| 1. |
- Pilheden, M., et al.
(author)
-
Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A-rearranged Acute Leukemia
- 2022
-
In: Hemasphere. - : Ovid Technologies (Wolters Kluwer Health). - 2572-9241. ; 6:10
-
Journal article (peer-reviewed)abstract
- Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with KMT2A-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3(D835H) or NRAS(G13D/G12S) mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Kotsopoulos, J, et al.
(author)
-
Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers
- 2005
-
In: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 1573-7225 .- 0957-5243. ; 16:6, s. 667-674
-
Journal article (peer-reviewed)abstract
- Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman's age at menarche. A matched case-control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associated with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was <= 11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30-0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation.
|
|
| 5. |
- Winter, C, et al.
(author)
-
Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic
- 2016
-
In: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 27:8, s. 8-1532
-
Journal article (peer-reviewed)abstract
- BACKGROUND: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear.PATIENTS AND METHODS: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden.RESULTS: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years).CONCLUSIONS: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.
|
|
| 6. |
- Zardavas, Dimitrios, et al.
(author)
-
Tumor PIK3CA Genotype and Prognosis in Early-Stage Breast Cancer: A Pooled Analysis of Individual Patient Data
- 2018
-
In: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 36:10, s. 981-
-
Journal article (peer-reviewed)abstract
- PurposePhosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data.Patients and MethodsAssociations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes.ResultsData from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P amp;lt; .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P amp;lt; .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P amp;lt; .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); amp;gt; 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS (P = .043), but not for the DDFS and OS end points.ConclusionIn this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors. (C) 2018 by American Society of Clinical Oncology
|
|
| 7. |
- Saal, Lao, et al.
(author)
-
PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma
- 2005
-
In: Cancer Research. - 1538-7445. ; 65:7, s. 2554-2559
-
Journal article (peer-reviewed)abstract
- Deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway either through loss of PTEN or mutation of the catalytic subunit alpha of PI3K (PIK3CA) occurs frequently in human cancer. We identified PIK3CA mutations in 26% of 342 human breast tumor samples and cell lines at about equal frequency in tumor stages I to IV. To investigate the relationship between PTEN and PIK3CA, we generated a cohort of tumors that had lost PTEN expression and compared it with a matched control set that had retained PTEN. A highly significant association between PIK3CA mutations and retention of PTEN protein expression was observed. In addition, PIK3CA mutations were associated with expression of estrogen and progesterone receptors (ER/PR), lymph node metastasis, and ERBB2 overexpression. The fact that PIK3CA mutations and PTEN loss are nearly mutually exclusive implies that deregulated phosphatidylinositol-3,4,5-triphosphate WIN is critical for tumorigenesis in a significant fraction of breast cancers and that loss Of PIP3 homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting of the other gene. The correlation of PIK3CA mutation to ER/PR-positive tumors and PTEN loss to ER/PR-negative tumors argues for disparate branches of tumor evolution. Furthermore, the association between ERBB2 overexpression and PIK3CA mutation implies that more than one input activating the PI3K/AKT pathway may be required to overcome intact PTEN. Thus, mutation of PIK3CA is frequent, occurs early in carcinoma development, and has prognostic and therapeutic implications.
|
|
| 8. |
- Troein, Carl, et al.
(author)
-
An introduction to BASE
- 2006
-
In: Methods in Enzymology: DNA Microarrays, Part B: Databases and DNA Microarrays, Part B: Databases and statistics. - 0121828166 ; 411, s. 99-119
-
Book chapter (other academic/artistic)
|
|
