bims-lifras 2023-10-01 papers

J Gynecol Oncol. 2023 Sep 05.

Comparison of immediate germline sequencing and multi-step screening for Lynch syndrome detection in high-risk endometrial and colorectal cancer patients.

An-Shine Chao, Angel Chao, Chyong-Huey Lai, Chiao-Yun Lin, Lan-Yan Yang, Shih-Cheng Chang, Ren-Chin Wu.

OBJECTIVE: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome with a significantly increased risk of colorectal and endometrial cancers. Current standard practice involves universal screening for LS in patients with newly diagnosed colorectal or endometrial cancer using a multi-step screening protocol (MSP). However, MSP may not always accurately identify LS cases. To address this limitation, we compared the diagnostic performance of immediate germline sequencing (IGS) with MSP in a high-risk group.
METHODS: A total of 31 Taiwanese women with synchronous or metachronous endometrial and colorectal malignancies underwent MSP which included immunohistochemical staining of DNA mismatch repair (MMR) proteins, MLH1 promoter hypermethylation analysis, and germline sequencing to identify pathogenic variants. All patients who were excluded during MSP received germline sequencing for MMR genes to simulate IGS for the detection of LS.
RESULTS: Our findings indicate that IGS surpassed MSP in terms of diagnostic yield (29.0% vs. 19.4%, respectively) and sensitivity (90% vs. 60%, respectively). Specifically, IGS successfully identified nine LS cases, which is 50% more than the number detected through MSP. Additionally, germline methylation analysis revealed one more LS case with constitutional MLH1 promoter hypermethylation, bringing the total LS cases to ten (32.3%). Intriguingly, we observed no significant differences in clinical characteristics or overall survival between patients with and without LS in our cohort.
CONCLUSION: Our study suggests that IGS may potentially offer a more effective approach compared to MSP in identifying LS among high-risk patients. This advantage is evident when patients have been pre-selected utilizing specific clinical criteria.

Keywords: Colorectal Cancer; DNA Mismatch Repair; Endometrial Cancer; Lynch Syndrome

DOI: https://doi.org/10.3802/jgo.2024.35.e5

Front Oncol. 2023 ;13 1222873

Case Report: Cancer spectrum and genetic characteristics of a de novo germline POLD1 p.L606M variant-induced polyposis syndrome.

Ying Zhang, Xiaolu Wang, Yuning Zhu, Chong Liang, Lijun Zhao, Qi Meng, Jiani C Yin, Yuqian Shi, Fufeng Wang, Feng Qin, Ji Xuan.

Germline variations in the DNA polymerase genes, POLE and POLD1, can lead to a hereditary cancer syndrome that is characterized by frequent gastrointestinal polyposis and multiple primary malignant tumors. However, because of its rare occurrence, this disorder has not been extensively studied. In this report, we present the case of a 22-year-old female patient who had been diagnosed with gastrointestinal polyposis, breast fibroadenoma, multiple primary colorectal cancers, and glioblastoma (grade IV) within a span of 4 years. Next-generation sequencing analysis revealed a germline variant in POLD1 (c.1816C>A; p.L606M). In silico analysis using protein functional predicting software, including SIFT, Polyphen, GERP++, and CADD, further confirmed the pathogenicity of POLD1 p.L606M (classified as ACMG grade Class 4). In line with polymerase deficiency, both rectal cancer and glioblastoma tissues exhibited a high tumor mutation burden, with 16.9 muts/Mb and 347.1 muts/Mb, respectively. Interestingly, the patient has no family history of cancer, and gene examination of both parents confirms that this is a de novo germline variant. Therefore, molecular screening for POLD1 may be necessary for patients with such a cancer spectrum, regardless of their family history.

Keywords: NGS; POLD1; POLE; germline POLD1 L606M; polyposis syndrome

DOI: https://doi.org/10.3389/fonc.2023.1222873

Genes (Basel). 2023 Aug 24. pii: 1670. [Epub ahead of print]14(9):

Simultaneous Occurrence of Multiple Neoplasms in Children with Cancer Predisposition Syndromes: Collaborating with Abnormal Genes.

Gabriela Telman, Ewa Strauss, Patrycja Sosnowska-Sienkiewicz, Magdalena Halasz, Danuta Januszkiewicz-Lewandowska.

The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that increase the risk of developing cancer at an earlier age compared to the risk for the general population. This article aims to provide a comprehensive analysis of three unique cases involving pediatric patients with CPS who were diagnosed with multiple simultaneous or metachronous cancers. The first case involves a child with embryonal rhabdomyosarcoma, nephroblastoma, glioma, and subsequent medulloblastoma. Genetic analysis identified two pathogenic variants in the BRCA2 gene. The second case involves a child with alveolar rhabdomyosarcoma, juvenile xanthogranuloma, gliomas, and subsequent JMML/MDS/MPS. A pathogenic variant in the NF1 gene was identified. The third case involves a child with pleuropulmonary blastoma and pediatric cystic nephroma/nephroblastoma, in whom a pathogenic variant in the DICER1 gene was identified. Multiple simultaneous and metachronous cancers in pediatric patients with CPSs are a rare but significant phenomenon. Comprehensive analysis and genetic testing play significant roles in understanding the underlying mechanisms and guiding treatment strategies for these unique cases. Early detection and targeted interventions are important for improving outcomes in these individuals.

Keywords: cancer predisposition syndromes; genetic abnormalities; neoplasms; pediatric cancers; personalized treatment; simultaneous occurrence; tumor suppressor genes

DOI: https://doi.org/10.3390/genes14091670

Int J Mol Sci. 2023 Sep 20. pii: 14348. [Epub ahead of print]24(18):

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients.

Ayman Al Saati, Pierre Vande Perre, Julien Plenecassagnes, Julia Gilhodes, Nils Monselet, Bastien Cabarrou, Norbert Lignon, Thomas Filleron, Dominique Telly, Emilie Perello-Lestrade, Viviane Feillel, Anne Staub, Mathilde Martinez, Edith Chipoulet, Gaëlle Collet, Fabienne Thomas, Laurence Gladieff, Christine Toulas.

Even though male breast cancer (MBC) risk encompasses both genetic and environmental aetiologies, the primary risk factor is a germline pathogenic variant (PV) or likely pathogenic variant (LPV) in BRCA2, BRCA1 and/or PALB2 genes. To identify new potential MBC-specific predisposition genes, we sequenced a panel of 585 carcinogenesis genes in an MBC cohort without BRCA1/BRCA2/PALB2 PV/LPV. We identified 14 genes carrying rare PVs/LPVs in the MBC population versus noncancer non-Finnish European men, predominantly coding for DNA repair and maintenance of genomic stability proteins. We identified for the first time PVs/LPVs in PRCC (pre-mRNA processing), HOXA9 (transcription regulation), RECQL4 and WRN (maintenance of genomic stability) as well as in genes involved in other cellular processes. To study the specificity of this MBC PV/LPV profile, we examined whether variants in the same genes could be detected in a female breast cancer (FBC) cohort without BRCA1/BRCA2/PALB2 PV/LPV. Only 5/109 women (4.6%) carried a PV/LPV versus 18/85 men (21.2%) on these genes. FBC did not carry any PV/LPV on 11 of these genes. Although 5.9% of the MBC cohort carried PVs/LPVs in PALLD and ERCC2, neither of these genes were altered in our FBC cohort. Our data suggest that in addition to BRCA1/BRCA2/PALB2, other genes involved in DNA repair/maintenance or genomic stability as well as cell adhesion may form a specific MBC PV/LPV signature.

Keywords: MBC-specific mutated profile; large multigene panel sequencing; male breast cancer predisposition; new genes potentially involved in MBC risk

DOI: https://doi.org/10.3390/ijms241814348