nach oben

Erschienen in:

17.08.2019 | Preclinical study

Genomic landscape of ductal carcinoma in situ and association with progression

verfasst von: Chieh-Yu Lin, Sujay Vennam, Natasha Purington, Eric Lin, Sushama Varma, Summer Han, Manisha Desa, Tina Seto, Nicholas J. Wang, Henning Stehr, Megan L. Troxell, Allison W. Kurian, Robert B. West

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The detection rate of breast ductal carcinoma in situ (DCIS) has increased significantly, raising the concern that DCIS is overdiagnosed and overtreated. Therefore, there is an unmet clinical need to better predict the risk of progression among DCIS patients. Our hypothesis is that by combining molecular signatures with clinicopathologic features, we can elucidate the biology of breast cancer progression, and risk-stratify patients with DCIS.

Methods

Targeted exon sequencing with a custom panel of 223 genes/regions was performed for 125 DCIS cases. Among them, 60 were from cases having concurrent or subsequent invasive breast cancer (IBC) (DCIS + IBC group), and 65 from cases with no IBC development over a median follow-up of 13 years (DCIS-only group). Copy number alterations in chromosome 1q32, 8q24, and 11q13 were analyzed using fluorescence in situ hybridization (FISH). Multivariable logistic regression models were fit to the outcome of DCIS progression to IBC as functions of demographic and clinical features.

Results

We observed recurrent variants of known IBC-related mutations, and the most commonly mutated genes in DCIS were PIK3CA (34.4%) and TP53 (18.4%). There was an inverse association between PIK3CA kinase domain mutations and progression (Odds Ratio [OR] 10.2, p < 0.05). Copy number variations in 1q32 and 8q24 were associated with progression (OR 9.3 and 46, respectively; both p < 0.05).

Conclusions

PIK3CA kinase domain mutations and the absence of copy number gains in DCIS are protective against progression to IBC. These results may guide efforts to distinguish low-risk from high-risk DCIS.

Nur mit Berechtigung zugänglich

Meijnen P, Oldenburg HS, Peterse JL et al (2008) Clinical outcome after selective treatment of patients diagnosed with ductal carcinoma in situ of the breast. Ann Surg Oncol 15:235–243PubMed

Cutuli B, Cohen-Solal-le Nir C, de Lafontan B et al (2002) Breast-conserving therapy for ductal carcinoma in situ of the breast: the French Cancer Centers’ experience. Int J Radiat Oncol Biol Phys 53:868–879PubMed

Wapnir IL, Dignam JJ, Fisher B et al (2011) Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 103:478–488PubMedPubMedCentral

Cuzick J, Sestak I, Pinder SE et al (2011) Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol 12:21–29PubMed

Ernster VL, Barclay J, Kerlikowske K et al (1996) Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA 275:913–918PubMed

Fisher ER, Dignam J, Tan-Chiu E et al (1999) Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86:429–438PubMed

Newburger DE, Kashef-Haghighi D, Weng Z et al (2013) Genome evolution during progression to breast cancer. Genome Res 23:1097–1108PubMedPubMedCentral

Weng Z, Spies N, Zhu SX et al (2015) Cell-lineage heterogeneity and driver mutation recurrence in pre-invasive breast neoplasia. Genome Med 7:28PubMedPubMedCentral

Johnson CE, Gorringe KL, Thompson ER et al (2012) Identification of copy number alterations associated with the progression of DCIS to invasive ductal carcinoma. Breast Cancer Res Treat 133:889–898PubMed

10.

Rane SU, Mirza H, Grigoriadis A et al (2015) Selection and evolution in the genomic landscape of copy number alterations in ductal carcinoma in situ (DCIS) and its progression to invasive carcinoma of ductal/no special type: a meta-analysis. Breast Cancer Res Treat 153:101–121PubMed

11.

Kroigard AB, Larsen MJ, Laenkholm AV et al (2015) Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis. Oncotarget 6:5634–5649PubMedPubMedCentral

12.

Afghahi A, Forgo E, Mitani AA et al (2015) Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer. Breast Cancer Res 17:108PubMedPubMedCentral

13.

Troxell ML, Brunner AL, Neff T et al (2012) Phosphatidylinositol-3-kinase pathway mutations are common in breast columnar cell lesions. Mod Pathol 25:930–937PubMed

14.

Xu R, Perle MA, Inghirami G et al (2002) Amplification of Her-2/neu gene in Her-2/neu-overexpressing and -nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material. Mod Pathol 15:116–124PubMed

15.

Weber SC, Seto T, Olson C et al (2012) Oncoshare: lessons learned from building an integrated multi-institutional database for comparative effectiveness research. AMIA Annu Symp Proc 2012:970–978PubMedPubMedCentral

16.

Kurian AW, Mitani A, Desai M et al (2014) Breast cancer treatment across health care systems: linking electronic medical records and state registry data to enable outcomes research. Cancer 120:103–111PubMed

17.

Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25:1754–1760PubMedPubMedCentral

18.

McKenna A, Hanna M, Banks E et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303PubMedPubMedCentral

19.

Cibulskis K, Lawrence MS, Carter SL et al (2013) Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31:213–219PubMedPubMedCentral

20.

Lai Z, Markovets A, Ahdesmaki M et al (2016) VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res 44:e108PubMedPubMedCentral

21.

Garrison E, Marth G (2012) Haplotype-based variant detection from short-read sequencing. arXiv:12073907

22.

Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164PubMedPubMedCentral

23.

Gao Y, Niu Y, Wang X et al (2009) Genetic changes at specific stages of breast cancer progression detected by comparative genomic hybridization. J Mol Med (Berl) 87:145–152

24.

R development Core Team (2015) R: a language and environment for statistical computing. The R Foundation for Statistical Computing, Vienna

25.

Porta-Pardo E, Godzik A (2014) e-Driver: a novel method to identify protein regions driving cancer. Bioinformatics 30:3109–3114PubMedPubMedCentral

26.

Porta-Pardo E, Garcia-Alonso L, Hrabe T et al (2015) A pan-cancer catalogue of cancer driver protein interaction interfaces. PLoS Comput Biol 11:e1004518PubMedPubMedCentral

27.

Yang F, Petsalaki E, Rolland T et al (2015) Protein domain-level landscape of cancer-type-specific somatic mutations. PLoS Comput Biol 11:e1004147PubMedPubMedCentral

28.

Curtis C, Shah SP, Chin SF et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486:346–352PubMedPubMedCentral

29.

Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70

30.

Horlings HM, Weigelt B, Anderson EM et al (2013) Genomic profiling of histological special types of breast cancer. Breast Cancer Res Treat 142:257–269PubMed

31.

Ciriello G, Gatza ML, Beck AH et al (2015) Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163:506–519PubMedPubMedCentral

32.

Desmedt C, Zoppoli G, Gundem G et al (2016) Genomic characterization of primary invasive lobular breast cancer. J Clin Oncol 34:1872–1881PubMed

33.

Yates LR, Gerstung M, Knappskog S et al (2015) Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med 21:751–759PubMedPubMedCentral

34.

Abba MC, Gong T, Lu Y et al (2015) A molecular portrait of high-grade ductal carcinoma in situ. Cancer Res 75:3980–3990PubMedPubMedCentral

35.

Kim SY, Jung SH, Kim MS et al (2015) Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer. Oncotarget 6:7597–7607PubMedPubMedCentral

36.

Pang JB, Savas P, Fellowes AP et al (2017) Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer. Mod Pathol 30:952–963PubMed

37.

Hernandez L, Wilkerson PM, Lambros MB et al (2012) Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection. J Pathol 227:42–52PubMedPubMedCentral

38.

Liao S, Desouki MM, Gaile DP et al (2012) Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast. Genes Chromosomes Cancer 51:1067–1078PubMedPubMedCentral

39.

Hwang ES, Lal A, Chen YY et al (2011) Genomic alterations and phenotype of large compared to small high-grade ductal carcinoma in situ. Hum Pathol 42:1467–1475PubMed

40.

Shah V, Nowinski S, Levi D et al (2017) PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression. Breast Cancer Res 19:7PubMedPubMedCentral

41.

Sakr RA, Weigelt B, Chandarlapaty S et al (2014) PI3 K pathway activation in high-grade ductal carcinoma in situ–implications for progression to invasive breast carcinoma. Clin Cancer Res 20:2326–2337PubMedPubMedCentral

42.

Zhao JJ, Liu Z, Wang L et al (2005) The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci USA 102:18443–18448PubMedPubMedCentral

43.

Zardavas D, Phillips WA, Loi S (2014) PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res 16:201PubMedPubMedCentral

44.

Fry EA, Taneja P, Inoue K (2017) Oncogenic and tumor-suppressive mouse models for breast cancer engaging HER2/neu. Int J Cancer 140:495–503PubMed

45.

Ang DC, Warrick AL, Shilling A et al (2014) Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions. Mod Pathol 27:740–750PubMed

46.

Allred DC, Clark GM, Molina R et al (1992) Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 23:974–979PubMed

47.

Latta EK, Tjan S, Parkes RK et al (2002) The role of HER2/neu overexpression/amplification in the progression of ductal carcinoma in situ to invasive carcinoma of the breast. Mod Pathol 15:1318–1325PubMed

48.

Jang M, Kim E, Choi Y et al (2012) FGFR1 is amplified during the progression of in situ to invasive breast carcinoma. Breast Cancer Res 14:R115PubMedPubMedCentral

49.

Park K, Han S, Kim HJ et al (2006) HER2 status in pure ductal carcinoma in situ and in the intraductal and invasive components of invasive ductal carcinoma determined by fluorescence in situ hybridization and immunohistochemistry. Histopathology 48:702–707PubMed

50.

Borgquist S, Zhou W, Jirstrom K et al (2015) The prognostic role of HER2 expression in ductal breast carcinoma in situ (DCIS); a population-based cohort study. BMC Cancer 15:468PubMedPubMedCentral

51.

Hoque A, Sneige N, Sahin AA et al (2002) Her-2/neu gene amplification in ductal carcinoma in situ of the breast. Cancer Epidemiol Biomark Prev 11:587–590

52.

Miron A, Varadi M, Carrasco D et al (2010) PIK3CA mutations in in situ and invasive breast carcinomas. Cancer Res 70:5674–5678PubMedPubMedCentral

53.

Dunlap J, Le C, Shukla A et al (2010) Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat 120:409–418PubMed

54.

Gorringe KL, Hunter SM, Pang JM et al (2015) Copy number analysis of ductal carcinoma in situ with and without recurrence. Mod Pathol 28:1174–1184PubMed

55.

Bhat-Nakshatri P, Goswami CP, Badve S et al (2016) Molecular insights of pathways resulting from two common PIK3CA mutations in breast cancer. Cancer Res 76:3989–4001PubMed

56.

Dogruluk T, Tsang YH, Espitia M et al (2015) Identification of variant-specific functions of PIK3CA by rapid phenotyping of rare mutations. Cancer Res 75:5341–5354PubMedPubMedCentral

Titel: Genomic landscape of ductal carcinoma in situ and association with progression
verfasst von: Chieh-Yu Lin
Sujay Vennam
Natasha Purington
Eric Lin
Sushama Varma
Summer Han
Manisha Desa
Tina Seto
Nicholas J. Wang
Henning Stehr
Megan L. Troxell
Allison W. Kurian
Robert B. West
Publikationsdatum: 17.08.2019
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2019
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05401-x

Neu im Fachgebiet Onkologie

19.04.2024 | EAU 2024 | Kongressbericht | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Genomic landscape of ductal carcinoma in situ and association with progression

Abstract

Purpose

Methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2019

A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients

Diffuse distribution of tumor-infiltrating lymphocytes is a marker for better prognosis and chemotherapeutic effect in triple-negative breast cancer

Rationale for evaluating breast cancers of Lynch syndrome patients for mismatch repair gene expression

HER2 double-equivocal breast cancer in Chinese patients: a high concordance of HER2 status between different blocks from the same tumor

Time-to-surgery and overall survival after breast cancer diagnosis in a universal health system

Pathologic complete response and outcomes by intrinsic subtypes in NSABP B-41, a randomized neoadjuvant trial of chemotherapy with trastuzumab, lapatinib, or the combination

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie