Primary Ovarian Insufficiency Diagnosis Linked to Breast Cancer

Variants of genes that repair DNA damage are associated with the link between primary ovarian insufficiency (POI) and cancer risk, according to the results of a study published in the Journal of Clinical Endocrinology and Metabolism.

POI, or primary hypogonadism that develops in women younger than 40 years of age, is mainly caused by autoimmune diseases, FMR1 pre-mutations, and deletions and translocations of the X chromosome. However, next generation sequencing has shown that POI is associated with a candidate or causal gene in as many as 43% of women. Moreover, half of the gene variants that cause POI were discovered in genes that affect meiosis, DNA damage repair and transcription, and translation fidelity. As a result, mutations in these genes may predispose women with POI to cancer.

To identify a subset of women with POI and their family members who are at increased risk for cancer, researchers conducted a case-control, population-based study by using electronic medical records from 1995 through 2022 from 2 major academic healthcare systems serving 85% of Utah residents. Women who were 40 years of age and younger with POI and without Turner syndrome, hysterectomy, oophorectomy, endometriosis with pelvic surgery, and pelvic radiation or chemotherapy before POI diagnosis were eligible for inclusion.

The researchers used the Utah Population Database to link genealogical information with the participants’ medical records data. To participate in this part of the study, individuals needed at least 3 generations of available genealogic information, including data from both parents and all grandparents or at least 6 ancestors.

The researchers estimated the relative risk (RR) of cancer among women with POI and their relatives by comparing their cancer rates to the cancer rate for the population. They also conducted whole genome sequencing for a subset of 6 women to identify causal and candidate gene variants for POI and cancer.

The study included 613 participants whose mean (SD) age was 32.7 (7.4) years at POI diagnosis and 48.3 (11.8) years at the time of the study. Of these participants, 78.8% were White, 10.4% were White Hispanic, and 1.6% were Asian. Of the 18 women who developed breast cancer, the mean (SD) age at diagnosis was 59.5 (12.7) years. The researchers identified 3 generations of genealogical data for 416 participants.

The breast cancer rate among women with POI was more than twice the rate among the general population (RR, 2.20; 95% CI, 1.30-3.47; P =.0023). This risk was still significant after including participants with early menopause (n=165). The researchers identified no pathogenic mutations among the participants with breast cancer who underwent genetic testing. 

Among the participants’ second-degree but not first-degree relatives, the researchers found an increased risk for breast (RR, 1.28; 95% CI, 1.08-1.52; P =.0078) and colon (RR, 1.50; 95% CI, 1.14-1.94; P =.0036) cancer.

Prostate cancer risk was also increased among participants’ first-degree (RR, 1.64; 95% CI, 1.18-2.23; P =.0026), second-degree (RR, 1.54; 95% CI, 1.32-1.79; P <.001), and third-degree (RR, 1.33; 95% CI, 1.20-1.48; P <.001) relatives.

Among the 6 participants who underwent whole genome sequencing, the researchers identified frameshift variants in RAD51D and MORC2 and a stop gain and missense variant in FANCM.

Study limitations include the exclusion of individuals with very early cancer diagnoses requiring radiation or chemotherapy who might have experienced POI when older, a primarily northern European study population, and the need for genetic testing to determine whether the family relationships actually indicate a shared genetic risk for reproductive cancers.

“Clinicians need tools to predict cancer risk and comorbid disease in women with POI to adequately counsel about future health in light of our findings,” the researchers concluded. “Our data suggest that a subset of women with POI need counseling regarding future cancer risk.”

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Endocrinology Advisor