenic variant had been identified, with an amplicon‐based NGS panel of 21 genes associated with acute and chronic hepatopathies. In 23 of these patients, we detected pathogenic or likely pathogenic variants in 10 different genes. We present 6 novel variants. A total of 14 of these patients presented with the characteristic phenotype of the related hepatopathy. Nine patients showed only few or atypical clinical symptoms or presented with additional signs. In another 13 out of 135 cases, we detected variants of unknown significance (VUS) in 9 different genes. Only 2 of these patients showed characteristic phenotypes conclusive with the detected variants, whereas 11 patients showed unspecific or atypical phenotypes. Our multi‐gene panel is a fast and comprehensive tool to diagnose inherited pediatric hepatopathies. We also illustrate the challenge of dealing with genetic variants and highlight arising clinical questions, especially in patients with atypical phenotypes.

Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

BackgroundBreast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria.MethodsTo specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants.ResultsWe identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14ARF, and RUNX1).ConclusionsOur study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.

KBG syndrome patient due to 16q24.3 microdeletion presenting with a paratesticular rhabdoid tumor: Coincidence or cancer predisposition?

KBG syndrome is a rare autosomal dominant disorder caused by constitutive haploinsufficiency of the ankyrin repeat domain‐containing protein 11 (ANKRD11) being the result of either loss‐of‐function gene variants or 16q24.3 microdeletions. The syndrome is characterized by a variable clinical phenotype comprising a distinct facial gestalt and variable neurological involvement. ANKRD11 is frequently affected by loss of heterozygosity in cancer. It influences the ligand‐dependent transcriptional activation of nuclear receptors and tumor suppressive function of tumor protein TP53. ANKRD11 thus serves as a candidate tumor suppressor gene and it has been speculated that its haploinsufficiency may lead to an increased cancer risk in KBG syndrome patients. While no systematic data are available, we report here on the second KBG syndrome patient who developed a malignancy. At 17 years of age, the patient was diagnosed with a left‐sided paratesticular extrarenal malignant rhabdoid tumor. Genetic investigations identified a somatic truncating gene variant in SMARCB1, which was not present in the germline, and a constitutional de novo 16q24.3 microdeletion leading to a loss of the entire ANKRD11 locus. Thus, KBG syndrome was diagnosed, which was in line with the clinical phenotype of the patient. At present, no specific measures for cancer surveillance can be recommended for KBG syndrome patients. However, a systematic follow‐up and inclusion of KBG syndrome patients in registries (e.g., those currently established for cancer prone syndromes) will provide empiric data to support or deny an increased cancer risk in KBG syndrome in the future.

Consider family history.

The authors (1) point out that the risk of developing cancer in young women after treatment for Hodgkins disease in childhood or adolescence corresponds, up to age 50, with the high risk in the case of hereditary disposition in the high risk genes BRCA1/2. We provided genetic counseling for a 36-year-old woman who developed bilateral breast cancer at the ages of 26 and 35, after having been treated for Hodgkins lymphoma and receiving radiotherapy at age 17. In her family history, we noticed an accumulation of cancers, among them breast cancer and prostate cancer. The patient opted for genetic testing, which identified the pathogenic mutation c.767_768delCA; p.(Thr256LysfsTer19) in the tumor suppressor gene BRCA2. To our knowledge, the current literature provides no evidence that women with Hodgkins disease and subsequent breast cancer are at higher risk for having a BRCA1/2 or other risk gene mutation. Individual cases have been reported (2), but no results from prospective clinical trials are available. It is therefore unclear to what extent these or other genetic factors influence the risk for radiotherapy-induced breast cancer subsequent to Hodgkins disease. For our patient, knowing that she carries a BRCA2 mutation implies a higher risk for other BRCA2 gene-associated cancers, especially ovarian cancer. According to the German breast cancer S3 guideline, prophylactic removal of the ovaries and Fallopian tubes (salpingo-oophorectomy) should be recommended to BRCA1/2 mutation carriers at the age of about 40, once they have had children if so desired. This procedure not only drastically reduces the risk of developing ovarian cancer but is also associated with improved overall survival. For this reason, we wish to point out the importance of considering the family history in women with breast cancer subsequent to radiotherapy for Hodgkins disease.