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IMPORTANCE: Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. OBJECTIVE: To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. DESIGN, SETTING, AND PARTICIPANTS: Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. EXPOSURES: Entrance into an MRI surveillance program. MAIN OUTCOMES AND MEASURES: Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. RESULTS: A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. CONCLUSION AND RELEVANCE: Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

The molecular diagnosis of mismatch repair–deficient cancer syndromes is hampered by difficulties in sequencing the PMS2gene, mainly owing to the PMS2CL pseudogene. Next-generation sequencing short reads cannot be mapped unambiguously by standard pipelines, compromising variant calling accuracy. This study aimed to provide a refined bioinformatic pipeline for PMS2mutational analysis and explore PMS2germline pathogenic variant prevalence in an unselected hereditary cancer (HC) cohort. PMS2mutational analysis was optimized using two cohorts: 192 unselected HC patients for assessing the allelic ratio of paralogous sequence variants, and 13 samples enriched with PMS2(likely) pathogenic variants screened previously by long-range genomic DNA PCR amplification. Reads were forced to align with the PMS2reference sequence, except those corresponding to exon 11, where only those intersecting gene-specific invariant positions were considered. Afterward, the refined pipeline's accuracy was validated in a cohort of 40 patients and used to screen 5619 HC patients. Compared with our routine diagnostic pipeline, the PMS2_vaR pipeline showed increased technical sensitivity (0.853 to 0.956) in the validation cohort, identifying all previously PMS2pathogenic variants found by long-range genomic DNA PCR amplification. Fifteen HC cohort samples carried a pathogenic PMS2variant (15 of 5619; 0.285%), doubling the estimated prevalence in the general population. The refined open-source approach improved PMS2mutational analysis accuracy, allowing its inclusion in the routine next-generation sequencing pipeline streamlining PMS2screening.

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome responsible for 1% of colorectal cancers. Up to 90% of classical FAP are caused by inactivating mutations in APC, and mosaicism has been previously reported in 20% of de novocases, usually linked to milder phenotypic manifestations. To explore the prevalence of mosaicism in 11 unsolved cases of classical FAP and to evaluate the diagnostic yield of somatic testing. Paired samples of colorectal polyps, tumors and/or mucosa were analyzed using a custom NGS panel targeting 15 polyposis and colorectal cancer-predisposing genes. Whenever possible, the extension of mosaicism to blood or sperm was also examined. Out of 11 patients with classical adenomatous polyposis, a mosaic pathogenic variant in APCwas identified in seven (64%). No other altered genes were identified. In 2/7 (29%) mosaicism was found restricted to colonic tissues, while in 5/7 (71%) it was extended to the blood. Germline affectation was confirmed in one patient. We report the first analysis at a somatic level of 15 genes associated with colorectal cancer susceptibility, which highlights the role of APCmosaicism in classical FAP etiology. The results further reinforce the importance of testing target tissues when blood test results are negative.