{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:36:36Z","timestamp":1790116596524,"version":"4.0.1"},"reference-count":30,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2023,7,1]]},"abstract":"<jats:sec id=\"ab-coi230014-4\"><jats:title>Importance<\/jats:title><jats:p>Increased cancer risk in first-degree relatives of probands with pancreatic ductal adenocarcinoma (PDAC probands) who carry pathogenic or likely pathogenic germline variants (PGVs) in cancer syndrome\u2013associated genes encourages cascade genetic testing. To date, unbiased risk estimates for the development of cancers on a gene-specific basis have not been assessed.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi230014-5\"><jats:title>Objective<\/jats:title><jats:p>To quantify the risk of development of PDAC and extra-PDAC among first-degree relatives of PDAC probands who carry a PGV in 1 of 9 cancer syndrome\u2013associated genes\u2014<jats:italic>ATM, BRCA1, BRCA2, PALB2<\/jats:italic>, <jats:italic>MLH1, MSH2, MSH6, PMS2<\/jats:italic>, and <jats:italic>CDKN2A<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi230014-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This case series focused on first-degree relatives of PDAC probands carrying PGVs in specific cancer syndrome\u2013associated genes. The cohort comprised clinic-ascertained patients enrolled in the Mayo Clinic Biospecimen Resource for Pancreas Research registry with germline genetic testing. In total, 234 PDAC probands carrying PGVs were drawn from the prospective research registry of 4562 participants who had undergone genetic testing of cancer syndrome\u2013associated genes. Demographic and cancer-related family histories were obtained by questionnaire. The data were collected from October 1, 2000, to December 31, 2021.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi230014-7\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>For the PDAC probands, the genetic test results of the presence of PGVs in 9 cancer syndrome\u2013associated genes were obtained by clinical testing. Cancers (ovary, breast, uterus or endometrial, colon, malignant melanoma, and pancreas) among first-degree relatives were reported by the probands. Standardized incidence ratios (SIRs) were used to estimate cancer risks among first-degree relatives of PDAC probands carrying a PGV.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi230014-8\"><jats:title>Results<\/jats:title><jats:p>In total, 1670 first-degree relatives (mean [SD] age, 58.1\u2009[17.8] years; 853 male [51.1%]) of 234 PDAC probands (mean [SD] age, 62.5 [10.1] years; 124 male [53.0%]; 219 [94.4%] White; 225 [98.7%] non-Hispanic or non-Latino]) were included in the study. There was a significantly increased risk of ovarian cancer in female first-degree relatives of probands who had variants in <jats:italic>BRCA1<\/jats:italic> (SIR, 9.49; 95% CI, 3.06-22.14) and <jats:italic>BRCA2<\/jats:italic> (SIR, 3.72; 95% CI, 1.36-8.11). Breast cancer risks were higher with <jats:italic>BRCA2<\/jats:italic> variants (SIR, 2.62; 95% CI, 1.89-3.54). The risks of uterine or endometrial cancer (SIR, 6.53; 95% CI, 2.81-12.86) and colon cancer (SIR, 5.83; 95% CI, 3.70-8.75) were increased in first-degree relatives of probands who carried Lynch syndrome mismatch repair variants. Risk of PDAC was also increased for variants in <jats:italic>ATM<\/jats:italic> (SIR, 4.53; 95% CI, 2.69-7.16), <jats:italic>BRCA2<\/jats:italic> (SIR, 3.45; 95% CI, 1.72-6.17), <jats:italic>CDKN2A<\/jats:italic> (SIR, 7.38; 95% CI, 3.18-14.54), and <jats:italic>PALB2<\/jats:italic> (SIR, 5.39; 95% CI, 1.45-13.79). Melanoma risk was elevated for first-degree relatives of probands with <jats:italic>CDKN2A<\/jats:italic> variants (SIR, 7.47; 95% CI, 3.97-12.77).<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi230014-9\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this case series, the presence of PGVs in 9 cancer syndrome\u2013associated genes in PDAC probands was found to be associated with increased risk of 6 types of cancers in first-degree relatives. These gene-specific PDAC and extra-PDAC cancer risks may provide justification for clinicians to counsel first-degree relatives about the relevance and importance of genetic cascade testing, with the goal of higher uptake of testing.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaoncol.2023.0806","type":"journal-article","created":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T15:02:04Z","timestamp":1684422124000},"page":"955","source":"Crossref","is-referenced-by-count":11,"title":["Risk of Syndrome-Associated Cancers Among First-Degree Relatives of Patients With Pancreatic Ductal Adenocarcinoma With Pathogenic or Likely Pathogenic Germline Variants"],"prefix":"10.1001","volume":"9","author":[{"given":"Xuan","family":"Chen","sequence":"first","affiliation":[{"name":"Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret 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