MLH1 – Breast Cancer

MLH1, a key DNA mismatch repair gene, has been evaluated for association with breast cancer primarily in Lynch syndrome (LS) families. In a case–control study of 423 women with germline MLH1 variants, breast cancer risk was not increased (SIR=0.87) (PMID:29345684). However, observational series identified defective MLH1 protein expression in 7 of 16 breast tumors from MLH1 mutation carriers, demonstrating mismatch repair deficiency in these cancers (PMID:20215533). A single case report described a patient with germline MLH1 c.1381A>T (p.Lys461Ter) who developed breast cancer showing loss of heterozygosity and dMMR (PMID:32040686).

Functional analyses of MLH1 truncating mutations, including c.1381A>T, revealed aberrant exon skipping and reduced full‐length transcript levels, consistent with loss‐of‐function haploinsufficiency in mismatch repair (PMID:11585727). Concordant immunohistochemistry and limited segregation data support a role for MLH1 deficiency in a subset of breast cancers arising in LS contexts. Overall, evidence for MLH1 as a breast cancer predisposition gene remains limited, and routine MLH1 testing for breast cancer risk outside LS families is not currently justified.

Key take-home: MLH1 loss contributes to breast tumorigenesis in Lynch syndrome but lacks robust epidemiological support as an independent breast cancer predisposition gene.

References

• Clinical Cancer Research • 2010 • Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry PMID:20215533
• Genetics in Medicine • 2018 • MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer PMID:29345684
• Breast Cancer Research and Treatment • 2020 • The implications of BRCA loss of heterozygosity (LOH) and deficient mismatch repair gene (dMMR) expression in the breast cancer of a patient with both inherited breast and ovarian cancer syndrome (BRCA2) and Lynch syndrome (MLH1) PMID:32040686
• Cancer Research • 2001 • A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families PMID:11585727

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