Whole-Genome Sequencing Reveals Breast Cancers With Mismatch-Repair Deficiencies

Key Points

  • Whole-genome profiling using mutational signature analysis revealed mismatch repair-deficient breast cancer tumors that could potentially be targeted with PD-1 immune checkpoint inhibitors.
  • As whole-genome sequencing continues to become more affordable, it could be used to expose individual abnormal tumors in tissue types where mismatch repair deficiency has been rarely detected.
  • Because mutational signatures are a direct pathophysiologic readout of MMR pathway abrogation, they confer a higher degree of sensitivity and specificity for tumor classification and could possibly out-perform current biomarkers of mismatch repair-deficiency.

Cancers caused by mismatch repair (MMR)-deficiency involve gene mutations that affect the ability of the cell to repair the mistakes that may occur during the DNA replication process. MMR-deficient tumors have 10 to 100 times more mutations than tumors with intact MMR pathways. A study investigating how to more precisely identify MMR-deficient breast tumors utilizing mutational signature analysis found that due to its high degree of sensitivity and specificity to classify tumors, genome profiling using mutational signature analysis revealed MMR-deficient breast cancer tumors that could potentially be targeted with programmed cell death protein 1 (PD-1) immune checkpoint inhibitors.

As whole-genome sequencing continues to become more affordable, it may be used to expose individual abnormal tumors in tissue types where MMR deficiency has been rarely detected, according to the study abstract. The study findings by Davies et al were published in Cancer Research.

Study Methodology

The researchers used previously published whole genome–sequencing data of breast cancer tumors from 640 patients and analyzed patterns of mutagenesis known as mutational signatures. They also looked for mutations in multiple genes known to be associated with MMR deficiency, including MLH1, MSH2, MSH6, PMS2, PMS1, SETD2, MYH11, EPCAM, TGFBR2, MLH3, and MUTYH, to identify the defects responsible for the MMR deficiency.

Study Findings

The researchers identified 11 of 640 tumors as MMR-deficient, but only 2 of the 11 exhibited germline mutations in MMR genes or Lynch syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity.

Overall, 6 of 11 of the MMR-deficient cases were confirmed genetically or epigenetically as having abrogation of MMR genes. However, immunohistochemistry analysis of MMR-related proteins revealed all but 1 of 10 samples available for testing as MMR-deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities.

“As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected but also rarely sought,” concluded the study authors.

Identifying MMR Deficiency in Breast Cancer

“Our research demonstrates the value of using mutation patterns to identify MMR deficiency in unselected breast cancer cases,” said Serena Nik-Zainal, MD, PhD, of the University of Cambridge and Wellcome Trust Sanger Institute, Genome Research Limited in Cambridge, United Kingdom, and a coauthor of this study, in a statement. “These findings are important because a subset of patients may be responsive to immunotherapies such as PD-1 checkpoint blockade, as has been demonstrated with MMR deficiency in colorectal and other cancers.”

This study was supported by grants from Wellcome Trust, Cancer Research UK Advanced Clinician Scientist Award, Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer, and the National Research Foundation of Korea.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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