SAN ANTONIO—Whole exome sequencing analysis reveals considerable mutational heterogeneity among cells within lobular carcinoma in situ (LCIS) lesions, and suggests that progression from LCIS to invasive disease involves different cell lines’ “mutational processes during clonal evolution,” reported researchers at the 2015 San Antonio Breast Cancer Symposium.1

That genomic heterogeneity of LCIS lesions might represent a reservoir of raw material from which clonal selection can drive transformation to invasive lobular carcinomas (ILC).

“Progression from LCIS to ILC may result in the selection of subclones, driven by distinct mutational signatures,” reported lead study author Jorge S. Reis-Filho, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY.

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Those mutational processes “may change during evolution” of lesions, he said.

A similar process may well drive progression from LCIS to invasive cancer, and LCIS is often clonally related to more advanced lesions.

But there appears to exist a “biological bottleneck” for that process, such that only a small minority of subclones will possess the relevant mutations. That results in growing heterogeneity among LCIS lesions to temporarily drop in those lesions that become malignant.

LCIS is believed to represent “both a risk factor and non-obligate precursor of invasive breast cancer,” Dr Reis-Fiho explained. “We sought to determine the genomic landscape of LCIS and the mutational processes involved in the clonal evolution and progression from LCIS to ductal carcinoma in situ (DCIS) and ILC.”

The study team prospectively enrolled patients with a history of LCIS who were undergoing therapeutic or prophylactic mastectomy. Frozen tissue samples were collected, screened for lesions of interest (LCIS, DCIS, ILC, invasive ductal carcinomas [IDC]) and “subjected to microdissection and DNA/RNA extraction.”

Whole exome sequencing was performed on a HiSeq2000. “Single nucleotide variants (SNVs) and small insertions/deletions were identified using MuTect and Varscan, respectively,” the team reported.

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“The repertoire of somatic mutations in LCIS was similar to that of luminal A breast cancers, with the exception of the significantly higher frequency of CDH1 mutations and the lower prevalence of TP53 mutations,” Dr Reis-Fiho reported.  


  1. Reis-Filho JS, Schizas M, Piscuoglio S, et al. Lobular carcinoma in situ displays intra-lesion genetic heterogeneity and its progression to invasive disease involves clonal selection and variations in mutational processes. Oral presentation at: San Antonio Breast Cancer Symposium 2015; December 10, 2015; San Antonio, TX.