Somatic mutations in early onset luminal breast cancer

Encinas, Giselly; Sabelnykova, Veronica Y.; Lyra, Eduardo Carneiro de; Katayama, Maria Lúcia Hirata; Maistro, Simone; Valle, Pedro Wilson Mompean de Vasconcellos; Pereira, Gláucia Fernanda de Lima; Rodrigues, Livia Munhoz; Serio, Pedro Adolpho de Menezes Pacheco; Gouvêa, Ana Carolina Ribeiro Chaves de; Geyer, Felipe C.; Basso, Ricardo Alves; Pasini, Fátima Solange; Diz, Maria Del Pilar Esteves; Brentani, Maria Mitzi; Góes, João Carlos Guedes Sampaio; Chammas, Roger; Boutros, Paul C.; Folgueira, Maria Aparecida Azevedo Koike

doi:10.18632/oncotarget.25123

Cited by 29 publications

(37 citation statements)

References 84 publications

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“…Our study included 5 major subtypes of breast cancer in young women (less than 40) and to the best of our knowledge, this is so far the only comprehensive study of EOBC in Taiwanese women. Similar to the previous reports by other groups, somatic mutations in genes such as TP53 , PIK3CA and GATA3 are associated with EOBC [ 19 , 20 , 30 , 33 ], while high prevalences in somatic mutations were observed in certain genes such as KMT2C , FLG , MUC17 and ASPM in our cohort.…”

Section: Discussionsupporting

confidence: 92%

“…Although BRCA1 /2 or TP53 mutations among the family members have been reported as a risk factors of EOBC, our study was limited due to the lack of background genetic information of family members for comparison. Several other studies related to breast cancers did not solely focus on EOBC in particular [ 18 , 26 , 27 , 28 , 29 ], while studies with a focus on EOBC either analyzed a particular subtype or preselected genes, and the cohort may be too small and thus not representative [ 19 , 20 , 23 , 30 , 31 , 32 , 33 , 34 ]. Our study included 5 major subtypes of breast cancer in young women (less than 40) and to the best of our knowledge, this is so far the only comprehensive study of EOBC in Taiwanese women.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

Midha

Huang

Yang

et al. 2020

Cancers

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Early onset breast cancer (EOBC), diagnosed at age ~40 or younger, is associated with a poorer prognosis and higher mortality rate compared to breast cancer diagnosed at age 50 or older. EOBC poses a serious threat to public health and requires in-depth investigation. We studied a cohort comprising 90 Taiwanese female patients, aiming to unravel the underlying mechanisms of EOBC etiopathogenesis. Sequence data generated by whole-exome sequencing (WES) and whole-genome sequencing (WGS) from white blood cell (WBC)–tumor pairs were analyzed to identify somatic missense mutations, copy number variations (CNVs) and germline missense mutations. Similar to regular breast cancer, the key somatic mutation-susceptibility genes of EOBC include TP53 (40% prevalence), PIK3CA (37%), GATA3 (17%) and KMT2C (17%), which are frequently reported in breast cancer; however, the structural protein-coding genes MUC17 (19%), FLG (16%) and NEBL (11%) show a significantly higher prevalence in EOBC. Furthermore, the top 2 genes harboring EOBC germline mutations, MUC16 (19%) and KRT18 (19%), encode structural proteins. Compared to conventional breast cancer, an unexpectedly higher number of EOBC susceptibility genes encode structural proteins. We suspect that mutations in structural proteins may increase physical permeability to environmental hormones and carcinogens and cause breast cancer to occur at a young age.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

Midha

Huang

Yang

et al. 2020

Cancers

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“…Compared to elderly, postmenopausal patients, young breast cancer patients more often have a family history of malignancy, deleterious germline mutations in BRCA1/2 and other highly penetrant cancer predisposing genes, such as TP53, and they also present with more aggressive disease: poorly differentiated, HER2-positive or triple negative (TNBC) tumors (9). Breast cancer in the young has been associated with increased likeliness for metastases (10,11), with poor overall prognosis (10,12), even for stage I-II disease (1,13), while the underlying biology of tumors in this age group has seldom been described in a context other than inherited breast cancer predisposition (14).…”

mentioning

confidence: 99%

Tumor Mutational Patterns and Infiltrating Lymphocyte Density in Young and Elderly Patients With Breast Cancer

Nikolaidi

Kotoula

Koliou

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Age may pertain to different tumor genotype characteristics which may interfere with treatment efficacy and prognosis. We investigated the distribution and prognostic effect of mutations and tumor infiltrating lymphocyte (stromal TIL density) in young (≤35 years) and elderly (>65 years) early breast cancer patients. Materials and Methods: Paraffin tumor genotypes of all clinical subtypes from 345 patients were examined. Results: A total of 638 mutations were detected in 221 patients (64.1%). Compared to young, elderly patients presented with lower TIL density (p<0.

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“…33,34 The first such mutation was reported in early onset luminal breast cancer. 35 It was a nonsense mutation near the 5ʹ end of the coding region of the GRHL2 gene, p.E32*. This mutation is expected to be strongly pathogenic, as it completely abolishes the functionality of GRHL2 protein – a truncated protein would lack all the functional domains: transactivation domain, DNA-binding domain as well as dimerization domain.…”

Section: Somatic Mutations In Grainyhead-like Genes In Cancermentioning

confidence: 99%

“…36 It was proposed that this is possibly a driver mutation in this type of cancer. 35 However, this mutation occurs at a very low frequency of only 0.79% in breast cancer. 35…”

Section: Somatic Mutations In Grainyhead-like Genes In Cancermentioning

confidence: 99%

Grainyhead-like transcription factors in cancer – Focus on recent developments

Kotarba

Taracha-Wisniewska

Wilanowski

2020

Exp Biol Med (Maywood)

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The role of grainyhead-like transcription factors in cancer has been widely investigated by the scientific community. However, some of its aspects do not seem to be adequately appreciated, and these are the topic of our article. In addition to their well-documented role as tumor suppressors, in many cases the grainyhead-like proteins perform tumor-promoting functions, which make them potential drug targets. However, it is difficult to directly target transcription factors, which is why we recommend an alternative approach. The transcriptional transactivation activity of grainyhead-like transcription factors is regulated by phosphorylation, and protein kinases are much more feasible drug targets. Studying the phosphorylation of grainyhead-like proteins may thus allow to identify protein kinases regulating the activity of these factors, and design inhibitors of these kinases to indirectly regulate the activity of grainyhead-like transcription factors. There are many somatic mutations in the GRHL genes that occur during cancer development. These mutations are widely distributed across the GRHL loci, and these mutations are very rare. For this reason, they are unlikely to become targets of future therapies, nevertheless some of them may be driver mutations and studying them may provide important novel information about the regulation of functioning of the GRHL genes and proteins. Analogous information may be obtained by studying single nucleotide polymorphisms in GRHL genes that are associated with disease risk. Such polymorphisms may also prove useful in identifying individuals with an increased risk of a particular disease. Impact statement In the present article, we focus on relatively little appreciated aspects of involvement of the grainyhead-like (GRHL) transcription factors in cancer. These aspects are nevertheless very important for the functioning of GRHL proteins, as well as for cancer development. Some of the GRHL factors perform tumor-promoting functions in certain types of cancer, which makes them potential drug targets. Much information is available about somatic cancer mutations in the GRHL genes, yet there are very few analyses of these mutations in the scientific literature. The activity of GRHL transcription factors is controlled by phosphorylation, and we suggest that regulating their phosphorylation with specific protein kinases provides an alternative approach to modify the activity of GRHL proteins. Some single nucleotide polymorphisms (SNPs) in the GRHL genes are associated with disease risk. Studying such SNPs may yield new information about the functioning of GRHL genes and proteins, and may also allow to identify people with an increased risk of a particular disease.

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Somatic mutations in early onset luminal breast cancer

Cited by 29 publications

References 84 publications

Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients

Tumor Mutational Patterns and Infiltrating Lymphocyte Density in Young and Elderly Patients With Breast Cancer

Grainyhead-like transcription factors in cancer – Focus on recent developments

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