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  1. Article ; Online: Nuclei instance segmentation from histopathology images using Bayesian dropout based deep learning.

    Gudhe, Naga Raju / Kosma, Veli-Matti / Behravan, Hamid / Mannermaa, Arto

    BMC medical imaging

    2023  Volume 23, Issue 1, Page(s) 162

    Abstract: Background: The deterministic deep learning models have achieved state-of-the-art performance in various medical image analysis tasks, including nuclei segmentation from histopathology images. The deterministic models focus on improving the model ... ...

    Abstract Background: The deterministic deep learning models have achieved state-of-the-art performance in various medical image analysis tasks, including nuclei segmentation from histopathology images. The deterministic models focus on improving the model prediction accuracy without assessing the confidence in the predictions.
    Methods: We propose a semantic segmentation model using Bayesian representation to segment nuclei from the histopathology images and to further quantify the epistemic uncertainty. We employ Bayesian approximation with Monte-Carlo (MC) dropout during the inference time to estimate the model's prediction uncertainty.
    Results: We evaluate the performance of the proposed approach on the PanNuke dataset, which consists of 312 visual fields from 19 organ types. We compare the nuclei segmentation accuracy of our approach with that of a fully convolutional neural network, U-Net, SegNet, and the state-of-the-art Hover-net. We use F1-score and intersection over union (IoU) as the evaluation metrics. The proposed approach achieves a mean F1-score of 0.893 ± 0.008 and an IoU value of 0.868 ± 0.003 on the test set of the PanNuke dataset. These results outperform the Hover-net, which has a mean F1-score of 0.871 ± 0.010 and an IoU value of 0.840 ± 0.032.
    Conclusions: The proposed approach, which incorporates Bayesian representation and Monte-Carlo dropout, demonstrates superior performance in segmenting nuclei from histopathology images compared to existing models such as U-Net, SegNet, and Hover-net. By considering the epistemic uncertainty, our model provides a more reliable estimation of the prediction confidence. These findings highlight the potential of Bayesian deep learning for improving medical image analysis tasks and can contribute to the development of more accurate and reliable computer-aided diagnostic systems.
    MeSH term(s) Humans ; Deep Learning ; Image Processing, Computer-Assisted/methods ; Bayes Theorem ; Neural Networks, Computer ; Cell Nucleus
    Language English
    Publishing date 2023-10-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2061975-3
    ISSN 1471-2342 ; 1471-2342
    ISSN (online) 1471-2342
    ISSN 1471-2342
    DOI 10.1186/s12880-023-01121-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Malignant and in situ subtypes of melanoma are associated with basal and squamous cell carcinoma and its precancerous lesions

    Suhonen, Ville / Siiskonen, Hanna / Suni, Maunu / Rummukainen, Jaana / Mannermaa, Arto / Harvima, Ilkka T

    European journal of dermatology : EJD

    2022  Volume 32, Issue 2, Page(s) 187–194

    Abstract: Background: Patients with cutaneous malignant melanoma (CMM) are at increased risk of non-melanoma skin cancers (NMSCs) and possibly precancerous lesions.: Objectives: To analyse the association between CMM and not only NMSCs but also precursor ... ...

    Title translation Malignant and.
    Abstract Background: Patients with cutaneous malignant melanoma (CMM) are at increased risk of non-melanoma skin cancers (NMSCs) and possibly precancerous lesions.
    Objectives: To analyse the association between CMM and not only NMSCs but also precursor lesions, actinic keratosis (AK) and Bowen disease (BD).
    Materials & methods: The Finnish Cancer Registry data was used to calculate the age-standardized incidence ratio during 2000-2013 for basal (BCC) and squamous (SCC) cell carcinoma in patients with CMM. All tissue material collected from 70,420 subjects during 2000-2013 and reposited in the Biobank of Eastern Finland was used to calculate the age-standardized prevalence of BCC, SCC, BD and AK in CMM patients.
    Results: In both genders, the age-standardized incidence ratio of BCC and SCC was increased in CMM patients. The age-standardized prevalence of NMSCs and precursor lesions was higher in patients with CMM than in those without CMM, and was higher in CMM patients with immunosuppression (IS) than in those without IS. The association of M-Snomed subtypes, lentigo maligna (LM), melanoma in situ (MIS) and malignant melanoma (MM) with AK and/or BD was stronger than with BCC. LM revealed the highest association with the combination of AKBD-SCC. Male subjects showed a higher age-standardized prevalence of CMM, MM and BCC than females, but the opposite was observed for AK.
    Conclusion: Melanoma increases the risk of NMSCs, and IS may enhance this risk. Both malignant and in situ subtypes of melanoma associate with not only BCC and SCC, but also precancerous lesions.
    MeSH term(s) Bowen's Disease/complications ; Bowen's Disease/epidemiology ; Carcinoma, Basal Cell/pathology ; Carcinoma, Squamous Cell/pathology ; Female ; Humans ; Hutchinson's Melanotic Freckle ; Keratosis, Actinic/pathology ; Male ; Melanoma/pathology ; Skin Neoplasms/pathology ; Melanoma, Cutaneous Malignant
    Language English
    Publishing date 2022-07-22
    Publishing country France
    Document type Journal Article
    ZDB-ID 1128666-0
    ISSN 1952-4013 ; 1167-1122
    ISSN (online) 1952-4013
    ISSN 1167-1122
    DOI 10.1684/ejd.2022.4221
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Expression profiles of small non-coding RNAs in breast cancer tumors characterize clinicopathological features and show prognostic and predictive potential.

    Kärkkäinen, Emmi / Heikkinen, Sami / Tengström, Maria / Kosma, Veli-Matti / Mannermaa, Arto / Hartikainen, Jaana M

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 22614

    Abstract: Precision medicine approaches are required for more effective therapies for cancer. As small non-coding RNAs (sncRNAs) have recently been suggested as intriguing candidates for cancer biomarkers and have shown potential also as novel therapeutic targets, ...

    Abstract Precision medicine approaches are required for more effective therapies for cancer. As small non-coding RNAs (sncRNAs) have recently been suggested as intriguing candidates for cancer biomarkers and have shown potential also as novel therapeutic targets, we aimed at profiling the non-miRNA sncRNAs in a large sample set to evaluate their role in invasive breast cancer (BC). We used small RNA sequencing and 195 fresh-frozen invasive BC and 22 benign breast tissue samples to identify significant associations of small nucleolar RNAs, small nuclear RNAs, and miscellaneous RNAs with the clinicopathological features and patient outcome of BC. Ninety-six and five sncRNAs significantly distinguished (Padj < 0.01) invasive local BC from benign breast tissue and metastasized BC from invasive local BC, respectively. Furthermore, 69 sncRNAs significantly associated (Padj < 0.01) with the tumor grade, hormone receptor status, subtype, and/or tumor histology. Additionally, 42 sncRNAs were observed as candidates for prognostic markers and 29 for predictive markers for radiotherapy and/or tamoxifen response (P < 0.05). We discovered the clinical relevance of sncRNAs from each studied RNA type. By introducing new sncRNA biomarker candidates for invasive BC and validating the potential of previously described ones, we have guided the way for further research that is warranted for providing novel insights into BC biology.
    MeSH term(s) Humans ; Animals ; Female ; RNA, Small Untranslated/genetics ; RNA, Small Untranslated/metabolism ; Breast Neoplasms/genetics ; Prognosis ; Sequence Analysis, RNA ; Mammary Neoplasms, Animal
    Chemical Substances RNA, Small Untranslated
    Language English
    Publishing date 2022-12-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-26954-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: High Numbers of CD163+ Tumor-Associated Macrophages Predict Poor Prognosis in HER2+ Breast Cancer.

    Jääskeläinen, Minna M / Tumelius, Ritva / Hämäläinen, Kirsi / Rilla, Kirsi / Oikari, Sanna / Rönkä, Aino / Selander, Tuomas / Mannermaa, Arto / Tiainen, Satu / Auvinen, Päivi

    Cancers

    2024  Volume 16, Issue 3

    Abstract: Tumor-associated macrophages (TAMs) are associated with a poor outcome in breast cancer (BC), but their prognostic value in different BC subtypes has remained somewhat unclear. Here, we investigated the prognostic value of M2-like TAMs (CD163+) and all ... ...

    Abstract Tumor-associated macrophages (TAMs) are associated with a poor outcome in breast cancer (BC), but their prognostic value in different BC subtypes has remained somewhat unclear. Here, we investigated the prognostic value of M2-like TAMs (CD163+) and all TAMs (CD68+) in a patient cohort of 278 non-metastatic BC patients, half of whom were HER2+ (
    Language English
    Publishing date 2024-02-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers16030634
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: High Cell-Free DNA Integrity Is Associated with Poor Breast Cancer Survival.

    Lamminaho, Maria / Kujala, Jouni / Peltonen, Hanna / Tengström, Maria / Kosma, Veli-Matti / Mannermaa, Arto

    Cancers

    2021  Volume 13, Issue 18

    Abstract: Background: A recent point of focus in breast cancer (BC) research has been the utilization of cell-free DNA (cfDNA) and its concentration (cfDConc) and integrity (cfDI) as potential biomarkers. Though the association of cfDConc and poor survival is ... ...

    Abstract Background: A recent point of focus in breast cancer (BC) research has been the utilization of cell-free DNA (cfDNA) and its concentration (cfDConc) and integrity (cfDI) as potential biomarkers. Though the association of cfDConc and poor survival is already recognized, studies on the prognostic value of cfDI have had contradictory results. Here, we provide further evidence to support the use of cfDI as a potential biomarker.
    Methods: We selected 204 Eastern Finnish BC cases with non-metastatic disease and isolated cfDNA from the serum collected at the time of diagnosis before any treatment was given. The cfDConc and cfDI were measured with a fluorometer and electrophoresis and analyzed with 25 years of survival data.
    Results: High cfDConc was not an independent prognostic factor in our analyses while high cfDI was found to be an independent prognostic factor for poor OS (
    Conclusions: Our results show high cfDI is an independent prognostic factor for poor OS and BCSS and improves the predictive performance of logistic regression models, thus supporting its prognostic potential.
    Language English
    Publishing date 2021-09-18
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13184679
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: High regional mortality due to malignant melanoma in Eastern Finland may be explained by the increase in aggressive melanoma types.

    Suhonen, Ville / Rummukainen, Jaana / Siiskonen, Hanna / Mannermaa, Arto / Harvima, Ilkka T

    BMC cancer

    2021  Volume 21, Issue 1, Page(s) 1155

    Abstract: Background: A regional skin cancer prevention program in Eastern Finland revealed a relatively high age-standardized mortality due to malignant melanoma during 2013-2017. An explanation for this is needed.: Purpose: To analyse the 543 melanoma ... ...

    Abstract Background: A regional skin cancer prevention program in Eastern Finland revealed a relatively high age-standardized mortality due to malignant melanoma during 2013-2017. An explanation for this is needed.
    Purpose: To analyse the 543 melanoma samples in 524 subjects collected during 2000-2013 at Kuopio University Hospital and reposited in the Biobank of Eastern Finland. A focus was directed to factors related to metastasis.
    Methods: The samples were analysed anonymously by examining the histopathological report, referral text and the list of diagnoses. A possible state of immunosuppression was evaluated.
    Results: The mean age at the diagnosis of malignant melanoma (MM), lentigo maligna (LM) and melanoma in situ was relatively high, i.e., 66.2, 72.1 and 63.3, respectively. Especially the MM type increased markedly during 2000-2013. In further analyses of a representative cohort of 337 samples, the proportion of nodular melanoma and LM/LMM melanoma was relatively high, 35.6 and 22.0%, respectively, but that from superficial spreading melanoma relatively low (33.8%). Metastasis correlated with immunosuppression, male gender, Clark level, Breslow thickness, ulceration, mitosis count, invasion into vessels and/or perineural area, microsatellites, melanoma subtype, body site, recidivism, and the absence of dysplastic nevus cells.
    Conclusion: The marked increase in aggressive melanomas with associated metastasis, and the relatively high age at diagnosis, can partially explain the mortality.
    MeSH term(s) Age Factors ; Aged ; Female ; Finland/epidemiology ; Humans ; Hutchinson's Melanotic Freckle/mortality ; Hutchinson's Melanotic Freckle/pathology ; Immunocompromised Host ; Incidence ; Male ; Melanoma/mortality ; Melanoma/secondary ; Middle Aged ; Mitotic Index ; Neoplasm Invasiveness ; Sex Distribution ; Skin Neoplasms/mortality ; Skin Neoplasms/pathology
    Language English
    Publishing date 2021-10-29
    Publishing country England
    Document type Journal Article
    ZDB-ID 2041352-X
    ISSN 1471-2407 ; 1471-2407
    ISSN (online) 1471-2407
    ISSN 1471-2407
    DOI 10.1186/s12885-021-08879-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: The debatable presence of PIWI-interacting RNAs in invasive breast cancer.

    Kärkkäinen, Emmi / Heikkinen, Sami / Tengström, Maria / Kosma, Veli-Matti / Mannermaa, Arto / Hartikainen, Jaana M

    Cancer medicine

    2021  Volume 10, Issue 11, Page(s) 3593–3603

    Abstract: Numerous factors influence breast cancer (BC) prognosis, thus complicating the prediction of outcome. By identifying biomarkers that would distinguish the cases with poorer response to therapy already at the time of diagnosis, the rate of survival could ... ...

    Abstract Numerous factors influence breast cancer (BC) prognosis, thus complicating the prediction of outcome. By identifying biomarkers that would distinguish the cases with poorer response to therapy already at the time of diagnosis, the rate of survival could be improved. Lately, Piwi-interacting RNAs (piRNAs) have been introduced as potential cancer biomarkers, however, due to the recently raised challenges in piRNA annotations, further evaluation of piRNAs' involvement in cancer is required. We performed small RNA sequencing in 227 fresh-frozen breast tissue samples from the Eastern Finnish Kuopio Breast Cancer Project material to study the presence of piRNAs in BC and their associations with the clinicopathological features and outcome of BC patients. We observed the presence of three small RNAs annotated as piRNA database entries (DQ596932, DQ570994, and DQ571955) in our samples. The actual species of these RNAs however remain uncertain. All three small RNAs were upregulated in grade III tumors and DQ596932 additionally in estrogen receptor negative tumors. Furthermore, patients with estrogen receptor positive BC and higher DQ571955 had shorter relapse-free survival and poorer BC-specific survival, thus indicating DQ571955 as a candidate predictive marker for radiotherapy response in estrogen receptor positive BC. DQ596932 showed possible prognostic value in BC, whereas DQ570994 was identified as a candidate predictive marker for tamoxifen and chemotherapy response. These three small RNAs appear as candidate biomarkers for BC, which could after further investigation provide novel approaches for the treatment of therapy resistant BC. Overall, our results indicate that the prevalence of piRNAs in cancer is most likely not as comprehensive as has been previously thought.
    MeSH term(s) Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor/analysis ; Breast/chemistry ; Breast Neoplasms/chemistry ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Breast Neoplasms/therapy ; Disease-Free Survival ; Female ; Humans ; Neoplasm Grading ; Prognosis ; RNA, Small Interfering/analysis ; Radiotherapy ; Receptors, Estrogen/analysis ; Sequence Analysis, RNA ; Tamoxifen/therapeutic use ; Treatment Outcome ; Up-Regulation
    Chemical Substances Antineoplastic Agents ; Biomarkers, Tumor ; RNA, Small Interfering ; Receptors, Estrogen ; Tamoxifen (094ZI81Y45)
    Language English
    Publishing date 2021-05-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2659751-2
    ISSN 2045-7634 ; 2045-7634
    ISSN (online) 2045-7634
    ISSN 2045-7634
    DOI 10.1002/cam4.3915
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Circulating Cell-Free DNA Reflects the Clonal Evolution of Breast Cancer Tumors.

    Kujala, Jouni / Hartikainen, Jaana M / Tengström, Maria / Sironen, Reijo / Auvinen, Päivi / Kosma, Veli-Matti / Mannermaa, Arto

    Cancers

    2022  Volume 14, Issue 5

    Abstract: Liquid biopsy of cell-free DNA (cfDNA) is proposed as a potential method for the early detection of breast cancer (BC) metastases and following the clonal evolution of BC. Though the use of liquid biopsy is a widely discussed topic in the field, only a ... ...

    Abstract Liquid biopsy of cell-free DNA (cfDNA) is proposed as a potential method for the early detection of breast cancer (BC) metastases and following the clonal evolution of BC. Though the use of liquid biopsy is a widely discussed topic in the field, only a few studies have demonstrated such usage so far. We sequenced the DNA of matched primary tumor and metastatic sites together with the matched cfDNA samples from 18 Eastern Finnish BC patients and investigated how well cfDNA reflected the clonal evolution of BC interpreted from tumor DNA. On average, liquid biopsy detected 56.2 ± 7.2% of the somatic variants that were present either in the matched primary tumor or metastatic sites. Despite the high discordance observed between matched samples, liquid biopsy was found to reflect the clonal evolution of BC and identify novel driver variants and therapeutic targets absent from the tumor DNA. Tumor-specific somatic variants were detected in cfDNA at the time of diagnosis and 8.4 ± 2.4 months prior to detection of locoregional recurrence or distant metastases. Our results demonstrate that the sequencing of cfDNA may be used for the early detection of locoregional and distant BC metastases. Observed discordance between tumor DNA sequencing and liquid biopsy supports the parallel sequencing of cfDNA and tumor DNA to yield the most comprehensive overview for the genetic landscape of BC.
    Language English
    Publishing date 2022-03-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14051332
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Area-based breast percentage density estimation in mammograms using weight-adaptive multitask learning.

    Gudhe, Naga Raju / Behravan, Hamid / Sudah, Mazen / Okuma, Hidemi / Vanninen, Ritva / Kosma, Veli-Matti / Mannermaa, Arto

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 12060

    Abstract: Breast density, which is a measure of the relative amount of fibroglandular tissue within the breast area, is one of the most important breast cancer risk factors. Accurate segmentation of fibroglandular tissues and breast area is crucial for computing ... ...

    Abstract Breast density, which is a measure of the relative amount of fibroglandular tissue within the breast area, is one of the most important breast cancer risk factors. Accurate segmentation of fibroglandular tissues and breast area is crucial for computing the breast density. Semiautomatic and fully automatic computer-aided design tools have been developed to estimate the percentage of breast density in mammograms. However, the available approaches are usually limited to specific mammogram views and are inadequate for complete delineation of the pectoral muscle. These tools also perform poorly in cases of data variability and often require an experienced radiologist to adjust the segmentation threshold for fibroglandular tissue within the breast area. This study proposes a new deep learning architecture that automatically estimates the area-based breast percentage density from mammograms using a weight-adaptive multitask learning approach. The proposed approach simultaneously segments the breast and dense tissues and further estimates the breast percentage density. We evaluate the performance of the proposed model in both segmentation and density estimation on an independent evaluation set of 7500 craniocaudal and mediolateral oblique-view mammograms from Kuopio University Hospital, Finland. The proposed multitask segmentation approach outperforms and achieves average relative improvements of 2.88% and 9.78% in terms of F-score compared to the multitask U-net and a fully convolutional neural network, respectively. The estimated breast density values using our approach strongly correlate with radiologists' assessments with a Pearson's correlation of [Formula: see text] (95% confidence interval [0.89, 0.91]). We conclude that our approach greatly improves the segmentation accuracy of the breast area and dense tissues; thus, it can play a vital role in accurately computing the breast density. Our density estimation model considerably reduces the time and effort needed to estimate density values from mammograms by radiologists and therefore, decreases inter- and intra-reader variability.
    MeSH term(s) Breast/diagnostic imaging ; Breast Density ; Breast Neoplasms/diagnostic imaging ; Female ; Humans ; Image Processing, Computer-Assisted ; Mammography ; Neural Networks, Computer
    Language English
    Publishing date 2022-07-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-16141-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: High mutation burden of circulating cell-free DNA in early-stage breast cancer patients is associated with a poor relapse-free survival.

    Kujala, Jouni / Hartikainen, Jaana M / Tengström, Maria / Sironen, Reijo / Kosma, Veli-Matti / Mannermaa, Arto

    Cancer medicine

    2020  Volume 9, Issue 16, Page(s) 5922–5931

    Abstract: Background: High tumor mutation burden is shown to be associated with a poor clinical outcome. As the tumor-derived fraction of circulating cell-free DNA (cfDNA) is shown to reflect the genetic spectrum of the tumor, we examined whether the mutation ... ...

    Abstract Background: High tumor mutation burden is shown to be associated with a poor clinical outcome. As the tumor-derived fraction of circulating cell-free DNA (cfDNA) is shown to reflect the genetic spectrum of the tumor, we examined whether the mutation burden of cfDNA could be used to predict the clinical outcomes of early-stage breast cancer (BC) patients.
    Methods: We selected a set of 79 Finnish early-stage BC cases with a good prognosis based on traditional prognostic parameters but some of which still developed relapsed disease during follow-up. cfDNA was isolated from the serum collected at the time of diagnosis, sequenced, and compared to matched primary tumors, clinical parameters, and survival data.
    Results: High cfDNA mutation burden was associated with the poor relapse-free survival (RFS) (P = .016, HR = 2.23, 95% Cl 1.16-4.27) when patients were divided into high and low mutation burden according to the median number of somatic variants. A high discordance was observed between the matched tumor and cfDNA samples, thus highlighting the challenges related to the liquid biopsy of early-stage cancer cases. Despite the low number of detected tumor-specific variants, the presence of tumor-specific somatic variants in the cfDNA was associated with the poor RFS (P = .009, HR = 2.31, 95% Cl 1.23-4.31).
    Conclusions: Our results confirm previously observed challenges about the accuracy of liquid biopsy-based genotyping of early-stage cancers and support the parallel sequencing of tumor and cfDNA while also demonstrating how the presence of tumor-specific somatic variants and the high mutation burden in the cfDNA are both associated with the poor RFS, thus indicating the prognostic potential of liquid biopsy in the context of early-stage cancers.
    MeSH term(s) Adult ; Aged ; Breast Neoplasms/blood ; Breast Neoplasms/genetics ; Breast Neoplasms/mortality ; Breast Neoplasms/pathology ; Cell-Free Nucleic Acids/blood ; Cell-Free Nucleic Acids/genetics ; Circulating Tumor DNA/blood ; Circulating Tumor DNA/genetics ; Disease-Free Survival ; Female ; Finland ; Genotype ; Humans ; Liquid Biopsy ; Middle Aged ; Mutation ; Prognosis ; Sequence Analysis, DNA
    Chemical Substances Cell-Free Nucleic Acids ; Circulating Tumor DNA
    Language English
    Publishing date 2020-06-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2045-7634
    ISSN (online) 2045-7634
    DOI 10.1002/cam4.3258
    Database MEDical Literature Analysis and Retrieval System OnLINE

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