Dr. Donna Albertson and Dr. Dan Pinkel, for providing

Clonality of Lobular Carcinoma in Situ and Synchronous Invasive Lobular Carcinoma

E.Shelley Hwang,M.D.1

Sarah J.Nyante,B.S.1

Yunn Yi Chen,M.D.,Ph.D.2

Dan Moore,Ph.D.3

Sandy DeVries,B.S.,M.S.3

James E.Korkola,Ph.D.3

Laura J.Esserman,M.D.,M.B.A.1 Frederic M.Waldman,M.D.,Ph.D.3–5

1Department of Surgery,University of California–San Francisco,San Francisco,California.

2Department of Pathology,University of Califor-nia–San Francisco,San Francisco,California.

3University of California–San Francisco Compre-hensive Cancer Center,San Francisco,California.

4Department of Laboratory Medicine,University of California–San Francisco,San Francisco,Califor-nia.

5Department of Urology,University of California–San Francisco,San Francisco,California.

Supported by grants from the National Institutes of Health(CA44768and CA58207)and by the Uni-versity of California–San Francisco Clinical Inves-tigator Research Program Award(to Dr.Hwang). The authors thank the University of California–San Francisco Cancer Center Array Core,directed by Dr.Donna Albertson and Dr.Dan Pinkel,for pro-viding Human Array2.0genomic arrays.

Address for reprints:E.Shelley Hwang,M.D.,De-partment of Pathology,University of California–San Francisco Cancer Center,1600Divisadero Avenue, B606,San Francisco,CA94115;Fax:(415)353-9571;E-mail:shelley.hwang@ Received January8,2004;revision received March2,2004;accepted March9,2004.BACKGROUND.Lobular carcinoma in situ(LCIS)of the breast is considered a marker for an increased risk of carcinoma in both breasts.However,the frequent association of LCIS with invasive lobular carcinoma(ILC)suggests a precursor-product relation.The possible genomic relation between synchronous LCIS and ILC was analyzed using the technique of array-based comparative genomic hy-bridization(CGH).

METHODS.Twenty-four samples from the University of California–San Francisco pathology archives that contained synchronous LCIS and ILC were identified. Array CGH was performed using random primer–amplified microdissected DNA. Samples were hybridized onto bacterial artificial chromosome arrays composed of approximately2400clones.Patterns of alterations within synchronous LCIS and ILC were compared.

RESULTS.A substantial proportion of the genome was altered in samples of both LCIS and ILC.The most frequent alterations were gain of1q and loss of16q,both of which usually occurred as whole-arm changes.Smaller regions of gain and loss were seen on other chromosome arms.Fourteen samples of LCIS were related more to their paired samples of ILC than to any other ILC,as demonstrated by a weighted similarity score.

CONCLUSIONS.LCIS and ILC are neoplastic lesions that demonstrate a range of genomic alterations.In the current study,the genetic relation between synchro-nous LCIS and ILC suggested clonality in a majority of the paired specimens.These data were consistent with a progression pathway from LCIS to ILC.The authors conclude that LCIS,which is known to be a marker for an environment that is permissive of neoplasia,may itself represent a precursor to invasive carcinoma. Cancer2004;100:2562–72.©2004American Cancer Society.

KEYWORDS:lobular carcinoma in situ,ductal carcinoma in situ,comparative genomic hybridization,breast neoplasms.

O ur clinical understanding of lobular carcinoma in situ(LCIS)of the breast has undergone a gradual evolution since the term was coined by Foote and Stewart in1941.1Although,histologically a neoplastic lesion,LCIS has long been considered a marker for in-creased breast carcinoma risk rather than a precursor for invasive carcinoma,because it appears to confer an equally increased risk of breast carcinoma in both the contralateral and ipsilateral breasts.2–5 Furthermore,over half of invasive carcinomas that develop after a diagnosis of LCIS developϾ10years subsequent to the index lesion, with most of these invasive carcinomas exhibiting ductal histology.2–4 Because of the concern regarding increased bilateral risk,the historically recommended treatment for LCIS included bilateral mas-tectomy.However,most clinicians now choose to follow their pa-tients with expectant management,sometimes in conjunction with

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©2004American Cancer Society

DOI10.1002/cncr.20273

Published online6May2004in Wiley InterScience().