Allelic Imbalance in Primary Breast Carcinomas and Metastatic Tumors of the Axillary Lymph Nodes

Ellsworth, Rachel E.; Ellsworth, Darrell L.; Neatrour, David M.; Deyarmin, Brenda; Lubert, Susan M.; Sarachine, Miranda J.; Brown, Patrick O.; Hooke, Jeffrey A.; Shriver, Craig D.

doi:10.1158/1541-7786.mcr-04-0180

Cited by 22 publications

(12 citation statements)

References 21 publications

(21 reference statements)

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“…Genotypes were determined using Genetic Profiler version 2.0 software. AI was detected using methods first described by Medintz et al [16] and defined by a threshold value of 0.35 which has been shown to have >80% reproducibility when AI events were confirmed on a second aliquot of DNA [17]. The following criteria were used to define AI for each region: when at least one marker for a given region showed an allelic ratio≤ 0.35, the region was considered to show AI; when neither marker had an allelic ratio≤0.35 and at least one marker was informative, the region was considered normal; and when both markers were homozygous, the region was considered uninformative.…”

Section: Methodsmentioning

confidence: 99%

Molecular Changes in Primary Breast Tumors and the Nottingham Histologic Score

Ellsworth

Hooke

Love³

et al. 2009

Pathol. Oncol. Res.

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Pathological grade is routinely used to stratify breast cancer patients into favorable and less favorable outcome groups. Mechanisms by which genomic changes in breast tumors specifically contribute to the underlying components of tumor grade - tubule formation, nuclear pleomorphism, and mitoses - are unknown. This study examined 26 chromosomal regions known to be altered in breast cancer in 256 invasive breast carcinomas. Differences in overall levels and patterns of allelic imbalance (AI) at each chromosomal region were compared for tumors with favorable (=1) and unfavorable (=3) scores for tubule formation, nuclear pleomorphism and mitotic count. Levels of AI were significantly different between samples with high and low scores for tubule formation (P < 0.001), nuclear pleomorphism (P < 0.001) and mitotic count (P < 0.05). Significantly higher levels of AI were detected at regions 11q23 and 13q12 for tumors with reduced tubule formation, chromosomes 9p21, 11q23, 13q14, 17p13 and 17q12 for those with high levels of nuclear atypia, and chromosomes 1p36, 11q23, and 13q14 for those with high mitotic counts. Region 16q11-q22 showed significantly more AI events in samples with low nuclear atypia. Patterns of genetic changes associated with poorly-differentiated breast tumors were recapitulated by the individual components of the Nottingham Histologic Score. While frequent alteration of 11q23 is common for reduced tubule formation, high nuclear atypia and high mitotic counts, suggesting that this is an early genetic change in the development of poorly-differentiated breast tumors, alterations at the other seven loci associated with poorly-differentiated tumors may specifically influence cell structure, nuclear morphology and cellular proliferation.

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Section: Methodsmentioning

confidence: 99%

Molecular Changes in Primary Breast Tumors and the Nottingham Histologic Score

Ellsworth

Hooke

Love³

et al. 2009

Pathol. Oncol. Res.

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“…AI was detected as previously described [13]. A cutoff value of 0.35 was selected for detecting AI because it provided > 80% reproducibility when AI events were confirmed on a second aliquot of DNA [14].…”

Section: Methodsmentioning

confidence: 99%

Correlation of levels and patterns of genomic instability with histological grading of invasive breast tumors

Ellsworth

Hooke

Love³

et al. 2007

Breast Cancer Res Treat

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Pathological grade is a useful prognostic factor for stratifying breast cancer patients into favorable (well-differentiated tumors) and less favorable (poorly-differentiated tumors) outcome groups. The current system of tumor grading, however, is subjective and a large proportion of tumors are characterized as intermediate-grade tumors, making determination of optimal treatments difficult. To determine whether molecular profiles can discriminate breast disease by grade, patterns and levels of allelic imbalance (AI) at 26 chromosomal regions frequently altered in breast disease were examined in 185 laser microdissected specimens representing well-differentiated (grade 1; n = 55), moderately-differentiated (grade 2; n = 71), and poorly-differentiated (grade 3; n = 59) stage I-IV breast tumors. Overall levels of AI were significantly higher in grade 3 compared to grade 1 tumors (P < 0.05). Grades 1 and 3 showed distinct genetic profiles--grade 1 tumors were associated with large deletions of chromosome 16q22, while alterations at 9p21, 11q23, 13q14, 17p13.1 and 17q12 were characteristics of grade 3 carcinomas. In general, levels and patterns of AI in grade 2 carcinomas were intermediate between grade 1 and grade 3 tumors. Patterns of AI accurately categorized approximately 70% of samples into high- or low-grade disease groups, suggesting that the majority of breast tumors have genetic profiles consistent with high- or low-grade, and that molecular signatures of breast tumors can be useful for more accurate characterization of invasive breast cancer.

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“…However, our results are in line with the observations of Ellsworth et al . reporting 25% allelic imbalance for RB1 in primary breast tumor but 17% only in matched axillary lymph node metastases [24]. To the best of our knowledge, we are not aware of any other study reporting RB1 allelic imbalance status in distant metastatic breast cancer lesions.…”

Section: Discussionmentioning

confidence: 99%

Alterations of the retinoblastoma gene in metastatic breast cancer

Berge

Knappskog

Lønning

2011

Clin Exp Metastasis

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Germline mutations affecting the retinoblastoma gene (RB1) predispose to inherited retinoblastomas but also other malignancies, including breast cancer. While somatic RB1 mutations have been detected in different malignancies, information about the potential role of RB1 mutations in breast cancer is limited. Recently, we discovered RB1 mutations to be associated with resistance to anthracyclines/mitomycin in primary breast cancer. The present work is the first report evaluating RB1 mutation and epigenetic status in metastatic breast cancer. Among 148 breast cancer samples analyzed by MLPA, four samples harbored intragenic deletions/duplications: Thus, exons 1–2 were deleted in two tumors and exons 21–23 in one tumor, while one sample harbored duplication of exons 18–23. The entire RB1 gene was duplicated in two tumors and multiple amplifications were revealed in one sample. Reduced copy number was observed in 17 samples (11.5%). No point mutation or promoter hypermethylation was discovered (n = 38 and 114 tumors analyzed, respectively). Interestingly, among seven tumors expressing lack of response to epirubicin, two samples harbored alterations in RB1, contrasting none out of 16 tumors with stable disease or an objective response (P = 0.08). In summary, the frequency of RB1 alterations in metastatic lesions was not increased when compared to primary breast cancer, indicating that RB1 alterations do not play a major role in metastatic development. While a non-significant association suggesting RB1 alterations to be linked to therapy resistance was observed, our data do not suggest a major role for RB1 alterations explaining acquired drug resistance.

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Allelic Imbalance in Primary Breast Carcinomas and Metastatic Tumors of the Axillary Lymph Nodes

Cited by 22 publications

References 21 publications

Molecular Changes in Primary Breast Tumors and the Nottingham Histologic Score

Molecular Changes in Primary Breast Tumors and the Nottingham Histologic Score

Correlation of levels and patterns of genomic instability with histological grading of invasive breast tumors

Alterations of the retinoblastoma gene in metastatic breast cancer

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