Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer or Suspected Related Hereditary Syndromes: Historical Prospective Analysis
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Next-Generation Sequencing
2.3. Bioinformatic Analyses and Variant Characterization
3. Results
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Syndrome | Gene | Cancer Type and Risk |
---|---|---|
Breast and ovarian cancer syndrome (HBOC) | BRCA1/2 | PDAC: relative risk of 2–10%, lifelong risk 3–10%. High risk of breast, ovarian, and prostate cancer. |
Lynch syndrome (LS) | MLH1 MSH2 MSH6 PMS2 EPCAM | PDAC: for MLH1 relative risk of ~7%, lifelong risk ~6%. Colorectal, gastric, and endometrial cancer. Phenotype depends on the specific gene and mutation. |
Familial atypical multiple mole melanoma syndrome (FAMM) | CDKN2A | PDAC: relative risk of 13–39%, lifelong risk ~17%. High risk of malignant melanoma. |
Peutz–Jeghers syndrome | STK11 | PDAC: relative risk of 70–75%, lifelong risk > 25%. Gastrointestinal polyposis. |
Li–Fraumeni syndrome | TP53 | PDAC: ~7% of lifelong risk. High risk of hematopoietic malignancies, breast cancer, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas. |
Others | PALB2 ATM BMPR1A SMAD4 | PDAC: relative risk ~2.5%, lifelong risk ~5%. Female breast and ovarian cancer. |
Patients’ Features | n = 113 n, (%) | PVs Carrier n (%) | p-Value |
---|---|---|---|
Sex (female) | 82 (72.6) | ||
Indication for genetic testing
| 31 (27.4) 15 (13.3) 55 (48.6) 26 (23.0) 28 (24.8) 1 (0.9) 12 (10.6) | 3/31 (9.7) * 2/15 (13.3) # 16/55 (29.1) 7/26 (26.9) ç 9/28 (32.1) ° 0/1 (0.0) 2/12 (16.7) & | 0.06 ∇ 0.05 ∇ |
Genetic Variant Details | n = 113 n (%) |
---|---|
Total mutations PVs (class 5) VUS | 58 (51.3) 23 (20.1) 35 (31.0) |
PVs BRCA2 CDKN2A ATM BRCA1 Others * | n = 24 9 (37.5) 6 (25.0) 3 (12.5) 2 (8.3) |
VUS Lynch genes † ATM BRCA ½ PALB2 APC Others ‡ | n = 39 16 (41.0) 9 (23.1) 6 (15.4) 2 (5.1) 2 (5.1) 4 (10.2) |
Patient | Indication for Genetic Testing | Clinical Features | Gene | Nomenclature | Protein Change | Variant Interpretation |
---|---|---|---|---|---|---|
1 | Ssyn | Unaffected; two first-degree relatives affected by melanomas and two first-degree relatives affected by PDAC | CDKN2A | c.142C>A | p.Pro48Thr | Class 5 |
2 | Ssyn | Affected by metastatic PDAC and metachronous breast cancer | MITF | c.1255G>A | p.Glu419Lys | Class 5 |
3 | FH | Unaffected; two first-degree and one second-degree relatives affected by PDAC | BRCA2 | c.6469C>T | p.Gln2157Ter | Class 5 |
4 | Ssyn | Affected by PDAC and metachronous melanoma, one first-degree relative affected by PDAC | CDKN2A | c.71G>C | p.Arg24Pro | Class 5 |
5 | Ssyn | Affected by PDAC and metachronous melanoma, one first-degree relative affected by PDAC | CDKN2A | c.(?_-1)_(*1_?)del | p.0? | Class 5 |
6 | Ssyn | Affected by PDAC with ≥2 first-degree relatives affected by PDAC | BRCA2 | c.4229dupC | p.Ala1411Cysfs*3 | Class 5 |
7 | Ssyn | Affected by PDAC with ≥2 first-degree relatives affected by breast cancer | BRCA2 | c.5073dupA | p.Trp1692MetfsTer3 | Class 5 |
8 | FH | Unaffected; two first-degree and one second-degree relatives affected by PDAC | CDKN2A | c.377T>A | p.Val126Asp | Class 5 |
9 | Ssyn | Affected by breast cancer with ≥2 first-degree relatives affected by PDAC | ATM | c.217_218delGA | p.Glu73MetfsTer26 | Class 5 |
10 | Ssyn | Affected by breast cancer with ≥2 first-degree relatives affected by PDAC | CHEK2 | c.660delA | p.Gly221GlufsTer6 | Class 5 |
11 | Ssyn | Affected by PDAC and metachronous breast cancer | BRCA2 | c.1238delT | p.Leu413Hisfs*17 | Class 5 |
12 | jPDAC | Affected by PDAC before 50 years of age | BRCA2 | c.3744_3747delTGAG | p.Ser1248Argfs*10 | Class 5 |
13 | Ssyn | Affected by PDAC with ≥2 first-degree relatives affected by breast cancer or PDAC | CDKN2A | c.301G>T | p.Gly101Trp | Class 5 |
14 | mPDAC | Affected by metastatic PDAC | BRCA2 | c.3028A>T | p.Arg1010Ter | Class 5 |
15 | Ssyn | Affected by PDAC and metachronous breast cancer | BRCA2 | c.2094delA | p.Gln699SerfsTer31 | Class 5 |
16 | mPDAC | Affected by metastatic PDAC with one first-degree relative affected by breast cancer (bilateral) | ATM | c.8147T>C | p.Val2716Ala | Class 5 |
17 | Ssyn | Affected by PDAC and metachronous melanoma, one first-degree relative affected by melanoma | CDKN2A | c.301G>T | p.Gly101Trp | Class 5 |
18 | Ssyn | Affected by breast cancer with ≥2 first-degree relatives affected by breast cancer or PDAC | BRCA2 | c.7060C>T | p.Gln2354* | Class 5 |
19 | Ssyn | Affected by PDAC and metachronous melanoma and breast cancer | ATM | c.5592delA | p.His1865MetfsTer52 | Class 5 |
20 | Ssyn | Affected by PDAC and metachronous breast cancer | FANCM | c.5101C>T | p.Gln1701Ter | Class 5 |
21 | jPDAC | Affected by PDAC before 50 years of age | BRCA1 | c.3756_3759delGTCT | p.Ser1253ArgfsTer10 | Class 5 |
22 | Ssyn | Affected by PDAC and metachronous bilateral breast cancer | BRCA1 BRCA2 | c.181T>G c.755_758del | p.Cys61Gly p.Asp252ValfsTer24 | Class 5 Class 5 |
23 | mPDAC | Affected by metastatic PDAC with one second-degree relative affected by breast cancer | PALB2 | c.1266del | p.Val423Ter | Class 5 |
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Share and Cite
Dal Buono, A.; Poliani, L.; Greco, L.; Bianchi, P.; Barile, M.; Giatti, V.; Bonifacio, C.; Carrara, S.; Malesci, A.; Laghi, L. Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer or Suspected Related Hereditary Syndromes: Historical Prospective Analysis. Cancers 2023, 15, 1852. https://doi.org/10.3390/cancers15061852
Dal Buono A, Poliani L, Greco L, Bianchi P, Barile M, Giatti V, Bonifacio C, Carrara S, Malesci A, Laghi L. Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer or Suspected Related Hereditary Syndromes: Historical Prospective Analysis. Cancers. 2023; 15(6):1852. https://doi.org/10.3390/cancers15061852
Chicago/Turabian StyleDal Buono, Arianna, Laura Poliani, Luana Greco, Paolo Bianchi, Monica Barile, Valentina Giatti, Cristiana Bonifacio, Silvia Carrara, Alberto Malesci, and Luigi Laghi. 2023. "Prevalence of Germline Mutations in Cancer Predisposition Genes in Patients with Pancreatic Cancer or Suspected Related Hereditary Syndromes: Historical Prospective Analysis" Cancers 15, no. 6: 1852. https://doi.org/10.3390/cancers15061852