Cancer Research and Treatment

Original Articles

Breast cancer

Genomic Signatures from Clinical Tumor Sequencing in Patients with Breast Cancer Having Germline BRCA1/2 Mutation: Ju Won Kim, Hyo Eun Kang, Jimi Choi, Seung Gyu Yun, Seung Pil Jung, Soo Yeon Bae, Ji Young You, Yoon-Ji Choi, Yeul Hong Kim, Kyong Hwa Park; Cancer Res Treat. 2023;55(1):155-166. Published online June 8, 2022; DOI: https://doi.org/10.4143/crt.2021.1567

Abstract PDF Supplementary Material PubReader ePub

Purpose
BRCA1 and BRCA2 are among the most important genes involved in DNA repair via homologous recombination (HR). Germline BRCA1/2 (gBRCA1/2)-related cancers have specific characteristics and treatment options but conducting gBRCA1/2 testing and interpreting the genetic imprint are sometimes complicated. Here, we describe the concordance of gBRCA1/2 derived from a panel of clinical tumor tissues using next-generation sequencing (NGS) and genetic aspects of tumors harboring gBRCA1/2 pathogenic variants.
Materials and Methods
Targeted sequencing was performed using available tumor tissue from patients who underwent gBRCA1/2 testing. Comparative genomic analysis was performed according to gBRCA1/2 pathogenicity.
Results
A total of 321 patients who underwent gBRCA1/2 testing were screened, and 26 patients with gBRCA1/2 pathogenic (gBRCA1/2p) variants, eight patients with gBRCA1/2 variants of uncertain significance (VUS; gBRCA1/2v), and 43 patients with gBRCA1/2 wild-type (gBRCA1/2w) were included in analysis. Mutations in TP53 (49.4%) and PIK3CA (23.4%) were frequently detected in all samples. The number of single-nucleotide variants (SNVs) per tumor tissue was higher in the gBRCA1/2w group than that in the gBRCA1/2p group (14.81 vs. 18.86, p=0.278). Tumor mutation burden (TMB) was significantly higher in the gBRCA1/2w group than in the gBRCA1/2p group (10.21 vs. 13.47, p=0.017). Except for BRCA1/2, other HR-related genes were frequently mutated in patients with gBRCA1/2w.
Conclusion
We demonstrated high sensitivity of gBRCA1/2 in tumors analyzed by NGS using a panel of tumor tissues. TMB value and aberration of non-BRCA1/2 HR-related genes differed significantly according to gBRCA1/2 pathogenicity in patients with breast cancer.

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Clinico-Pathological Factors Determining Recurrence of Phyllodes Tumors of the Breast: The 25-Year Experience at a Tertiary Cancer Centre
Baijaeek Sain, Arnab Gupta, Aruni Ghose, Sudip Halder, Vishal Mukherjee, Samir Bhattacharya, Radha Raman Mondal, Aditya Narayan Sen, Bijan Saha, Shravasti Roy, Stergios Boussios
Journal of Personalized Medicine.2023; 13(5): 866. CrossRef

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Gynecologic cancer

Uptake of Family-Specific Mutation Genetic Testing Among Relatives of Patients with Ovarian Cancer with BRCA1 or BRCA2 Mutation: Go Woon Jeong, Wonkyo Shin, Dong Ock Lee, Sang-Soo Seo, Sokbom Kang, Sang-Yoon Park, Myong Cheol Lim; Cancer Res Treat. 2021;53(1):207-211. Published online August 11, 2020; DOI: https://doi.org/10.4143/crt.2020.364

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Purpose
The BRCA1 or BRCA2 gene is transmitted in an autosomal dominant fashion, and genetic testing of first-degree relatives of patients with family-specific mutation (FSM) is recommended. This study examined factors affecting the uptake of FSM testing among relatives of patients with peritoneal, ovarian, or fallopian tube (POFT) cancer with confirmed BRCA1 or BRCA2 germline mutation.
Materials and Methods
Data from medical charts of 392 eligible patients and their relatives who had undergone outpatient genetic counseling/testing were retrospectively reviewed. Clinical factors were compared between family members who had and had not undergone genetic counseling/testing.
Results
The uptake of FSM testing was 30.5% (129/423) among first-degree living relatives and 53.5% (69/129) within the overall family unit. The average time from genetic testing of the proband to the first FSM test within a family was 168 days (range, 23 to 681 days). Having a living father (33.8% vs. 13.3%, p=0.007) and daughter (79.4% vs. 60.3%, p=0.019) increased the uptake of FSM testing. FSM testing was more likely among female than among male relatives of cancer patients (40.9% vs. 17.6%, p < 0.001).
Conclusion
Approximately one-third of first-degree relatives of patients with a POFT cancer with BRCA1 or BRCA2 mutation underwent FSM testing. Having a living father or daughter was a factor affecting the uptake of FSM testing, which was higher among female than among male relatives of the proband. This discrepancy might be due to a misconception that the BRCA gene is associated with women rather than with men.

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Cascade testing in Italian Hereditary Breast Ovarian Cancer families: a missed opportunity for cancer prevention?
Lucia Trevisan, Lea Godino, Linda Battistuzzi, Giovanni Innella, Elena Luppi, Giulia Buzzatti, Viviana Gismondi, Eva Blondeaux, Luigina Ada Bonelli, Daniela Turchetti, Liliana Varesco
Familial Cancer.2024; 23(2): 197. CrossRef
Cancer burden in individuals with single versus double pathogenic variants in cancer susceptibility genes
Nihat B. Agaoglu, Brittany L. Bychkovsky, Carolyn Horton, Min-Tzu Lo, Linda Polfus, Cassidy Carraway, Parichehr Hemyari, Colin Young, Marcy E. Richardson, Rochelle Scheib, Judy E. Garber, Huma Q. Rana
Genetics in Medicine Open.2024; 2: 101829. CrossRef
Streamlined Genetic Education and Cascade Testing in Men from Hereditary Breast Ovarian Cancer Families: A Randomized Trial
Christopher Grisham, Beth N. Peshkin, Lia Sorgen, Claudine Isaacs, Mary Kathleen Ladd, Aryana Jacobs, Savannah Binion, Mara Tynan, Emily Kuchinsky, Susan Friedman, Kathryn L. Taylor, Kristi Graves, Suzanne O’Neill, David Kim, Marc D. Schwartz
Public Health Genomics.2024; 27(1): 100. CrossRef
Uptake of Cascade Genetic Testing for Hereditary Breast and Ovarian Cancer: A Systematic Review and Meta-Analysis
Muhammad Danyal Ahsan, Isabelle R. Chandler, Samantha Min, Benjamin Grant, Michelle Primiano, Jamieson Greenwald, Tamar N. Soussana, Becky Baltich Nelson, Charlene Thomas, Eloise Chapman-Davis, Ravi N. Sharaf, Melissa K. Frey
Clinical Obstetrics & Gynecology.2024; 67(4): 702. CrossRef
Prevalence and spectrum of pathogenic variants among patients with multiple primary cancers evaluated by clinical characteristics
Brittany L. Bychkovsky, Min‐Tzu Lo, Amal Yussuf, Carrie Horton, Marcy Richardson, Holly LaDuca, Judy E. Garber, Huma Q. Rana
Cancer.2022; 128(6): 1275. CrossRef
Health equity in the implementation of genomics and precision medicine: A public health imperative
Muin J. Khoury, Scott Bowen, W. David Dotson, Emily Drzymalla, Ridgely F. Green, Robert Goldstein, Katherine Kolor, Leandris C. Liburd, Laurence S. Sperling, Rebecca Bunnell
Genetics in Medicine.2022; 24(8): 1630. CrossRef
Cascade Testing for Hereditary Cancer Syndromes: Should We Move Toward Direct Relative Contact? A Systematic Review and Meta-Analysis
Melissa K. Frey, Muhammad Danyal Ahsan, Hannah Bergeron, Jenny Lin, Xuan Li, Rana K. Fowlkes, Priyanka Narayan, Roni Nitecki, Jose Alejandro Rauh-Hain, Haley A. Moss, Becky Baltich Nelson, Charlene Thomas, Paul J. Christos, Jada G. Hamilton, Eloise Chapma
Journal of Clinical Oncology.2022; 40(35): 4129. CrossRef
Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care—Checking CHEK2
Brittany L. Bychkovsky, Nihat B. Agaoglu, Carolyn Horton, Jing Zhou, Amal Yussuf, Parichehr Hemyari, Marcy E. Richardson, Colin Young, Holly LaDuca, Deborah L. McGuinness, Rochelle Scheib, Judy E. Garber, Huma Q. Rana
JAMA Oncology.2022; 8(11): 1598. CrossRef

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Case Report

Novel Germline Mutation of BRCA1 Gene in a 56-Year-Old Woman with Breast Cancer, Ovarian Cancer, and Diffuse Large B-Cell Lymphoma: Hye Sook Kim, Soon Wook Lee, Yoon Ji Choi, Sang Won Shin, Yeul Hong Kim, Min Sun Cho, Soon Nam Lee, Kyong Hwa Park; Cancer Res Treat. 2015;47(3):534-538. Published online October 17, 2014; DOI: https://doi.org/10.4143/crt.2013.151

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We report a case of a 56-year-old woman with breast cancer, ovarian cancer, and diffuse large B-cell lymphoma with a BRCA1 gene mutation. Evidence is mounting that there is a large increase in the risk for hematologic malignancies among patients with genetic changes in the BRCA pathways. The genomic analysis demonstrated a frameshift mutation in the BRCA1 gene: 277_279delinsCC (Phe93fs). It is a novel BRCA1 mutation that has never been reported, and caused malignant lymphoma as well as breast and ovarian cancer.

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An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers
Ewa Przybytkowski, Thomas Davis, Abdelrahman Hosny, Julia Eismann, Ursula A. Matulonis, Gerburg M. Wulf, Sheida Nabavi
BMC Cancer.2020;[Epub] CrossRef
Lymphoma in Australian Border Collies: survey results and pedigree analyses
KY Cheng, PXY Soh, PF Bennett, P Williamson
Australian Veterinary Journal.2019; 97(1-2): 14. CrossRef
Germline mutations predisposing to diffuse large B-cell lymphoma
O C Leeksma, N F de Miranda, H Veelken
Blood Cancer Journal.2017; 7(2): e532. CrossRef
Genetic testing and counseling of a recipient after bone marrow transplant from a sibling harboring a germline BRCA1 pathogenic mutation
Petra Škerl, Mateja Krajc, Ana Blatnik, Srdjan Novaković
Oncology Reports.2017; 38(1): 279. CrossRef
Risk of lymphoma subtypes by occupational exposure in Southern Italy
Giovanni Maria Ferri, Giorgina Specchia, Patrizio Mazza, Giuseppe Ingravallo, Graziana Intranuovo, Chiara Monica Guastadisegno, Maria Luisa Congedo, Gianfranco Lagioia, Maria Cristina Loparco, Annamaria Giordano, Tommasina Perrone, Francesco Guadio, Cater
Journal of Occupational Medicine and Toxicology.2017;[Epub] CrossRef
How breast cancer chemotherapy increases the risk of leukemia: Thoughts about a case of diffuse large B-cell lymphoma and leukemia after breast cancer chemotherapy
Bin Zhang, Xia Zhang, Minghuan Li, Li Kong, Xiaoqin Deng, Jinming Yu
Cancer Biology & Therapy.2016; 17(2): 125. CrossRef
Germline Mutations of BRCA1 and BRCA2 in Korean Ovarian Cancer Patients Finding Founder Mutations
Min Chul Choi, Jin-Hyung Heo, Ja-Hyun Jang, Sang Geun Jung, Hyun Park, Won Duk Joo, Chan Lee, Je Ho Lee, Jun Mo Lee, Yoon Young Hwang, Seung Jo Kim
International Journal of Gynecological Cancer.2015; 25(8): 1386. CrossRef

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Original Articles

Flow Cytometric Analysis of BRCA1 Protein in Sporadic Breast Cancer: Seung Moo Lee, Kyung Soon Sons, Hee Dae Lee; J Korean Cancer Assoc. 1998;30(4):701-710.

Abstract PDF: PURPOSE
To study the subcellular localization with flow-cytometry and to evaluate their prognostic values.
MATERIALS AND METHODS
The breast tissues were obtained from 28 patients with breast cancer and 6 patients with benign mass. The expression of BRCA1 protein was analyzed with the flow cytometry(Coulter Epics-XL, Coulter Corps, FL, USA) using the monoclonal antibody(BRCA1(Ab-1), Calbiochem, MA, USA) before and after nuclear and cytoplasmic permeabilization in association with DNA ploidy analysis. Several BRCA1 protein indices were derived including 95 percentile channel fluorescence(95% CF) and mean channel fluorescence(MCF) and percentage of BRCA 1 positive cell population arbitarily defined as those above 0.12 channel fluorescence.
RESULTS
Cytoplasmic 95% CF were higher in breast cancer(n=28, 0.65+/-0.26) than in benign mass(n=6, 0.40+/-0.13, p=0.0211). Cytoplasmic BRCAl positive cell percentages were significantly higher in malignant tissues(24.0+/-10.3) than in benign mass(43.4+/-15.2, p=0.0059). Cytoplasmic BRCA1 positive cell percentages were significantly different according to the stages(stage I vs II, 32.6+/-9.8 vs 48.3+/-18.8, p=0.048, stage I vs stage III, 32.6+/-9.8 vs 47.0+/-10.9, p=0.010). The BRCA1 protein indices were not significantly correlated with histologic grades and DNA indices(aneuploidy, S phase and proliferation fractions).
CONCLUSIONS
Flowcytometric assay offers an alternative approach to evaluating BRCA1 protein status of breast cancer tissue and detection of cytoplasmic BRCA1 protein by this method may help to understand the role of BRCA1 in breast cancer cell biology. The further study on cytoplasmic or nuclear BRCA1 protein in association with clinical therapeutic response or prognosis seems to be warranted.

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Germline Mutation of BRCA2 Gene in Korean Breast / Ovarian Cancer Families: Yong Jin Won, Jae Hwan Oh, Ji Hyun Kim, Dong Young Noh, Kuk Jin Choe, Soon Beom Kang, Lee Su Kim, Man Su Ro, Nam Sun Paik, Dae Hyun Yang, Se Min Oh, Soon Nam Lee, Kyung Kook Kim, Jae Gahb Park; J Korean Cancer Assoc. 1998;30(2):242-252.

Abstract PDF: PURPOSE
Recent discovery of BRCA1 and BRCA2 genes has made it possible to perform presymptomatic diagnosis in hereditary breast/ovarian cancer families. We have previously reported germline mutations of the BRCA1 gene in Korean hereditary breast/ovarian cancer families. In that study two out of 13 families were found to have germline mutations in BRCA1 gene. One was a nonsense mutation in codon 1815, and the other was a frameshift mutation due to 2 base-pair deletion in codon 1701 of BRCA1 gene. This study was intended to identify germline mutations of the BRCA2 gene in Korean breast/ovarian cancer families.
MATERIALS AND METHODS
Peripheral blood DNA was obtained from 10 breast cancer patients registered at the Korean Hereditary Tumor Registry with positive family history of breast and/or ovarian cancer. Exons 11 and 27 of the BRCA2 gene(together accounting for 50% of the coding region of the BRCA2 gene) were amplified by polymerase chain reaction(PCR) and screened for mutations by in vitro transcription/translation method. For confirmation of the mutations, automatic sequencing of the PCR products displaying abnormal truncated protein bands was perfomed.
RESULT
We identified an abnormal truncated protein in the exon 11 of the BRCA2 gene from a member of hereditary breast cancer family, SNU-B4. Sequencing analysis revealed a 4 bp deletion in codons 1248-49 of the exon 11, resulting in frameshift that led to premature stop codon and truncation of the protein product.
CONCLUSION
We have identified a germline mutation from a Korean hereditary breast cancer family. So far only one case of the same mutation has been registered in Database of BRCA2 mutation (BIC) by a commercial genetic diagnosis company, Myriad Genetics, Inc. Identification of the germline mutation in BRCA2 gene should aid in the accurate presymptomatic diagnosis of the at-risk members in this family.

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Germline Mutations of BRCA1 Gene in Korean Breast and/or Ovarian Cancer Families: Yong Jin Won, Jae Hwan Oh, Xiao Hong Huang, Dong Young Noh, Kuk Jin Choe, Soon Beom Kang, Lee Su Kim, Man Su Noh, Nam Sun Paik, Dae Hyun Yang, Se Min Oh, Soon Nam Lee, Jae Gahb Park; J Korean Cancer Assoc. 1997;29(5):713-723.

Abstract PDF: PURPOSE
To understand the involvement of BRCA1 gene in Korean breast and/or ovarian cancer families.
MATERIALS AND METHODS
Germline mutations of BRCA1 gene were analyzed in 13 families which included 3 hereditary site-specific breast cancer families, 6 suspected breast cancer families, and 3 suspected breast-ovarian cancer family, and one Li-Fraumeni family by screening BRCA1 gene using single strand conformation polymorphism (SSCP) analysis on polymerase chain reaction (PCR) amplified genomic DNA and confirmed the results by sequencing.
RESULTS
Including one family with previously reported nonsense mutation of BRCA1 gene, we detected two mutations in unrelated families. One newly identified mutation was frame shift mutation resulting from TG deletion in codon 1701, which results in a truncated BRCA1 protein, at codon 1714.
CONCLUSION
The proportion of families who inherit the mutated BRCA1 gene seems to be small among Korean breast and/or ovarian cancer families.

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Germline Mutation of BRCA1 Gene in Korean Breast and Overian Cancer Patients: Jae Hwan Oh, Dong Young Noh, Kuk Jin Choe, Soon Beom Kang, Lee Su Kim, Man Su Ro, Nam Sun Paik, Dae Hyun Yang, Se Min Oh, Soon Nam Lee, Jae Gahb Park; J Korean Cancer Assoc. 1995;27(6):1061-1070.

Abstract PDF: We analyzed germline mutations of the BRCAl gene in 29 Korean breast cancer patients, which included ¨c 10 breast cancer patients with family history of breast or ovarian cancer, ¨e 7 early onset breast cancer patients without family history of breast or ovarian cancer(1ess than 40 years old at diagnosis) and ¨e 12 breast cancer patients without family history of breast or ovarian cancer(more than 40 years old at diagnosis), and 1 hereditary ovarian cancer patient. One nonsense mutation at codon 1815 encoding a truncated protein was detected in a breast cancer patient with family history of ovarian cancer. One missense mutation at codon 1630 was detected in a group of breast cancer patients without family history(more than 40 years old at diagnosis), but still not determined whether it was polymorphism or not. Three polymorphisms were detected, which included 2 cases of silent mutation and a case of missense mutation. In early onset breast cancer group and a familial ovarian cancer patient, there was no detected mutation. We confirmed a germline BRCAl gene mutation in one Korean patient of hereditary breast-ovarian cancer family.

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Extraskeletal Mesenchymal Chondrosarcoma of Thigh with Metastasis to Pancreas : A case report and literature review: g Hun Byun, Jin Hyoung Kang, Jung Ah Kim, Hoon Kyo Kim, Kyung Shik Lee, Eun Deok Chang; J Korean Cancer Assoc. 1995;27(6):1070-1077.

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