Background
Mutations of the BRCA2 gene are the most frequent alterations found in germline DNA from men with prostate cancer (PrCa), but clinical parameters that could better orientate for BRCA2 ...mutation screening need to be established.
Methods
Germline DNA from 325 PrCa patients (median age at diagnosis: 57 years old) was screened for BRCA2 mutation. The mutation frequency was compared between three subgroups: patients with an age at diagnosis at 55 years old and under (Group I); a personal or family history of breast, uterine or ovarian cancer (Group II); or a metastatic disease (Group III). Frequency of BRCA2 mutations was established for each combination of phenotypes, and compared between patients meeting or not the criteria for each subgroup using Fisher's exact test. Mutual information, direct effect, elasticity and contribution to the mutational status of each phenotype, taking into account overlap between subgroups, were also estimated using Bayesian algorithms.
Results
The proportion of BRCA2 mutation was 5.9% in Group I, 10.9% in Group II and 6.9% in Group III. The frequency of BRCA2 mutation was significantly higher among patients of Group II (p = .006), and reached 15.6% among patients of this group who presented a metastatic disease. Mutual information, direct effect, elasticity and contribution to the mutational status were the highest for phenotype II. Fifteen (71.4%) of the 21 BRCA2 mutation carriers had an aggressive form of the disease. Four (19%) of them died from PrCa after a median follow‐up duration of 64.5 months.
Conclusions
Our results showed that a higher frequency of BRCA2 mutation carriers is observed, not only among PrCa patients with young onset or a metastatic disease, but also with a personal or a familial history of breast cancer.
Aims
The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an ...adenomatous polyposis called MUTYH‐associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH.
Methods
Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma.
Results
The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis.
Conclusions
Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH.
Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MAP. Predisposition to other tumours in MAP patients is suspected but remains unclear. We report the first case of medulloblastoma in a MAP patient. The tumour presents a somatic mutation profile close to the mutational signature associated with MUTYH deficiency (SBS36), associated with driver pathogenic variants in well‐known genes involved in medulloblastoma tumorigenesis corresponding to G:C → T:A transversions. Therefore, medulloblastoma could be a rare manifestation associated with MAP.
Ataxia‐telangiectasia‐like disorder (ATLD) is a rare genomic instability syndrome caused by biallelic variants of MRE11 (meiotic recombination 11) characterized by progressive cerebellar ataxia and ...typical karyotype abnormalities. These symptoms are common to those of ataxia‐telangiectasia, which is consistent with the key role of MRE11 in ataxia‐telangiectasia mutated (ATM) activation after DNA double‐strand breaks. Three unrelated French patients were referred with ataxia. Only one had typical karyotype abnormalities. Unreported biallelic MRE11 variants were found in these three cases. Interestingly, one variant (c.424G>A) was present in two cases and haplotype analysis strongly suggested a French founder variant. Variants c.544G>A and c.314+4_314+7del lead to splice defects. The level of MRE11 in lymphoblastoid cell lines was consistently and dramatically reduced. Functional consequences were evaluated on activation of the ATM pathway via phosphorylation of ATM targets (KAP1 and CHK2), but no consistent defect was observed. However, an S‐phase checkpoint activation defect after camptothecin was observed in these patients with ATLD. In conclusion, we report the first three French ATLD patients and a French founder variant, and propose an S‐phase checkpoint activation study to evaluate the pathogenicity of MRE11 variants.
Ataxia‐Telangiectasia‐Like Disorder (ATLD) is a rare genomic instability syndrome caused by biallelic variants of MRE11 (meiotic recombination 11) characterized by progressive cerebellar ataxia. We describe the first three French patients with progressive cerebellar ataxia diagnosed with ATLD, associated with compound heterozygosity for unreported MRE11 variants. Functional consequences were evaluated on activation of the ataxia‐telangiectasia mutated (ATM) pathway via phosphorylation of ATM targets, but no consistent defect was observed. However, an S‐phase checkpoint activation defect after camptothecin was observed in these ATLD patients.
Genome-wide association studies (GWAS) explore the genetic causes of complex diseases. However, classical approaches ignore the biological context of the genetic variants and genes under study. To ...address this shortcoming, one can use biological networks, which model functional relationships, to search for functionally related susceptibility loci. Many such network methods exist, each arising from different mathematical frameworks, pre-processing steps, and assumptions about the network properties of the susceptibility mechanism. Unsurprisingly, this results in disparate solutions. To explore how to exploit these heterogeneous approaches, we selected six network methods and applied them to GENESIS, a nationwide French study on familial breast cancer. First, we verified that network methods recovered more interpretable results than a standard GWAS. We addressed the heterogeneity of their solutions by studying their overlap, computing what we called the consensus. The key gene in this consensus solution was COPS5, a gene related to multiple cancer hallmarks. Another issue we observed was that network methods were unstable, selecting very different genes on different subsamples of GENESIS. Therefore, we proposed a stable consensus solution formed by the 68 genes most consistently selected across multiple subsamples. This solution was also enriched in genes known to be associated with breast cancer susceptibility (BLM, CASP8, CASP10, DNAJC1, FGFR2, MRPS30, and SLC4A7, P-value = 3 × 10-4). The most connected gene was CUL3, a regulator of several genes linked to cancer progression. Lastly, we evaluated the biases of each method and the impact of their parameters on the outcome. In general, network methods preferred highly connected genes, even after random rewirings that stripped the connections of any biological meaning. In conclusion, we present the advantages of network-guided GWAS, characterize their shortcomings, and provide strategies to address them. To compute the consensus networks, implementations of all six methods are available at https://github.com/hclimente/gwas-tools.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Therapeutic strategies targeting Homologous Recombination Deficiency (HRD) in breast cancer requires patient stratification. The LST (Large‐scale State Transitions) genomic signature previously ...validated for triple‐negative breast carcinomas (TNBC) was evaluated as biomarker of HRD in luminal (hormone receptor positive) and HER2‐overexpressing (HER2+) tumors. The LST genomic signature related to the number of large‐scale chromosomal breakpoints in SNP‐array tumor profile was applied to identify HRD in in‐house and TCGA sets of breast tumors, in which the status of BRCA1/2 and other genes was also investigated. In the in‐house dataset, HRD was predicted in 5% (20/385) of sporadic tumors luminal or HER2+ by the LST genomic signature and the inactivation of BRCA1, BRCA2 or RAD51C confirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring in BRCA1/2 mutant carriers, the corresponding wild‐type allele was retained emphasizing the importance of determining the tumor status. In the TCGA luminal and HER2+ subtypes HRD incidence was estimated at 5% (18/329, 95%CI: 5–8%) and 2% (1/59, 95%CI: 2–9%), respectively. In TNBC cisplatin‐based neo‐adjuvant clinical trials, HRD is shown to be a necessary condition for cisplatin sensitivity. This analysis demonstrates the high performance of the LST genomic signature for HRD detection in breast cancers, which suggests its potential as a biomarker for genetic testing and patient stratification for clinical trials evaluating platinum salts and PARP inhibitors.
What's new?
The BRCA1/2 tumor suppressors play a key role in DNA repair by homologous recombination, and inactivation of these factors is associated with high breast and ovarian cancer risk. Here, the authors performed a comprehensive study of breast tumors screening for homologous recombination deficiency (HRD) measured by large‐scale chromosomal breaks. They find good overlap between HRD‐positivity and BRCA mutations, but also identify a small subset of HRD+ tumors in which the sole determination of BRCA1/2 mutational status is insufficient. This points to HRD determination as a potentially important method to find patients benefiting most from emerging new therapies such as PARP inhibitors.
The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity.
From 1,730 French patients ...suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation.
The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations.
The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.
Counseling for familial breast cancer focuses on communicating the gene test result (GENE) to counselees, but risk prediction models have become more complex by including non‐genetic risk factors ...(NGRF) and polygenic risk scores (PRS). We examined genetic clinicians' confidence in counseling and counselees' psychosocial outcomes, using the BOADICEA risk prediction tool with different categories of risk factors as input. A prospective observational study in Dutch, French and German genetic clinics was performed including 22 clinicians, and 406 of 460 (88.3%) eligible cancer‐unaffected women at high breast cancer risk assessed at pre‐test and 350 (76.1%) at post‐test. We performed multilevel analyses accounting for the clinician, and counselees' characteristics. Overall, risk estimates category by GENE versus GENE+ NGRF, or GENE+NGRF+PRS differed in 11% and 25% of counselees, respectively. In multilevel analyses, clinicians felt less confident in counseling when the full model provided lower breast cancer risks than GENE (i.e., in 8% of cases). Older counselees expressed higher breast cancer risk perception and worries about the hereditary predisposition when the full model provided higher breast cancer risks than GENE only. Genetic clinicians appear confident with breast cancer risk comprehensive models, which seem only to affect perceptions of older counselees.
BOADICEA breast cancer risk prediction models, genetic clinicians' confidence in risk communication and counselees' psychosocial outcomes.
In breast or ovarian cancer (BC/OC) patients with evocative personal and/or family history, multigene panel sequencing is performed on blood to diagnose hereditary predispositions. Additionally, ...BRCA1/BRCA2 testing can be performed on tumor sample for therapeutic purpose. The accuracy of multigene panel tumor analysis on BC/OC to detect predisposing germline pathogenic variants (gPV) has not been precisely assessed. By comparing sequencing data from blood and fresh‐frozen tumor we show that tumor genomic instability causes pitfalls to consider when performing tumor testing to detect gPV. Even if loss of heterozygosity increases germline signal in most cases, somatic copy number variants (CNV) can mask germline CNV and collapse point gPV variant allele frequency (VAF). Moreover, VAF does not allow an accurate distinction between germline and somatic pathogenic variants.
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