Israel Medical Association Journal

Background: BRCA1/BRCA2 female pathogenic sequence variant (PSV) carriers in Israel are offered semiannual cancer antigen 125 (CA125) serum level determination and transvaginal ultrasound until performing risk reducing salpingo-oophorectomy (RRSO), even with the lack of proven efficacy of these procedures in providing adequate early detection of ovarian cancer.

Objectives: To report the results of longitudinal CA125 measurements in BRCA1/BRCA2 carriers as a tool for ovarian cancer detection in a single medical center in Israel.

Methods: Asymptomatic BRCA1/BRCA2 PSV carriers attending the Meirav High Risk Clinic at Sheba Medical Center for more than 3 years were eligible. Data on specific PSV, risk reducing surgeries, and cancer diagnoses were obtained from participant records. We used chi-square and Wilcoxon-Rank tests for statistical analyses.

Results: Overall, 739 (399 BRCA1, 336 BRCA2, 4 BRCA1 + BRCA2) PSV carriers were included. Mean age at the start of follow-up was 38.96 ± 11.13 years, mean follow-up time was 7.93 ± 2.34 years, (5860.80 women/years). Most participants (490/739 [66.3%]) had stable CA125 levels (± 5 U/µl). Of participants, 61 had CA125 levels > 35 U/µl at least twice (n=42) or at least doubling of marker levels to a minimum of 20 U/µl (n=19), results that have led to further cancer defining investigations. Of these, 14 and 4 were diagnosed with breast and ovarian cancer, respectively.

Conclusions: Longitudinally stable CA125 levels were noted in most BRCA1/BRCA2 PSV carriers and elevated levels were a poor marker for ovarian cancer development.

Germline pathogenic variants (PVs) in the RET proto-oncogene (OMIM 164761) are associated with a diverse phenotype based on the type of PV. Gain-of-function (GOF) PVs are associated with the highly penetrant multiple endocrine neoplasia type 2 (MEN2-OMIM 171400), which are hallmarked by an increased risk for developing medullary thyroid cancer (MTC), pheochromocytoma, and parathyroid adenomas. Loss-of-function (LOF) RET PVs are associated with incompletely penetrant Hirschsprung's disease (HSCR OMIM 142623), which are pathologically characterized by the absence of enteric ganglia affecting the distal colon and clinically manifest as neonatal intestinal obstruction. Despite anecdotal reports of familial clustering of neoplasms in HSCR families, mostly MEN2-associated tumors [1,2], HSCR is not considered to be associated with an increased risk for developing cancer [3]. We report on a family with an unusual multigenerational solid tumor phenotype and severe HSCR phenotype with a LOF RET PV.

Background: Biallelic BLM gene mutation carriers are at an increased risk for cancer, including colorectal cancer (CRC). Whether heterozygous BLM gene mutations confer an increased cancer risk remains controversial.

Objectives: To evaluate CRC and endometrial cancer risk in BLM heterozygous mutation carriers.

Methods: Jewish Ashkenazim at high risk for colon or endometrial cancer and endometrial cancer cases unselected for family history were genotyped for the BLM^Ash predominant mutation.

Results: Overall, 243 high-risk individuals were included: 97 men CRC patients (55.12 ± 12.3 years at diagnosis), 109 women with CRC (56.5 ± 13.7 years), 32 women with endometrial cancer (58.25 ± 13.4 years) and 5 women with both CRC and endometrial cancer. In addition, 120 unselected Ashkenazi women with endometrial cancer (64.2 ± 11.58 years) were genotyped. The BLM^Ash mutation was present in 4/243 (1.65%) high-risk patients; 2 CRC (0.97%) 2 endometrial cancer (5.4%), and 1/120 unselected endometrial cancer patients (0.84%). Notably, in high-risk cases, BLM^Ash mutation carriers were diagnosed at a younger age (for CRC 47.5 ± 7.8 years; P = 0.32 ; endometrial cancer 49.5 ± 7.7 years; P = 0.36) compared with non-carriers.

Conclusions: Ashkenazi high risk CRC/endometrial cancer, and women with endometrial cancer have a higher rate of BLM^Ash heterozygous mutation compared with the general population. BLM^Ash heterozygous mutation carriers are diagnosed with CRC and endometrial cancer at a younger age compared with non-carriers. These observations should be validated and the possible clinical implications assessed.