Molecular pathogenesis of bilateral breast cancer

Imyanitov, Evgeny N.; Hanson, Kaido P.

doi:10.1016/s0304-3835(02)00523-2

Cited by 35 publications

(37 citation statements)

References 46 publications

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“…The ARLTS1 Trp149Stop mutation might have a stronger risk impact in individuals with an unfavorable genetic constellation, such as further risk variants in susceptibility genes, as proposed for high-risk familial and bilateral BC. 28 In summary, we revealed an association of the ARLTS1 Cys148Arg variant with an increased high-risk familial and familial BC risk in a dose-dependent manner. Furthermore, our study showed an increased risk of bilateral BC for carriers of the ARLTS1 Stop149 allele, supporting the role of ARLTS1 in human cancer.…”

mentioning

confidence: 56%

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk

Frank¹,

Hemminki²,

Meindl³

et al. 2006

Intl Journal of Cancer

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Recently, ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) has been identified as a tumor suppressor gene, playing a major role in apoptotic signaling. The ARLTS1 Trp149Stop mutation has been shown to predispose to general familial cancer and high-risk familial breast cancer (BC), provoking the attenuation of apoptotic function. We studied the impact of the ARLTS1 Pro131Leu and Cys148Arg variants on high-risk familial and familial BC risk, investigating 482 familial BC cases (including 305 high-risk cases) and 530 control individuals. Unlike ARLTS1 Pro131Leu, Cys148Arg revealed a significant association with an increased risk of high-risk familial BC (odds ratio (OR) 5 1.47, 95% confidence interval (95% CI) 5 1.04-2.06, p 5 0.03) in a dose-dependent manner (p trend 5 0.007). The genotype distribution of Cys148Arg in familial cases was similar, indicating significance as well (OR 5 1.48, 95% CI 5 1.10-1.99, p 5 0.009; p trend 5 0.003). On the basis of the small number of 46 cases, we additionally showed an association between the Trp149Stop mutation and an increased risk of bilateral BC (OR 5 4.11, 95% CI 5 1.27-13.31, p 5 0.011). BC risk is usually increased by 2-to 3-fold in first-degree relatives of an affected individual.3 According to twin studies, most of this familial aggregation is explained by inherited susceptibility. 4,5 Mutations in the high-penetrance genes BRCA1 and BRCA2 account for only 20-25% of this effect, considering genetic variation in lowpenetrance genes to substantially dictate BC susceptibility. 6-8ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) is a member of the ADP-ribosylation factor (ARF) family that has recently been identified as a tumor suppressor gene. 9,10 It is located on chromosome 13q14.3, a region frequently deleted in chronic lymphocytic leukemia, prostate as well as in BC. [11][12][13][14][15][16][17] Moreover, ARLTS1 inactivation is triggered by promoter hypermethylation in human cancer.9 ARLTS1 closely resembles ARF6, which has been shown to be an integral component of BC invasive activities.18 Calin et al. (2005) identified the ARLTS1 mutation Trp149Stop, leading to premature termination of translation and thus to the attenuation of tumor suppression and apoptosis, to predispose to familial cancer.9 A consecutive case-control study by our group revealed the ARLTS1 Trp149Stop mutation to be associated with an increased risk of high-risk familial BC. 19 We showed the ARLTS1 Trp149Stop variant to be significantly more frequent in women from high-risk families than in control individuals, supporting the role of the ARLTS1 gene in human cancer. This is the first case-control study to investigate the effects of the novel ARLTS1 variants Pro131Leu and Cys148Arg on highrisk familial BC risk, revealing an increased risk for carriers of the Arg148 allele. Additionally, we report an association between Trp149Stop and an increased risk of bilateral BC. Material and methods Study populationThe familial BC cohort comprised 482 unrelated German, female index...

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confidence: 56%

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk

Frank¹,

Hemminki²,

Meindl³

et al. 2006

Intl Journal of Cancer

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“…show some CBC to have features similar enough to BC1 that a metastatic spread is possible (11)(12)(13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy

Alkner¹,

Ehinger²,

Bendahl³

et al. 2015

European Journal of Cancer

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Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy.Alkner, Sara; Ehinger, Anna; Bendahl, Pär-Ola; Rydén, Lisa; Fernö, Mårten Link to publication Citation for published version (APA): Alkner, S., Ehinger, A., Bendahl, P-O., Rydén, L., & Fernö, M. (2015). Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy. European Journal of Cancer, 51(16), 2304 -2313 . DOI: 10.1016 /j.ejca.2015 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Role of the Funding Sources:None of the funding sources had any impact on study design; the collection, analysis and interpretation of data; the writing of the report; or in the decision to submit the article for publication.3 Abstract Aim: A contralateral breast cancer (CBC) is today treated as an independent primary tumor, although recent data suggest risk and prognosis of CBC to be influenced by characteristics of and treatment given for the first tumor (BC1). We hereby investigate phenotypical and prognostic features of the second tumor (BC2) in relation to prior endocrine treatment and radiotherapy.Methods: From a well-defined population-based cohort of CBC-patients, we have constructed a unique tissue-microarray including 600 pairs of primary tumors and CBCs.Breast cancer mortality was primary end-point for prognosis. Results: Both estrogen receptor (ER) status and stage was strongly correlated between BC1and BC2 within CBC-pairs. Although BC2 had the highest prognostic impact, BC1 continued to influence prognosis after diagnosis of CBC. Patients diagnosed with two high stage tumors within a short time-interval had a particularly bad prognosis. Prior endocrine therapy and radiotherapy both correlated to ER-negativity of BC2. An ER-negative BC2 was associated with an inferior prognosis compared to an ER-positive BC2 regardless of ER-status of BC1 or prior endocrine therapy. Conclusions:Our results suggest that both the residual prognostic impact of BC1, the possibility of contralateral metastasis, as well as prior treatment given, need to be considered when determining appropriate diagnostic work-up and treatment of CBC. In addition, radiation to the contralateral breast and risk of inducing CBC with an aggressive ER-negative phenotype should be considered when establishing new radiation treatm...

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“…Different histologic types, a better histologic differentiation, presence of in situ component, and absence of metastatic spread would favor a second primary. 8,15,16 In addition, long time interval between the tumor onsets may be regarded as a proof of the true bilaterality. However, in breast cancer patients, there are many exceptions where the latency intervals for metastases or recurrence might be as long as 20 years.…”

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confidence: 99%

“…However, in breast cancer patients, there are many exceptions where the latency intervals for metastases or recurrence might be as long as 20 years. 15 Accumulating literature presents contradicting results. 11,[17][18][19][20][21][22][23][24][25] Some authors have demonstrated similarity in histologic subtype, 12,23 tumor grade, 17 and hormone receptor status 16,18 between the two tumors, suggesting a single-cell origin, whereas others had different results.…”

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confidence: 99%

Diagnostic and Prognostic Utility of Molecular Markers in Synchronous Bilateral Breast Carcinoma

et al. 2008

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Histologic criteria have a limited role in determining whether the synchronous bilateral breast carcinomas represent two primaries or a metastasis to the contralateral breast. We studied the molecular analysis of synchronous bilateral breast carcinoma and whether they are originating from a single or different clone. We examined 17 patients with breast carcinoma, including 12 patients with synchronous bilateral carcinomas and control group of 5 infiltrating ductal carcinomas with regional lymph node metastases. Mutations were quantitatively determined to detect loss of heterozygosity (LOH) and microsatellite size alterations for a broad panel of 15 markers, involving 10 chromosomes using polymerase chain reaction. The carcinomas were classified as de novo or metastasis based on three levels of concordance: (1) marker-affected tumors were considered concordant if 50% or more of the same markers were mutated, (2) same gene copy affected, and (3) temporal sequence of mutation acquisition. In synchronous bilateral breast carcinoma patients, molecular analysis showed discordant mutations in all cases, supporting the diagnosis of de novo bilateral primary breast carcinomas. In patients with lymph node metastases, the primary breast carcinoma and metastases shared the same mutations, revealing a metastatic lesion. In conclusion, the application of molecular technology may play an important role for the differential diagnosis of dual primary carcinomas vs a metastatic breast cancer to contralateral breast. In this study, synchronous bilateral breast cancers represent two independent primaries rather than metastatic events. Keywords: synchronous bilateral breast carcinoma; molecular pathology; LOH Contralateral breast carcinoma is the most common second malignancy for breast carcinoma patients, with an incidence as high as 12%.1-3 Bilateral breast carcinomas exist in two forms, synchronous, in which both tumors occur at the same time, or metachronous, in which the carcinomas occur at different times. Synchronous bilateral breast carcinoma is uncommon, reported to range from 0.3 to 8% in the literature. [4][5][6][7] This wide range of reported incidence rates for synchronous bilateral breast carcinoma is a result of different time cutoff. Although some authors require both breast carcinomas to be diagnosed simultaneously or within less than 1 month, 7-10 others used up to 12 months as a cutoff time to differentiate synchronous from metachronous bilateral breast carcinomas.11-13 Using criteria of less than 1 month, the incidence of synchronous bilateral breast is less than 2%. 7,14 When cancer is detected in the opposite breast, the question arises whether this tumor is a second cancer (polyclonal origin) or a metastatic spread from the first breast cancer (monoclonal origin). The answer to this question is critical as both tumor staging and management will be different depending upon the results.11 Currently, this distinction is attempted using histopathologic features. Different histologic types, a better histologic diff...

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Molecular pathogenesis of bilateral breast cancer

Cited by 35 publications

References 46 publications

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk

Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy

Diagnostic and Prognostic Utility of Molecular Markers in Synchronous Bilateral Breast Carcinoma

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