Silencing of tumor suppressor genes by promoter hypermethylation is a key mechanism to facilitate cancer progression in many malignancies. While promoter hypermethylation can occur at later stages of the carcinogenesis process, constitutional methylation of key tumor suppressors may be an initiating event whereby cancer is started. Constitutional
BRCA1
methylation due to
cis
-acting germline genetic variants is associated with a high risk of breast and ovarian cancer. However, this seems to be a rare event, restricted to a very limited number of families. In contrast, mosaic constitutional
BRCA1
methylation is detected in 4-7% of newborn females without germline
BRCA1
mutations. While the cause of such methylation is poorly understood, mosaic normal tissue
BRCA1
methylation is associated with a 2-3 fold increased risk of high-grade serous ovarian cancer (HGSOC). As such,
BRCA1
methylation may be the cause of a significant number of ovarian cancers. Given the molecular similarities between HGSOC and basal-like breast cancer, the findings with respect to HGSOC suggest that constitutional
BRCA1
methylation could be a risk factor for basal-like breast cancer as well. Similar to
BRCA1
, some specific germline variants in
MLH1
and
MSH2
are associated with promoter methylation and a high risk of colorectal cancers in rare hereditary cases of the disease. However, as many as 15% of all colorectal cancers are of the microsatellite instability (MSI) “high” subtype, in which commonly the tumors harbor
MLH1
hypermethylation. Constitutional mosaic methylation of
MLH1
in normal tissues has been detected but not formally evaluated as a potential risk factor for incidental colorectal cancers. However, the findings with respect to
BRCA1
in breast and ovarian cancer raises the question whether mosaic
MLH1
methylation is a risk factor for MSI positive colorectal cancer as well. As for
MGMT
, a promoter variant is associated with elevated methylation across a panel of solid cancers, and
MGMT
promoter methylation may contribute to an elevated cancer risk in several of these malignancies. We hypothesize that constitutional mosaic promoter methylation of crucial tumor suppressors may trigger certain types of cancer, similar to germline mutations inactivating the same particular genes. Such constitutional methylation events may be a spark to ignite cancer development, and if associated with a significant cancer risk, screening for such epigenetic alterations could be part of cancer prevention programs to reduce cancer mortality in the future.