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Mutational landscape differences between young-onset and older-onset breast cancer patients.

ABSTRACT: BACKGROUND:The incidence of breast cancer among young women (aged ?40?years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. METHODS:In this study we characterized the mutational landscape of 89 young-onset breast tumours (?40?years) and examined differences with 949 older-onset tumours (>?40?years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages "deconstructSigs" and "SomaticSignatures" to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. RESULTS:Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young-onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young-onset tumours, and a higher proportion of these mutations were C?>?A mutations, but a lower proportion were C?>?T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. Signatures resembling COSMIC signatures 2 and 13 were observed among both age groups. We identified a class of tumours with a unique combination of signatures that may be associated with young age of onset. CONCLUSIONS:The results of this exploratory study provide some evidence that the mutational landscape and mutational signatures among young-onset breast cancer are different from those of older-onset patients. The characterization of young-onset tumours could provide clues to their etiology which may inform future prevention. Further studies are required to confirm our findings.

SUBMITTER: Mealey NE

PROVIDER: S-EPMC7068998 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Mutational landscape differences between young-onset and older-onset breast cancer patients.

Mealey Nicole E NE O'Sullivan Dylan E DE Pader Joy J Ruan Yibing Y Wang Edwin E Quan May Lynn ML Brenner Darren R DR

BMC cancer 20200312 1

<h4>Background</h4>The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours.<h4>Methods</h4>In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined di ...[more]

PMID: 32164620

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Project description:BackgroundAround 5%-7% of breast cancer cases are diagnosed in women younger than 40, making it the leading cause of female cancer in the 25- to 39-year-old age group. Unfortunately, young age at diagnosis is linked to a more aggressive tumor biology and a worse clinical outcome. The identification of the mutational landscape of breast cancer in this age group could optimize the management.MethodsWe performed NGS analysis in paraffin blocks and blood samples of 32 young patients with breast cancer [<40 years] and 90 older patients during the period 2019 through 2021. All patients were treated in a single institution at the Oncology Department of "Alexandra" Hospital, Medical School, University of Athens, Greece.ResultsBreast tumors were characterized more frequently by HER2 overexpression [25% vs 18.9%], higher ki67 levels [75% vs 61%] and lower differentiation [71.9% vs 60%] in the younger group. PIK3CA [6/20; 30%] and TP53 [6/20; 30%] were the most frequent pathogenic somatic mutations identified in young patients, while one case of BRCA2 somatic mutation [1/20; 5%] and one case of PTEN somatic mutation [1/20; 5%] were also identified. PIK3CA mutations [16/50; 32%] and TP53 mutations [20/50; 40%] were the most common somatic mutations identified in older patients, however other somatic mutations were also reported (ATM, AKT, CHEK2, NRAS, CDKN2A, PTEN, NF1, RB1, FGFR1, ERBB2). As for germline mutations, CHEK2 [3/25; 12%] was the most common pathogenic germline mutation in younger patients followed by BRCA1 [2/25; 8%]. Of note, CHEK2 germline mutations were identified less frequently in older patients [2/61; 3%] among others [BRCA1 (2/61; 3%), ATM (2/61; 3%), APC (1/61; 1,6%) and BRCA2 (1/61; 1,6%)].ConclusionWe here report the mutational profile identified via NGS in patients with early-onset breast cancer compared to their older counterparts. Although the sample size is small and no statistically significant differences were detected, we highlight the need of genetic testing to most patients in this subgroup.

Project description:BackgroundGenetic testing for breast cancer (BC) patients may shift the paradigm towards more personalized management and treatment strategies. While gene alterations may be ethnic-specific in breast cancer, our understanding of genetic epidemiology of BC remains mainly driven by data from Caucasian populations and further limited to selected handful of genes.MethodsWe collected whole blood samples from 356 BC patients at metastatic first line BC and primary stage IV disease at Beijing Cancer Hospital between Jan. 2013 to Dec. 2019. A comprehensive 600-gene cancer panel was used to detect germline variants in the covered genes with a median 300x sequencing depth. Variants were classified into pathogenic, likely pathogenic, variant of uncertain significance, likely benign and benign groups according to the ACMG/AMP Standards and Guidelines. Pathogenic and likely pathogenic variants were considered as deleterious mutations.ResultsThe median age of 356 BC patients was 49 years (range, 21-87 years) at the first diagnosis of BC. Deleterious germline mutations across 48 cancer-related genes were identified in 21.6% (77/356) of the patients. The most prevalent mutations were BRCA1/2 mutations (7.0%), followed by ATM and RAD50 mutations (1.4% each). In addition, patients with family history were more likely to carry BRCA1 mutations (P=0.04). Moreover, patients with triple-negative breast cancer (TNBC) were more likely to harbor BRCA1 mutations than those with HR+ or HER2+ breast cancer (P=0.006). While there was no significant survival difference observed in BRCA1/2 carriers relative to non-carriers, patients with DNA damage repair (DDR) gene mutations (mostly frequently BRCA, ATM, RAD50) had worse disease-free survival (P=0.02).ConclusionsThe most prevalent germline mutations in a large cohort of Chinese patients with advanced BC were BRCA1/2 mutations, followed by ATM and RAD50 mutations. In total, approximately 16.0% (57/356) of patients carry deleterious mutations in DDR pathway. Patients with breast or ovarian cancer family history were more likely to carry BRCA1/2 mutations, and ones with DDR mutations had worse survival. These findings suggest that DDR mutations are prevalent in Chinese BC patients who may potentially benefit from treatment with Poly (ADP-ribose) polymerase inhibitors.

Project description:This study represents the first attempt to perform a profiling analysis of the intergenerational differences in the microRNAs (miRNAs) of melanocytic neoplasms in young adult and older adult groups. Our comparative miRNA profiling provides a novel characterization of the miRnomes of melanocytic neoplasms and melanomas of different age groups and identifies a set of potential diagnostic and potential clinico-pathologic biomarkers that may serve as targets for development of novel miR-based modalities in cancer diagnosis and treatment. An exploratory miRNA analysis of 666 miRs was conducted on formalin fixed and paraffin embedded tissues from 10 adults and 10 young adults including conventional melanoma and melanocytic neoplasms of uncertain biological significance. Age-matched benign melanocytic nevi were used as controls. The comparative profiling was intentionally performed at two extremes of age, i.e., less than 30 years (Mel 30) and greater than 60 years (Mel 60). Primary melanoma in patients greater than 60 years old was characterized by the increased expression of miRs regulating TLR-MyD88-NF-kappaB pathway (hsa-miR -199a), RAS/RAB22A pathway (hsa-miR-204); growth differentiation and migration (hsa-miR337), epithelial mesenchymal transition EMT (let-7b, hsa-miR-10b/10bSTAR(*)), invasion and metastasis (hsa-miR-10b/10bSTAR(*), hsa-miR-30a/e*, hsa-miR-29c*; cellular matrix components (hsa-miR-29c*); invasion-cytokinesis (hsa-miR 99b*) compared to melanoma of younger patients. miR 211 was dramatically downregulated in primary melanoma compared to nevi controls, decreased with increasing age and was among the miRs linked to metastatic processes and potentially targeting the inflammatory receptor CCR10; Primary melanoma in young adult patients was characterized by the increased expression of hsa-miR-449a and decreased expression of hsa-miR146b, hsa-miR 214*. Among the miRs expressed at higher levels in control nevi, compared to adult or young adult melanoma, was hsa-miR 574-3p. Only 2 miRs distinguished adult from young adult-pediatric nevi, hsa-miR374a* and has-miR-566. MiR 30a* appeared to be a strong marker of differentiation in clinical stages I-II adult and pediatric melanoma, and could predict classification of melanoma tissue in the two age groups. Furthermore, lymph node status in the two age groups was characterized by the statistically significant expression of hsa-miR-30a* and hsa-miR-204 (F-test, p-value <0.001).

Project description:Whole-genome sequencing provides a powerful tool to obtain more genetic variability that could produce a range of benefits for cattle breeding industry. Nanyang (Bos indicus) and Qinchuan (Bos taurus) are two important Chinese indigenous cattle breeds with distinct phenotypes. To identify the genetic characteristics responsible for variation in phenotypes between the two breeds, in the present study, we for the first time sequenced the genomes of four Nanyang and four Qinchuan cattle with 10 to 12 fold on average of 97.86% and 98.98% coverage of genomes, respectively. Comparison with the Bos_taurus_UMD_3.1 reference assembly yielded 9,010,096 SNPs for Nanyang, and 6,965,062 for Qinchuan cattle, 51% and 29% of which were novel SNPs, respectively. A total of 154,934 and 115,032 small indels (1 to 3 bp) were found in the Nanyang and Qinchuan genomes, respectively. The SNP and indel distribution revealed that Nanyang showed a genetically high diversity as compared to Qinchuan cattle. Furthermore, a total of 2,907 putative cases of copy number variation (CNV) were identified by aligning Nanyang to Qinchuan genome, 783 of which (27%) encompassed the coding regions of 495 functional genes. The gene ontology (GO) analysis revealed that many CNV genes were enriched in the immune system and environment adaptability. Among several CNV genes related to lipid transport and fat metabolism, Lepin receptor gene (LEPR) overlapping with CNV_1815 showed remarkably higher copy number in Qinchuan than Nanyang (log2 (ratio) = -2.34988; P value = 1.53E-102). Further qPCR and association analysis investigated that the copy number of the LEPR gene presented positive correlations with transcriptional expression and phenotypic traits, suggesting the LEPR CNV may contribute to the higher fat deposition in muscles of Qinchuan cattle. Our findings provide evidence that the distinct phenotypes of Nanyang and Qinchuan breeds may be due to the different genetic variations including SNPs, indels and CNV.

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Mutational landscape differences between young-onset and older-onset breast cancer patients.

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Mutational landscape differences between young-onset and older-onset breast cancer patients.

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