bims-lifras 2023-08-27 papers

J Clin Oncol. 2023 Aug 22. JCO2300561

Genomic Profiling Reveals Germline Predisposition and Homologous Recombination Deficien cy in Pancreatic Acinar Cell Carcinoma.

PURPOSE: To determine the genetic predisposition underlying pancreatic acinar cell carcinoma (PACC) and characterize its genomic features.
METHODS: Both somatic and germline analyses were performed using an Food and Drug Administration-authorized matched tumor/normal sequencing assay on a clinical cohort of 28,780 patients with cancer, 49 of whom were diagnosed with PACC. For a subset of PACCs, whole-genome sequencing (WGS; n = 12) and RNA sequencing (n = 6) were performed.
RESULTS: Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). Thirty-one PACCs displayed pure, and 18 PACCs harbored mixed acinar cell histology. Fifteen of 31 (48%) pure PACCs harbored a germline pathogenic variant affecting HR-/DDR-related genes. BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma (86 of 2,739, 3.1%; P < .001), high-grade serous ovarian carcinoma (67 of 1,318, 5.1%; P < .001), prostate cancer (116 of 3,401, 3.4%; P < .001), and breast cancer (79 of 3,196, 2.5%; P < .001). Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs undergoing WGS, including 100% (n = 6) of PACCs with germline HR-related pathogenic mutations and 1 of 6 PACCs lacking known pathogenic alterations in HR-related genes. Exploratory analyses revealed that in PACCs, the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity varied according to the presence of germline pathogenic alterations affecting HR-/DDR-related genes and/or HRD.
CONCLUSION: In a large pan-cancer cohort, PACC was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that PACC should be considered as part of the spectrum of BRCA-related malignancies.

DOI: https://doi.org/10.1200/JCO.23.00561

Genes (Basel). 2023 Aug 03. pii: 1580. [Epub ahead of print]14(8):

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients.

Luiza Côrtes, Tatiane Ramos Basso, Rolando André Rios Villacis, Jeferson Dos Santos Souza, Mads Malik Aagaard Jørgensen, Maria Isabel Achatz, Silvia Regina Rogatto.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is an autosomal dominant disease associated with a high risk of developing breast, ovarian, and other malignancies. Lynch syndrome is caused by mutations in mismatch repair genes predisposing to colorectal and endometrial cancers, among others. A rare phenotype overlapping hereditary colorectal and breast cancer syndromes is poorly characterized. Three breast and colorectal cancer unrelated patients fulfilling clinical criteria for HBOC were tested by whole exome sequencing. A family history of colorectal cancer was reported in two patients (cases 2 and 3). Several variants and copy number variations were identified, which potentially contribute to the cancer risk or prognosis. All patients presented copy number imbalances encompassing PMS2 (two deletions and one duplication), a known gene involved in the DNA mismatch repair pathway. Two patients showed gains covering the POLE2 (cases 1 and 3), which is associated with DNA replication. Germline potentially damaging variants were found in PTCH1 (patient 3), MAT1A, and WRN (patient 2). Overall, concurrent genomic alterations were described that may increase the risk of cancer appearance in HBOC patients with breast and colorectal cancers.

Keywords: PMS2; colorectal cancer; copy number alteration; hereditary breast and ovarian cancer syndrome; whole exome sequencing

DOI: https://doi.org/10.3390/genes14081580

Cancers (Basel). 2023 Aug 12. pii: 4074. [Epub ahead of print]15(16):

Variant Characterization of a Representative Large Pedigree Suggests "Variant Risk Clusters" Convey Varying Predisposition of Risk to Lynch Syndrome.

Mouadh Barbirou, Amanda A Miller, Amel Mezlini, Balkiss Bouhaouala-Zahar, Peter J Tonellato.

Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three "variant risk clusters" shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different "variant risk clusters" can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree.

Keywords: Lynch syndrome; colorectal cancer; familial germline variants; whole-genome sequencing; “variant risk cluster” predisposition

DOI: https://doi.org/10.3390/cancers15164074

Front Oncol. 2023 ;13 1205847

A complex rearrangement between APC and TP63 associated with familial adenomatous polyposis identified by multimodal genomic analysis: a case report.

Satoyo Oda, Mineko Ushiama, Wataru Nakamura, Masahiro Gotoh, Noriko Tanabe, Tomoko Watanabe, Yoko Odaka, Kazuhiko Aoyagi, Hiromi Sakamoto, Takeshi Nakajima, Kokichi Sugano, Teruhiko Yoshida, Yuichi Shiraishi, Makoto Hirata.

Genetic testing of the APC gene by sequencing analysis and MLPA is available across commercial laboratories for the definitive genetic diagnosis of familial adenomatous polyposis (FAP). However, some genetic alterations are difficult to detect using conventional analyses. Here, we report a case of a complex genomic APC-TP63 rearrangement, which was identified in a patient with FAP by a series of genomic analyses, including multigene panel testing, chromosomal analyses, and long-read sequencing. A woman in her thirties was diagnosed with FAP due to multiple polyps in her colon and underwent total colectomy. Subsequent examination revealed fundic gland polyposis. No family history suggesting FAP was noted except for a first-degree relative with desmoid fibromatosis. The conventional APC gene testing was performed by her former doctor, but no pathogenic variant was detected, except for 2 variants of unknown significance. The patient was referred to our hospital for further genetic analysis. After obtaining informed consent in genetic counseling, we conducted a multigene panel analysis. As insertion of a part of the TP63 sequence was detected within exon16 of APC, further analyses, including chromosomal analysis and long-read sequencing, were performed and a complex translocation between chromosomes 3 and 5 containing several breakpoints in TP63 and APC was identified. No phenotype associated with TP63 pathogenic variants, such as split-hand/foot malformation (SHFM) or ectrodactyly, ectodermal dysplasia, or cleft lip/palate syndrome (EEC) was identified in the patient or her relatives. Multimodal genomic analyses should be considered in cases where no pathogenic germline variants are detected by conventional genetic testing despite an evident medical or family history of hereditary cancer syndromes.

Keywords: APC regulator of WNT signaling pathway; adaptive sampling; familial adenomatous polyposis; multi-gene panel testing; tumor protein 63

DOI: https://doi.org/10.3389/fonc.2023.1205847

Cancer Med. 2023 Aug 23.

Prevalence and spectrum of cancer predisposition germline mutations in young patients with the common late-onset cancers.

Shaoyu Hao, Ximeng Zhao, Yue Fan, Zhengchuang Liu, Xiang Zhang, Wei Li, Hongling Yuan, Jie Zhang, Yanxiang Zhang, Tonghui Ma, Houquan Tao.

BACKGROUND: Pathogenic germline variants (PGVs) can play a vital role in the oncogenesis process in carriers. Previous studies have recognized that PGVs contribute to early onset of tumorigenesis in certain cancer types, for example, colorectal cancer and breast cancer. However, the reported prevalence data of cancer-associated PGVs were highly inconsistent due to nonuniform patient cohorts, sequencing methods, and prominent difficulties in pathogenicity interpretation of variants. In addition to the above difficulties, due to the rarity of cases, the prevalence of cancer PGV carriers in young cancer patients affected by late-onset cancer types has not been comprehensively evaluated to date.
METHODS: A total of 131 young cancer patients (1-29 years old at diagnosis) were enrolled in this study. The patients were affected by six common late-onset cancer types, namely, lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and head-neck cancer. Cancer PGVs were identified and analyzed. based on NGS-based targeted sequencing followed by bioinformatic screening and strict further evaluations of variant pathogenicity.
RESULTS: Twenty-three cancer PGVs in 21 patients were identified, resulting in an overall PGV prevalence of 16.0% across the six included cancer types, which was approximately double the prevalence reported in a previous pancancer study. Nine of the 23 PGVs are novel, thus expanding the cancer PGV spectrum. Seven of the 23 (30.4%) PGVs are potential therapeutic targets of olaparib, with potential implications for clinical manipulation. Additionally, a small prevalence of somatic mutations of some classic cancer hallmark genes in young patients, in contrast to all-age patients, was revealed.
CONCLUSION: This study demonstrates the high prevalence of PGVs in young cancer patients with the common late-onset cancers and the potentially significant clinical implications of cancer PGVs, the findings highlight the value of PGV screening in young patients across lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, or head-neck cancer.

Keywords: Chinese; cancer; early onset; germline variation

DOI: https://doi.org/10.1002/cam4.6445