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Breast Cancer Mutation Signatures Suggest Mismatch Repair Subset

NEW YORK (GenomeWeb) – A subset of breast cancers contain mutational signatures consistent with DNA mismatch repair (MMR) deficiency, new research reveals, suggesting that some individuals with the disease may benefit from immune checkpoint blockade immunotherapies similar to those being used in other types of cancer with MMR deficits.

"[T]hese tumors would not have been detected as being deficient in the mismatch repair pathway [under current clinical criteria]," Wellcome Trust Sanger Institute researcher Helen Davies said in a statement. "We have shown that there is in fact another category of breast cancers — those with defective mismatch repair."

In an effort to more fully characterize mutational signatures contributing to breast cancer, Davies and colleagues from the Sanger Institute and other centers from around the world did whole-genome sequencing on matched tumor and normal samples from 640 individuals with breast cancer. Their analyses led to 11 tumors with mutation signatures resembling those found in MMR-deficient cancers that tend to respond to anti-PD-1 or anti-PD-L1 checkpoint blockade treatments. A paper outlining these and other results appeared online today in Cancer Research.

"As these tumors have the same mutational signatures as those of other cancers, like colorectal cancer, they should in theory respond to the same immunotherapy drugs," senior author Serena Nik-Zainal, a human genetics researcher at the Sanger Institute, said in a statement. "Our results suggest expanding the cohort of cancer patients that could possibly be treated with checkpoint inhibitors to include these mismatch repair deficient breast cancer patients."

Germline mutations affecting MMR genes such as MSH2, MSH6, MLH1, or PMS2 are well known for their roles in Lynch syndrome, an inherited condition that predisposes individuals to colorectal cancer and other cancer types.

Even so, the authors explained, somatic mutations in these or other genes — or related regulatory sequences — can also produce MMR deficiencies that lead to DNA repair problems and rampant mutation. With that in mind, they set out to scrutinize a large set of breast cancer cases, searching for mutational signatures associated with MMR deficiency.

In a study published in Nature Medicine in March, members of the same team described mutational signatures associated with BRCA1 or BRCA2 deficiency, which turned up in dozens of tumors in a genome sequencing analysis of 560 breast cancer cases.

For the latest analysis, Davies, Nik-Zainal, and their colleagues focused on whole-genome sequence data for tumor-normal pairs from 640 individuals with breast cancer, aligning genome sequence reads from these samples to the human reference genome to help narrow in on roughly 3.8 million somatic substitutions, nearly 400,000 small insertions and deletions, and more than 83,000 rearrangements in the tumors.

Using Affymetrix and Illumina arrays, respectively, they also profiled copy number and DNA methylation patterns in the tumors. And with immunohistochemistry staining, the investigators got a look at MLH1, PMS2, MHS2, and MSH6 protein levels in formalin-fixed, paraffin-embedded tumor samples.

The 11 tumors with mutation signatures similar to other MMR-deficient tumors included five estrogen receptor-positive tumors and six ER-negative cases, they reported. Indels appeared to be rampant across the MMR-deficiency-like set and nine of the tumors had broader hypermutation patterns.

The team then did a series of analyses to verify MMR deficiency in the 11 tumors. Indeed, half a dozen cases were marked by genetic or epigenetic changes expected to inactivate MMR pathway genes. And IHC staining picked up declines in related repair proteins in 10 of the 11 tumors.

When they expanded their search to 1,100 breast cancers previously assessed by exome sequencing, the researchers saw evidence of MMR deficiencies in 1 percent of those cases using the protein-coding sequences.

"The next step will be to test this approach in clinical trials to find out if identifying these patterns and using them to tailor breast cancer treatments helps to improve survival," Cancer Research UK chief scientist Karen Vousden, who was not directly involved in the study, said in a statement.