NORMAL TISSUE BRCA1 METHYLATION MAY OCCUR BEFORE BIRTH

BRCA1 methylation in normal tissue raises the risk for high-grade ovarian cancer and may occur before birth, according to a study from Norway.

The role of aberrant promoter methylation in normal tissue in cancer risk is “poorly understood,” Dr. Per Lonning from Haukeland University Hospital, in Bergen, and colleagues point out in an article online January 15 in Annals of Internal Medicine.

They assessed associations between normal BRCA1 methylation in normal tissue and ovarian cancer risk in initial and validation case-control studies.

In the initial study of 934 women with ovarian cancer and 1,698 healthy controls, BRCA1 methylation in white blood cells (WBCs) was significantly more common in cancer patients than controls (6.4% vs. 4.2%; age-adjusted odds ratio, 1.83).

WBC BRCA1 methylation was detected in 9.6% of women with high-grade serous ovarian cancer (HGSOC), the most aggressive form and the variant associated with BRCA1 mutations, versus in 5.1% and 4.0% of women with nonserous and low-grade serous ovarian cancer, respectively.

These findings were replicated in the validation study involving 607 ovarian cancer patients and 1,984 controls, with WBC BRCA1 methylation seen in 9.1% of patients with HGSOC versus 4.3% of controls.

The authors say it's also noteworthy that WBC BRCA1 methylation also was identified in newborns (7.0%) and young women (4.1%), indicating that normal-tissue BRCA1 methylation is “probably an embryonic event that might influence the risk for HGSOC later in life,” they write.

Commenting on the findings by email, Dr. Lonning said, “As for the moment, women are not screened for ovarian cancer. Taking into account the significant enhanced risk associated with WBC BRCA1 methylation, together with the serious prognoses of high-grade ovarian cancer, I envision there may be a discussion among gynecologists whether there may be indications to evaluate screening procedures for early ovarian cancer detection for women carrying BRCA1 methylation.”

The findings linking early life gene methylation to increased cancer risk in adult life “should have significant implications to further research in this area,” Dr. Lonning said. “Two important questions remain to be addressed: First, what is the actual cause of methylation in some individuals? Second, is similar methylation happening in respect to other tumor-suppressor genes as well? In other words, what are the general implications of these findings in respect to other genes and cancer forms as well?”

In a linked editorial, Dr. Alexander Dobrovic from Olivia-Newton John Cancer Research Institute in Heidelberg, Victoria, Australia, says this research is “admirable not only because of the large number of patients and control participants studied, but also because the investigators conducted additional research to interpret their findings. In particular, they showed that tumor burden is not a contributor to the levels of BRCA1 methylation in WBCs, confirming that methylation is intrinsic to these cells rather than the result of contaminating tumor cells. BRCA1 methylation also was shown in other, non-WBC tissues, unrelated to the tumor, further supporting the concept of constitutional methylation.”

“This and previous studies,” writes Dr. Dobrovic, “make it clear that BRCA1 constitutional methylation is strongly associated with the same tumor types as those with mutation of the gene. BRCA1 constitutional methylation is an alternate mechanism of BRCA1 inactivation that leads to an increased risk for breast or ovarian cancer that is methylated for BRCA1.”

The study was funded primarily by the Norwegian Cancer Society. The authors have disclosed no relevant conflicts of interest.

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