UNASSIGNED: Accurate identification and characterization of Large Genomic Rearrangements (LGR), especially duplications, are crucial for precise diagnosis and risk assessment. In this report, we characterized an intragenic duplication breakpoint of PALB2 to determine its pathogenicity significance.
UNASSIGNED: A 52-year-old female with triple-negative breast cancer was diagnosed with a novel PALB2 LGR. An efficient and accurate methodology was applied, combining long-read sequencing and transcript analysis for the rapid characterization of the duplication.
UNASSIGNED: Duplication of exons 5 and 6 of PALB2 was validated by transcript analysis. Long-read sequencing enabled the localization of breakpoints within Alu elements, providing insights into the mechanism of duplication via non-allelic homologous recombination.
UNASSIGNED: Using our combined methodology, we reclassified the PALB2 duplication as a pathogenic variant. This reclassification suggests a possible causative link between this specific genetic alteration and the aggressive phenotype of the patient.

Germline pathogenic variants (PV) of the PALB2 tumor suppressor gene are associated with an increased risk of breast, pancreatic, and ovarian cancer. In previous research, PALB2-associated breast cancer showed aggressive clinicopathological phenotypes, particularly triple-negative subtype, and higher mortality regardless of tumor stage, type of chemotherapy nor hormone receptor status. The identification of this germline alteration may have an impact on clinical management of breast cancer (BC) from the surgical approach to the systemic treatment choice. We herein report the case of a patient with a germline PV of PALB2, diagnosed with locally advanced PD-L1 positive triple-negative BC, who progressed after an immune checkpoint inhibitor (ICI)-containing regimen and then experienced a pathologic complete response after platinum-based chemotherapy. This case report hints a major role of the germline PALB2 alteration compared to the PD-L1 expression as cancer driver and gives us the opportunity to extensively review and discuss the available literature on the optimal management of PALB2-associated BC. Overall, our case report and review of the literature provide additional evidence that the germline analysis of PALB2 gene should be included in routine genetic testing for predictive purposes and to refine treatment algorithms.

Germline pathogenic variants (PVs) in BRCA1/2 genes are associated with breast cancer (BC) risk in both women and men. Multigene panel testing is being increasingly used for BC risk assessment, allowing the identification of PVs in genes other than BRCA1/2. While data on actionable PVs in other cancer susceptibility genes are now available in female BC, reliable data are still lacking in male BC (MBC). This study aimed to provide the patterns, prevalence and risk estimates associated with PVs in non-BRCA1/2 genes for MBC in order to improve BC prevention for male patients.
We performed a large case-control study in the Italian population, including 767 BRCA1/2-negative MBCs and 1349 male controls, all screened using a custom 50 cancer gene panel.
PVs in genes other than BRCA1/2 were significantly more frequent in MBCs compared with controls (4.8% vs 1.8%, respectively) and associated with a threefold increased MBC risk (OR: 3.48, 95% CI: 1.88-6.44; p < 0.0001). PV carriers were more likely to have personal (p = 0.03) and family (p = 0.02) history of cancers, not limited to BC. PALB2 PVs were associated with a sevenfold increased MBC risk (OR: 7.28, 95% CI: 1.17-45.52; p = 0.034), and ATM PVs with a fivefold increased MBC risk (OR: 4.79, 95% CI: 1.12-20.56; p = 0.035).
This study highlights the role of PALB2 and ATM PVs in MBC susceptibility and provides risk estimates at population level. These data may help in the implementation of multigene panel testing in MBC patients and inform gender-specific BC risk management and decision making for patients and their families.

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with no established treatment protocol. The authors report the case of a young woman diagnosed with PEH. DNA and RNA analysis by next-generation sequencing was performed on the tumor tissue. A novel germline PALB2 mutation and classical WWTR1-CAMTA1 fusion were identified. She experienced a poor response to sintilimab (a PD-1 inhibitor) plus platinum-based chemotherapy as the first-line treatment. PEH patients harboring a germline PALB2 mutation and WWTR1-CAMTA1 gene fusion may respond poorly to treatment with PD-1 inhibitors plus chemotherapy.
Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with no established treatment protocol. Although PD-1 inhibitors have dramatically improved the prognosis of some tumors, the efficacy is unknown in PEH patients. The authors report an advanced PEH patient treated with sintilimab plus platinum-based chemotherapy, who died after two cycles of treatment. The authors inferred that PEH patients with a germline PALB2 mutation and WWTR1-CAMTA1 fusion may not benefit from PD-1 inhibitors plus chemotherapy.

PARP inhibitors have recently emerged as a maintenance treatment option for metastatic pancreatic cancer patients with germline BRCA mutations. However, the possibility of PARP-inhibitor use as a standalone-targeted therapy for patients with various homologous repair pathway alterations remains mostly undetermined. Here we report a clinical case of a 56-year-old woman with pancreatic ductal adenocarcinoma harboring a somatic PALB2 mutation. Following disease progression after 10 cycles of FOLFIRINOX chemotherapy and two cycles of second-line gemcitabine, she was switched to talazoparib and achieved a complete clinical response after 25 months of treatment. The patient remains alive without clinical or radiological signs of disease progression three years after the start of talazoparib with no targeted therapy-related toxicities. This case highlights the role of broad molecular profiling as a window of opportunity to achieve a durable response for selected pancreatic cancer patients while pinpointing our gaps in understanding the whole picture of management of these patients since a new puzzle element represented by PARP inhibitors was introduced to clinical practice.

The partner and localizer of BRCA2 (PALB2) is a major BRCA2 binding partner that participates in homologous recombination repair in response to DNA double-strand breaks. Germline alterations of the PALB2 gene have recently been associated with a high risk of developing breast cancer. We investigated a 37-year-old Caucasian woman with breast cancer and family history of breast cancer using targeted next generation sequencing. A novel heterozygous deletion involving exons 5 and 6 was found in the PALB2 gene, and resulted in the production of a truncated PALB2 protein. These findings expand the mutational spectra of PALB2-associated breast cancer, and may improve the mutation-based screening and genetic diagnosis of breast cancer.

BACKGROUND: Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis.
METHODS: Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary.
CONCLUSIONS: Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

UNASSIGNED: Mutation-caused loss-of-function of factors involved in DNA damage response (DDR) is responsible for the development and progression of ~20% of prostate cancer (PCa). Some mutations can be used in cancer risk assessment and informed treatment decisions.
UNASSIGNED: Target capture-based deep sequencing of 11 genes was conducted with total DNA purified from the proband\'s peripheral blood. Sanger sequencing was conducted to screen potential germline mutations in the proband\'s family members. Targeted sequencing of a panel of 1,021 genes was done with DNA purified from the tumor tissue.
UNASSIGNED: Two previously unreported germline mutations in the DDR pathway, BRCA2 (c.8474_8487delCATACCCTATACAG, p.A2825Vfs*15) and PALB2 (c.472delC, p.Q158Rfs*19) were identified in a patient with metastatic PCa. A specific therapeutic regimen including androgen deprivation therapy, locally radical radiotherapy, and systemic platinum chemotherapy worked well against his cancer. In addition, the metastatic ovarian cancer in the proband\'s half-sister harboring the same BRCA2 germline mutation also responded well to platinum chemotherapy.
UNASSIGNED: The newly identified germline mutations in DDR plays important role in PCa development. Since specific regimen worked well against this cancer, screening of DDR mutation could provide better management for patients with these mutation-mediated PCa.

Partner and localizer of breast cancer 2 (PALB2) was identified as a moderate-risk gene of breast and pancreas cancer. The present authors previously reported that no PALB2 germline mutations with a deleterious frameshift or stop codons were identified in 155 Japanese patients with breast and/or ovarian cancer who were estimated to be at risk of hereditary cancer, according to the National Comprehensive Cancer Network (NCCN) criteria. In the present study, one patient with a deleterious mutation of PALB2 (c. 2834+2 T>C) has been identified from a study of an additional 128 cases. Therefore, the prevalence of PALB2 among Japanese patients is now estimated to be 0.35% (1/283). The proband was a 63-year-old woman with bilateral breast cancer, although she had experienced no other cancers. The proband had two elder sisters, the eldest of whom died from pancreatic cancer at 60 years of age. The proband\'s 40-year-old daughter was affected, but did not show any malignancies. There are only a few reports concerning PALB2 mutations in Japan. To the best of our knowledge, this is the first case study to reveal the significance of DNA-repair genes in the development of malignancies in Japanese patients with breast cancer.

We describe the association of familial multiple subcutaneous lipomatosis with a PALB2 gene mutation (c.2716delT) and its increased predilection to cancers.