Disease Spectrum of Breast Cancer Susceptibility Genes

Wang, Jin; Singh, Preeti; Yin, Kanhua; Zhou, June; Bao, Yujia; Wu, Menghua; Pathak, Kush; McKinley, Sophia K.; Braun, Danielle; Hughes, Kevin S.

doi:10.3389/fonc.2021.663419

Cited by 6 publications

(6 citation statements)

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“…First, patients with HCS may develop late-onset malignancies due to low expressivity of a trait [ 33 ], which precludes suspicion of its inherited nature. Secondly, the spectrum of malignancies among affected individuals in the same family may vary [ 34 – 37 ]. Monogenic hereditary cancer syndromes are rarely limited to the development of only one tumor type but rather associated with a range of malignancies.…”

Section: Discussionmentioning

confidence: 99%

Incidental germline findings during molecular profiling of tumor tissues for precision oncology: molecular survey and methodological obstacles

Lebedeva

Shaykhutdinova²,

Seriak

et al. 2022

J Transl Med

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Background A fraction of patients referred for complex molecular profiling of biopsied tumors may harbor germline variants in genes associated with the development of hereditary cancer syndromes (HCS). Neither the bioinformatic analysis nor the reporting of such incidental germline findings are standardized. Methods Data from Next-Generation Sequencing (NGS) of biopsied tumor samples referred for complex molecular profiling were analyzed for germline variants in HCS-associated genes. Analysis of variant origin was performed employing bioinformatic algorithms followed by manual curation. When possible, the origin of the variant was validated by Sanger sequencing of the sample of normal tissue. The variants’ pathogenicity was assessed according to ACMG/AMP. Results Tumors were sampled from 183 patients (Males: 75 [41.0%]; Females: 108 [59.0%]; mean [SD] age, 57.7 [13.3] years) and analysed by targeted NGS. The most common tumor types were colorectal (19%), pancreatic (13%), and lung cancer (10%). A total of 56 sequence variants in genes associated with HCS were detected in 40 patients. Of them, 17 variants found in 14 patients were predicted to be of germline origin, with 6 variants interpreted as pathogenic (PV) or likely pathogenic (LPV), and 9 as variants of uncertain significance (VUS). For the 41 out of 42 (97%) missense variants in HCS-associated genes, the results of computational prediction of variant origin were concordant with that of experimental examination. We estimate that Sanger sequencing of a sample of normal tissue would be required for ~ 1–7% of the total assessed cases with PV or LPV, when necessity to follow with genetic counselling referral in ~ 2–15% of total assessed cases (PV, LPV or VUS found in HCS genes). Conclusion Incidental findings of pathogenic germline variants are common in data from cancer patients referred for complex molecular profiling. We propose an algorithm for the management of patients with newly detected variants in genes associated with HCS.

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Section: Discussionmentioning

confidence: 99%

Incidental germline findings during molecular profiling of tumor tissues for precision oncology: molecular survey and methodological obstacles

Lebedeva

Shaykhutdinova²,

Seriak

et al. 2022

J Transl Med

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“…The TMB was assessed by the local app as the ratio between the total somatic, non-synonymous variants with a variant allele frequency (VAF) > 0.05 and the sequenced genome for each sample, as reported here [ 17 ]. InterVar pipeline [ 18 ] and ClinVar significance [ 19 ] were used to assess the germline pathogenic variants in BC susceptibility genes [ 20 ]. The level of pathogenicity was annotated by using the ANNOVAR tool [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas

et al. 2022

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Background The “HER2-low” nomenclature identifies breast carcinomas (BCs) displaying a HER2 score of 1+/2+ in immunohistochemistry and lacking ERBB2 amplification. Whether HER2-low BCs (HLBCs) constitute a distinct entity is debated. Methods We performed DNA and RNA high-throughput analysis on 99 HLBC samples (n = 34 cases with HER2 score 1+/HLBC-1, n = 15 cases with HER2 score 2+ and ERBB2 not amplified/HLBC-2N, and n = 50 cases with score 2+ and ERBB2 copy number in the equivocal range/HLBC-2E). We compared the mutation rates with data from 1317 samples in the Memorial Sloan-Kettering Cancer Center (MSKCC) BC cohort and gene expression data with those from an internal cohort of HER2-negative and HER2-positive BCs. Results The most represented mutations affected PIK3CA (31/99, 31%), GATA3 (18/99, 18%), TP53 (17/99, 17%), and ERBB2 (8/99, 8%, private to HLBC-2E). Tumor mutational burden was significantly higher in HLBC-1 compared to HLBC-2E/N (P = 0.04). Comparison of mutation spectra revealed that HLBCs were different from both HER2-negative and HER2-positive BCs, with HLBC-1 resembling more HER2-negative tumors and HLBC-2 mutationally related to HER2-addicted tumors. Potentially actionable alterations (annotated by using OncoKB/ESCAT classes) affected 52 patients. Intra-group gene expression revealed overlapping features between HLBC-1 and control HER2-negative BCs, whereas the HLBC-2E tumors showed the highest diversity overall. The RNA-based class discovery analysis unveiled four subsets of tumors with (i) lymphocyte activation, (ii) unique enrichment in HER2-related features, (iii) stromal remodeling alterations, and (iv) actionability of PIK3CA mutations (LAURA classification). Conclusions HLBCs harbor distinct genomic features when compared with HER2-positive and HER2-negative BCs; however, differences across IHC classes were also unveiled thus dissecting the full picture of heterogeneity across HER2-low disease. The HLBC-2E category harbors most distinctive features, whereas HLBC-1 seems superimposable to HER2-negative disease. Further studies are needed to ascertain whether the four genomic-driver classes of the LAURA classification hold prognostic and/or predictive implications.

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“…Some genes have limited or yet insufficient evidence available concerning their association with cancer and the magnitude of the cancer risk. This classification is constantly evolving in reflection to the accumulated clinical evidence from different clinical resources towards a universal scientific agreement (16).…”

Section: Methodsmentioning

confidence: 99%

Revisiting the Implications of Positive Germline Testing Results Using Multi-gene Panels in Breast Cancer Patients

Tsaousis

Papadopoulou

Αγιαννιτόπουλος

et al. 2021

Cancer Genomics Proteomics

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Background/Aim: The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options. The aim of this study was to present data that demonstrate the different levels of actionability for multi-gene panels used in genetic testing of breast cancer patients and their family members. Materials and Methods:We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing. We reviewed positive results in respect of risk estimation and management, cascade family testing, secondary findings and information for treatment decision-making. Results: A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high, moderate, low and with insufficient evidence for breast cancer risk genes, respectively. Six point seven percent of 60 This article is freely accessible online.

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Disease Spectrum of Breast Cancer Susceptibility Genes

Cited by 6 publications

References 50 publications

Incidental germline findings during molecular profiling of tumor tissues for precision oncology: molecular survey and methodological obstacles

Incidental germline findings during molecular profiling of tumor tissues for precision oncology: molecular survey and methodological obstacles

Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas

Revisiting the Implications of Positive Germline Testing Results Using Multi-gene Panels in Breast Cancer Patients

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