Data from: Clonal relatedness between lobular carcinoma in situ and synchronous malignant lesions

INTRODUCTION: Lobular carcinoma in situ (LCIS) has been accepted as a marker of risk for the development of invasive breast cancer, yet modern models of breast carcinogenesis include LCIS as a precursor of low-grade carcinomas. We provide evidence favoring a clonal origin for LCIS and synchronous estrogen receptor-positive malignant lesions of the ductal and lobular phenotype. METHODS: Patients with prior LCIS undergoing mastectomy were identified preoperatively from 2003-2008. Specimens were widely sampled, and frozen blocks were screened for LCIS and co-existing malignant lesions, and subject to microdissection. Samples from 65 patients were hybridized to the Affymetrix SNP 6.0 array platform. Cases with both an LCIS sample and an associated ductal carcinoma in situ (DCIS) or invasive tumor sample were evaluated for patterns of somatic copy number changes to assess evidence of clonal relatedness. RESULTS: LCIS was identified in 44 of the cases, and among these, a DCIS and/or invasive lesion was also identified in 21 cases. A total of 17 tumor pairs had adequate DNA/array data for analysis, including 9 pairs of LCIS/invasive lobular cancer (ILC), 4 pairs of LCIS/DCIS, and 4 LCIS/invasive ductal cancer (IDC). Overall, 7 pairs (41%) were judged to be clonally related; in 5 (29%), evidence suggested clonality but was equivocal, and 5 (29%) were considered independent. Clonal pairs were observed with all matched lesion types and low and high histological grades. We also show anecdotal evidence of clonality between a patient-matched triplet of LCIS, DCIS, and IDC. CONCLUSIONS: Our results support the role of LCIS as a precursor in the development of both high- and low-grade ductal and lobular cancers.引言：小叶原位癌（Lobular carcinoma in situ, LCIS）已被公认为浸润性乳腺癌发病风险的标志物，而现代乳腺癌变模型则将LCIS列为低级别癌的前驱病变。本研究旨在为LCIS的克隆起源，以及导管和小叶表型的同步雌激素受体阳性恶性病变提供佐证。 方法：本研究纳入2003年至2008年术前确诊为既往罹患LCIS并接受乳房切除术的患者。对手术标本进行广泛取材，通过冰冻切片筛选LCIS及共存恶性病变，并实施显微切割。共获取65例患者的样本，采用Affymetrix SNP 6.0基因芯片平台进行杂交。选取同时具备LCIS样本以及伴发的导管原位癌（ductal carcinoma in situ, DCIS）或浸润性肿瘤样本的病例，分析其体细胞拷贝数变异模式，以评估克隆相关性的证据。 结果：本研究共在44例样本中检出LCIS，其中21例同时检出DCIS和/或浸润性病变。最终共有17组肿瘤配对样本获得足够的DNA及芯片数据用于分析，包括9组LCIS/浸润性小叶癌（invasive lobular cancer, ILC）配对、4组LCIS/DCIS配对，以及4组LCIS/浸润性导管癌（invasive ductal cancer, IDC）配对。总体而言，17组样本中有7组（41%）被判定为克隆相关；5组（29%）显示出克隆性证据但结果不确定，另有5组（29%）被认为无克隆相关性。所有匹配病变类型以及不同组织学分级（低级别与高级别）的样本中均观察到克隆相关配对。本研究还提供了1例患者匹配的LCIS、DCIS及IDC三联体样本存在克隆性的佐证案例。 结论：本研究结果支持LCIS作为高级别与低级别导管癌及小叶癌发生发展前驱病变的角色。