Table 2 A compendium of studies using LR DNA-Seq in cancer patients with known or suspected hereditary cancer conditions.
From: Sequencing approaches in hereditary cancer testing: strengths, limitations and future directions
Study (PMID) | LRS Cohort | Study Typea | Cancer typesb | LRS Technology | LRS Approachesc | Primary findingsd |
|---|---|---|---|---|---|---|
Baumann A, 2025 (40180948) | 1 | V | FAP | PacBio | DNA: LR-WGS | APC In7 LINE-1 INS (6.1 kb) that resulted in abnormal splicing. |
Ohori S, 2025 (40629180) | 2 (related) | D | BC | ONT | DNA: AS, Amplicon Seq; RNA: RT-PCR Seq | BRCA1 In15 SVA INS (2.7 kb). Aberrant BRCA1 transcript showing SVA INS ( ~ 730 bp) |
Zheng Y, 2025 (40719757) | 191 (9 related) | V/D | SWN | PacBio | DNA: Amplicon Seq (NF1) | In 186 patients (97.4%), results were concordant with ES. 51/186 (27.4%) remained negative. In 2 patients, breakpoints for 2 NF1 SV were resolved: Ex49-58 DEL (53 kb) and Ex37-40 DEL (25.8 kb). LRS refuted a previously miscalled DEL by ES. In 2 patients, LRS identified deep intronic SNVs: 1 PV, 1 VUS. |
Jacobson AL, 2025 (40571398) | 4 (unrelated) | D | CRC/Polyposis | ONT | DNA: AS; RNA: Direct RNA-Seq (WTS) | SV in MSH2 (INS, 326 bp) and APC (INS, 6 kb). 2x VUS in MLH3 and MUTYH were phased in trans with known PV. All 4 variants resulted in abnormal splicing. |
Stacey AW, 2024 (39724000) | 16 (unrelated) | PofO | RB | ONT | DNA: AS | PofO identification in all 16 patients enabled by phasing of PV with iDMR in RB1 In1. Paternally inherited allele associated with higher disease severity. |
Kramer M, 2024 (39005350) | 10 (2 Trios, 1 Quad) | D | CRC (Trios), TGCT (Quad) | ONT | DNA: LR-WGS | Candidate SV and DMRs identified |
Nakamura W, 2024 (38368425) | 33 (unrelated) | V/D | Multiple | ONT | DNA: AS | In 2 FAP patients: APC SVA INS in In8 or In9 (2.7 kb); In 1 LS patient: Allele-specific MLH1 epimutation; In 2 RB patients: Resolved breakpoints of RB1 In20-3’UTR DEL (44 kb) or a balanced TRA affecting RB1 and LRMDA; In 2 FAP patients: Resolved APC breakpoints supporting a TRA, or complex rearrangements involving INV and DEL; Identified robust SNP imputation accuracy from AS off-target reads, showing good concordance with SR-WGS (99.8%), leading to optimal PRS calculations. |
Perez-Becerril C, 2024 (38302265) | 1 | V/D | SWN | PacBio | DNA: LR-WGS | Complex rearrangement ( ~ 15 Mb). Multiple breakpoints/breakends identified, including in NF2 |
Bjørnstad PM, 2024 (38030917) | 2 (unrelated) | V | LS | ONT | DNA: LR-WGS | MSH2 In7 INS (39 kb) in both patients |
Gulsuner S, 2024 (39271294) | 240 (from 120 families) | D | HBOPP | ONT | DNA: AS; RNA: RT-PCR Seq | In 8/120 families (6%): Rare deep intronic SNVs in BRCA1, PALB2 and ATM, that resulted in RNA pseudoexon inclusion. |
Oda S, 2023 (37601671) | 1 | V | FAP | ONT | DNA: AS | APC-TP63 TRA |
Kumpula TA, 2023 (37578974) | 2 (unrelated) | V | BC | PacBio | DNA: LR-WGS | Identified 2 events: 1) RAD52 Ex2-9 DEL (31.5 kb) + RAD52 In10 SVA INS (2.8 kb); 2) RAD51C 5’UTR-Ex7 DUP |
Filser M, 2023 (37263769) | 1 | V | BC | ONT | DNA: AS | BRCA1 Ex18-20 tandem DUP. Breakpoints resolved. |
Dixon K, 2023 (36797466) | 19 (from 18 families) | V | BC | ONT | DNA: LR-WGS | Breakpoints fully resolved for 13 SV, and partially for 1 SV, in BRCA1, BRCA2, CHEK2 and PALB2 (510bp-108kb). Identified SV allelic heterogeneity and shared megabase long haplotypes. |
Akbari V, 2022 (36777186) | 5 (trios) | PofO | Multiple | ONT | DNA: LR-WGS | Parent of origin identified in all 5 trios for all autosomes with average mismatch error rate of 0.31% for SNVs and 1.89% for indels. |
Watson CM, 2022 (35014072) | 1 | V | RB | ONT | DNA: Amplicon Seq | Resolved breakpoint of RB1 Ex23 DEL (4 kb), unexpectedly uncovering a previously missed RB1 Ex24 DUP (85 bp). |
Paske IBAWT, 2022 (36037994) | 32 (unrelated) | D | LS | PacBio | DNA: Amplicon seq | In 6/32 patients (19%): Non-coding MMR PV that resulted in abnormal splicing, including 4 deep intronic SNV/indels and 1 Alu INS. |
Scharf F, 2022 (34911816) | 1 | V/D | (A)FAP | ONT | DNA: LR-WGS; RNA: cDNA Seq Hybrid Capture | Resolved breakpoints of multiple chromothripsis fragments. Identified 1 complex rearrangement affecting APC and separating promoter 1B from the rest of the coding sequencing. LR RNA-Seq identified downregulated APC expression. |
Kwong A, 2021 (34994627) | 1 | V | BC | ONT | DNA: LR-WGS | PALB2 Ex13 DUP (13.4 kb) |
Sabatella M, 2021 (34231212) | 2 (siblings) | V | ATRT | PacBio | DNA: LR-WGS | Precise breakpoints defined for SMARCB1 SVA INS In2 (2.8 kb). |
Yamaguchi K, 2021 (33958709) | 5 (unrelated) | V/D | LS | ONT | DNA: Hybrid capture | In 4/5: Confirmed and resolved breakpoints for PV (DEL/DUP) in MLH1/MSH2 (1.2-109 kb). In 1 case: discovered MSH2 Ex7-16 DEL (84 kb) |
Walsh T, 2021 (33060287) | 19 (unrelated) | D | BC | PacBio | DNA: CRISPR/Cas9 Excision | In 1/19 patients: BRCA1 SVA INS In13 (2.9 kb) resulting in pseudoexon inclusion |
Aagaard KS, 2020 (33058509) | 1 | V | JPS-HHT | ONT | DNA: LR-WGS | Validated a balanced TRA (Chr1-18) affecting SMAD4. Precise breakpoints resolved. |
Thibodeau ML, 2020 (32624572) | 13 (unrelated) | V/D | Multiple | ONT | DNA: LR-WGS | In 3/13: Resolved TSC2 INV-DUP (downgraded to LB). Event was originally miscalled by SR-WGS. In 2/13: Resolved complex rearrangements in TSC2/NTHL1 (PV) or NSD1 DUP (downgraded to LB). In 6/13: Confirmed PV (DEL) breakpoints in BRCA1, EPCAM-MSH2, FANCA or PALB2. In 2/13: Resolved PV (DEL) breakpoints in ATM or RAD51C. |
