Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction

Bryan, Molly Scannell; Argos, Maria; Andrulis, Irene L.; Hopper, John L.; Chang‐Claude, Jenny; Malone, Kathleen E.; John, Esther M.; Gammon, Marilie D.; Daly, Mary B.; Terry, Mary Beth; Buys, Saundra S.; Huo, Dezheng; Olopade, O. I.; Genkinger, Jeanine M.; Jasmine, Farzana; Kibriya, Muhammad G.; Chen, Lin; Ahsan, Habibul

doi:10.1007/s10549-017-4287-4

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…In 2017, Bryan et al proved that no germline mutations were associated with the mortality rate and aggressive nature of EOBC [ 30 ], directing later research towards somatic and transcriptomic variations. Using The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, young age estrogen receptor-positive breast cancer patients (≤45 years) showed high mutational rate in CDH1 gene in comparison to older age patients (≥55 years) (14.5% vs. 2.9%).…”

Section: Somatic Mutationsmentioning

confidence: 99%

The Unique Biology behind the Early Onset of Breast Cancer

Siddig

Din

Nafi

et al. 2021

Genes

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Breast cancer commonly affects women of older age; however, in developing countries, up to 20% of breast cancer cases present in young women (younger than 40 years as defined by oncology literature). Breast cancer in young women is often defined to be aggressive in nature, usually of high histological grade at the time of diagnosis and negative for endocrine receptors with poor overall survival rate. Several researchers have attributed this aggressive nature to a hidden unique biology. However, findings in this aspect remain controversial. Thus, in this article, we aimed to review published work addressing somatic mutations, chromosome copy number variants, single nucleotide polymorphisms, differential gene expression, microRNAs and gene methylation profile of early-onset breast cancer, as well as its altered pathways resulting from those aberrations. Distinct biology behind early-onset of breast cancer was clear among estrogen receptor-positive and sporadic cases. However, further research is needed to determine and validate specific novel markers, which may help in customizing therapy for this group of patients.

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Section: Somatic Mutationsmentioning

confidence: 99%

The Unique Biology behind the Early Onset of Breast Cancer

Siddig

Din

Nafi

et al. 2021

Genes

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“…Less than 10% of breast cancer incidence among young women is attributable to heritable mutations in the BRCA1 or BRCA2 genes. Further, Bryan et al (2017) found no evidence that germline mutations are related to mortality or tumour aggressiveness among breast cancer patients under age 50 [21]. Neither the incidence nor worse outcomes seen in young breast cancer patients can be entirely explained by inherited mutations.…”

Section: Somatic Mutationsmentioning

confidence: 99%

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

et al. 2020

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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 youngonset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for youngonset 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.

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“…All three are expressed in normal breast tissue, and FGFR2 and NEK10 are reported as under-expressed in breast tumors when compared to normal breast tissue. Additionally, NEK10 is part of a gene-rich region on chromosome 3 that also includes SLC4A7 , which has previously been implicated in breast cancer risk,(7,35) and, as our recent work suggests, may be related to progesterone receptor status of the tumor,(36) suggesting that future research in the NEK10 region may further elucidate the mechanisms of breast cancer initiation.…”

Section: Discussionmentioning

confidence: 85%

Germline Variation and Breast Cancer Incidence: A Gene-Based Association Study and Whole-Genome Prediction of Early-Onset Breast Cancer

Bryan

Argos

Andrulis

et al. 2018

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established. To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset. Three gene regions were associated with breast cancer incidence: ( = 1.23 × 10; replication < 1.00 × 10), ( = 3.57 × 10; replication < 1.00 × 10), and ( = 5.49 × 10; replication < 1.00 × 10). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association ( < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614-0.659 compared with 0.601; 95% CI, 0.578-0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640-0.684). This research supports a role for variation within and in breast cancer incidence, and suggests as a novel risk locus. This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. .

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Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction

Cited by 4 publications

References 37 publications

The Unique Biology behind the Early Onset of Breast Cancer

The Unique Biology behind the Early Onset of Breast Cancer

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

Germline Variation and Breast Cancer Incidence: A Gene-Based Association Study and Whole-Genome Prediction of Early-Onset Breast Cancer

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