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Background BRCA2 germline mutations are known to predispose carriers to various cancer types, including breast, ovarian, pancreatic and prostate cancer. An association with melanoma has also been reported. However, the full tumour spectrum associated with BRCA2 mutations, particularly in patients with other concurrent pathogenetic mutations, is unexplored. Case presentation We present a 70-year-old female patient with a pathogenic BRCA2 c.5946del variant. Over a period of 15 years, she has developed two independent breast cancers, well-differentiated liposarcoma, clear cell renal cell carcinoma and myeloproliferative neoplasia. This unusual tumour spectrum and the staggered occurrence of these tumours required multiple rounds of genetic testing and led to a delayed diagnosis of the BRCA2-associated tumour predisposition. In addition to the BRCA2 mutation, extended germline testing revealed an APC c.3920T > A variant and variants of unknown significance in the BRIP1 and ATR genes. The molecular analysis of the tumours revealed distinct profiles with differences in HRD status and in copy number variations, indicating no common origin. Conclusions Our case study revealed that the pathogenic BRCA2 c.5946del germline variant can be associated with an unusual tumour spectrum, which may lead to a delayed diagnosis of a hereditary tumour predisposition. Thus, upfront genetic testing using large multigene panels or whole-genome sequencing in encouraged, especially in cases with a prominent family history. Keywords: BRCA2 mutation, APC, Genetic testing, Whole-genome sequencing, Breast cancer, Renal cell carcinoma, Liposarcoma, Myeloproliferative neoplasia, Author(s): Elena Su[sup.1], Yann Christinat[sup.2], Thomas McKee[sup.3], Silvia Azzarello-Burri[sup.4], Wolfram Jochum[sup.4], Stefanie Fischer[sup.5] and Christian Rothermundt[sup.6] Background Mutations in the BRCA1 and BRCA2 genes have long been known to predispose [...]

Background While the role of BRCA1/2 genes in familial breast and ovarian cancer is well established, their implication in the sporadic form of both cancers is still controversial. With the development of poly (ADP-ribose) polymerase (PARP) inhibitors, the exact relationship between BRCA1/2 genes and sporadic triple negative breast cancer/high grade serous carcinoma (TNBC/HGSC) needs to be further investigated. Therefore, we conducted a study in which we analyze BRCA1/2 point mutations and copy number alterations in Moroccan patients suffering from TNBC/HGSC. Methods To achieve our goal, we analyzed BRCA1/2 genes in the FFPE tissue blocks and blood samples of 65 TNBC/HGSC selected patients, using next generation sequencing technology. Results From the 65 successfully sequenced patients in our cohort, we detected five-point variants in six different patients, four variants were classified as pathogenic and one of unknown significance. Regarding copy number alterations we detected one copy number loss in BRCA1 gene and one copy number gain in BRCA2 gene. The genetic screening of BRCA1/2 genes using these patients' genomic DNA indicated that five harbored a germline genetic alteration. While three harbored a somatic genetic alteration. To the best of our knowledge, three-point variants detected in our study have never been reported before. Conclusion According to the results found in the present study, in a population without a family history of cancer, the possibility of a BRCA1/2 somatic pathogenic variant in high grade serous carcinoma is 7%. While for Triple negative breast cancer somatic point variants and copy number alterations seems to be a very rare genetic event. Keywords: Triple negative breast cancer, High grade serous ovarian Cancer, BRCA1/2, Morocco, Author(s): Fatima Zahra El Ansari[sup.1,2], Farah Jouali[sup.2], Rim Fekkak[sup.2], Joaira Bakkach[sup.1], Naima Ghailani Nourouti[sup.1], Amina Barakat[sup.1], Mohcine Bennani Mechita[sup.1] and Jamal Fekkak[sup.2] Background BRCA1 and BRCA2 genes encode for tumor [...]

Background The data on prevalence and clinical relevance of TP53 germline mutations in early onset Middle-Eastern breast cancer (BC) is limited. Methods We determined TP53 germline mutations in a cohort of 464 early onset BC patients from Saudi Arabia using capture sequencing based next generation sequencing. Results Germline TP53 pathogenic mutations were found in 1.5% (7/464) of early onset Saudi BC patients. A total of six pathogenic missense mutations, one stop gain mutation and two variants of uncertain significance (VUS) were detected in our cohort. No TP53 pathogenic mutations were detected among 463 healthy controls. TP53 mutations carriers were significantly more likely to have bilateral breast cancer (p = 0.0008). At median follow-up of 41 months, TP53 mutations were an unfavorable factor for overall survival in univariate analysis. All the patients carrying TP53 mutations were negative for BRCA1 and BRCA2 mutations. Majority of patients (85.7%; 6/7) carrying TP53 mutation had no family history suggestive of Li-Fraumeni Syndrome (LFS) or personal history of multiple LFS related tumors. Only one patient had a positive family history suggestive of LFS. Conclusions TP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations. Keywords: TP53 mutation, Breast cancer, Li-Fraumeni syndrome, Lifetime risk, Author(s): Abdul Khalid Siraj[sup.1], Tariq Masoodi[sup.1], Rong Bu[sup.1], Sandeep Kumar Parvathareddy[sup.1], Kaleem Iqbal[sup.1], Saud Azam[sup.1], Maha Al-Rasheed[sup.1], Dahish Ajarim[sup.2], Asma Tulbah[sup.3], Fouad Al-Dayel[sup.3] and Khawla Sami Al-Kuraya[sup.1,4] Background TP53 (RefSeq [...]

Background A small but important proportion of patients (4-10 %) with AML have germline mutations. They can cause the development of AML at an earlier age, confer a higher risk of relapse or predispose to secondary leukemias, including therapy-related leukemias. The analysis of germline mutations in a patient and his/her family is also critical for the selection of suitable family donors if the patient is a candidate for hematopoietic stem cell transplantation (HSCT). Methods 103 unrelated consecutive patients with de novo AML were enrolled in the study. Control group consisted of 103 persons from the general population. We performed NGS sequencing of bone marrow cells and buccal swabs DNA of six genes: CEBPA, DDX41, ETV6, TERT, GATA2, and IDH2 to detect germline pathogenic mutations. Results In the investigated group, 49 variants were detected in six genes. 26 of them were somatic and 23 germline. Germline variants were detected in all six tested genes. Eight pathogenic germline mutations were detected in 7 AML patients, in three genes: CEBPA, ETV6, and IDH2. One patient had two pathogenic germinal mutations, one in ETV6 and one in CEBPA gene. We identified one novel pathogenic germline mutation in CEBPA gene. The difference in frequency of all pathogenic germline mutations between the tested (7.77 %) and control groups (0.97 %) was statistically significant (p = 0.046). In the tested group, the median age at AML diagnosis was 11 years lower in patients with pathogenic germline mutations than in patients without them (p = 0.028). Conclusions We showed higher frequency of CEBPA, ETV6, and IDH2 germline mutations in AML patients than in control group, which confirms the role of these mutations in the development of AML. We also showed that the median age at the onset of AML in patients with pathogenic germline mutations is significantly lower than in patients without them. Keywords: Acute myeloid leukemia, AML, germline mutations, CEBPA, DDX41, ETV6, TERT, GATA2, IDH2, Author(s): Aneta BÄk[sup.1], Katarzyna Skonieczka[sup.1], Anna JaÅkowiec[sup.2], Anna Junkiert-Czarnecka[sup.1], Marta Heise[sup.1], Maria Pilarska-Deltow[sup.1], StanisÅaw Potoczek[sup.2], Maria Czyżewska[sup.3] and Olga Haus[sup.1] Background AML (acute myeloid leukemia) is one of the most [...]

Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons. Keywords: Genetic predisposition, Lynch syndrome, Mismatch repair genes, Whole-genome sequencing, Author(s): Abhishek Kumar[sup.1,2,3], Nagarajan Paramasivam[sup.4], Obul Reddy Bandapalli[sup.1,5,6], Matthias Schlesner[sup.7], Tianhui Chen[sup.8], Rolf Sijmons[sup.9], Dagmara Dymerska[sup.10], Katarzyna Golebiewska[sup.10], Magdalena Kuswik[sup.10], Jan Lubinski[sup.10], Kari Hemminki[sup.1,11,12] and Asta Försti[sup.1,5,6] Background Familial cancer, [...]

Background Mutations in the BRCA1, BRCA2 and PALB2 genes are well-established risk factors for the development of breast and/or ovarian cancer. The frequency and spectrum of mutations in these genes has not yet been examined in the population of Southern Poland. Methods We examined the entire coding sequences of the BRCA1 and BRCA2 genes and genotyped a recurrent mutation of the PALB2 gene (c.509_510delGA) in 121 women with familial and/or early-onset breast or ovarian cancer from Southern Poland. Results A BRCA1 mutation was identified in 11 of 121 patients (9.1 %) and a BRCA2 mutation was identified in 10 of 121 patients (8.3 %). Two founder mutations of BRCA1 accounted for 91 % of all BRCA1 mutation carriers (c.5266dupC was identified in six patients and c.181 T > G was identified in four patients). Three of the seven different BRCA2 mutations were detected in two patients each (c.9371A > T, c.9403delC and c.1310_1313delAAGA). Three mutations have not been previously reported in the Polish population (BRCA1 c.3531delT, BRCA2 c.1310_1313delAAGA and BRCA2 c.9027delT). The recurrent PALB2 mutation c.509_510delGA was identified in two patients (1.7 %). Conclusions The standard panel of BRCA1 founder mutations is sufficiently sensitive for the identification of BRCA1 mutation carriers in Southern Poland. The BRCA2 mutations c.9371A > T and c.9403delC as well as the PALB2 mutation c.509_510delGA should be included in the testing panel for this population. Keywords: BRCA1, BRCA2, PALB2, Breast cancer, Ovarian cancer, Author(s): P. Wojcik[sup.1] , M. Jasiowka[sup.2] , E. Strycharz[sup.1] , M. Sobol[sup.1] , D. Hodorowicz-Zaniewska[sup.3] , P. Skotnicki[sup.4] , T. Byrski[sup.6] , P. Blecharz[sup.2] , E. Marczyk[sup.2] , I. Cedrych[sup.2] [...]