Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

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. Case presentation 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

Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing

The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in<3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs

Germline multigene panel testing revealed a BRCA2 pathogenic variant in a patient with suspected Lynch syndrome

There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a BRCA2 pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic BRCA2 variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing

The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in<3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs

九州大学農学部附属演習林宮崎演習林におけるブナ科樹木萎凋病の被害報告

九州大学農学部附属演習林宮崎演習林において，カシノナガキクイムシ（以下カシナガ）が媒介するブナ科樹木萎凋病（ナラ枯れ）の初年度被害状況を調査した。演習林内のブナ属を除いたブナ科樹木の18％がカシナガの被害を受けていた。樹種ごとの本数被害率はマテバシイが最も高かったが，被害木の枯死率はミズナラが最も高く，今後の森林生態系の著しい変化が懸念された。樹種ごと，樹木のDBHクラスごとの被害率の違いから，カシナガが樹種や樹木サイズを選別している可能性が示唆された。地理的には演習林の南側からカシナガが北上している可能性があり，まだ被害を受けていない北側の林分の今後の経過観察や，被害防除手法の検討・被害収束後の植生回復などに向けた取り組みが必要である。We investigated the first year damage caused by Japanese oak wilt which is a vector-borne disease transmitted by Platypus quercivorus in the Shiiba Research Forest, Faculty of Agriculture, Kyushu University. We found that 18 % of the Fagaceous trees in the study sites, excluding those of the genus Fagus, were damaged by Platypus quercivorus. The proportion of damaged trees per species was the highest for Lithocarpus edulis, but the mortality rate of damaged trees was the highest for Quercus crispula, raising concerns about significant changes in the forest ecosystem in the future. Differences in damage rates of individual tree species and tree DBH classes suggested that Platypus quercivorus may be selecting tree species and tree sizes. There is a possibility that Platypus quercivorus are migrating northward from the south side of the forest. It is necessary to observe the progress of the forest on the north side, which has not been damaged yet, and to study damage control methods and to restore vegetation after the damage has been controlled

福岡演習林の学術参考保護林の5年間の動態

九州大学農学部附属演習林福岡演習林の第9 次森林管理計画書（2015 ～ 2024 年度）において指定されたつる性木本植物，モミ・コバノミツバツツジ，ネズミサシ，リュウキュウマメガキ，シイ・カシ類の５つの学術参考保護林に設置した20m × 20m の調査区における森林構造および種組成の5 年間の変化を調査した。つる性木本植物学術参考保護林では幹数がわずかに減少したが，胸高断面積はほとんど変化しなかった。モミ・コバノミツバツツジ学術参考保護林とリュウキュウマメガキ学術参考保護林では幹数がわずかに減少したが，胸高断面積は増加した。ネズミサシ学術参考保護林では幹数，胸高断面積とも大きく増加した。シイ・カシ類学術参考保護林では幹数，胸高断面積とも減少した。The ninth Kasuya Research Forest Management Plan (2015-2024) designated five reserved forests (Woody liana, Abies firma and Rhododendron farrenrae, Juniperus rigida, Diospyros japonica, and Castanopsis and Quercus). We surveyed the 5 years dynamics of stand structure and species composition of 20m × 20m monitoring plot established in each model forest. In woody liana reserved forest, tree and liana density decreased slightly, while the basal area did not change. In Abies firma and Rhododendron farrenrae, and Diospyros japonica reserved forests, tree density decreased slightly, while the basal area increased. In Juniperus rigida reserved forest, both of tree density and basal area increased largely. In Castanopsis and Quercus reserved forest, both of tree density and basal area decreased

福岡演習林の見本林（Ⅱ）

九州大学農学部附属演習林福岡演習林の第９次森林管理計画書（2015 〜 2024 年度）において設定された見本林のうち，クスノキ見本林，外国産ヒノキ科見本林，ヒノキ見本林，高田外国産樹種見本林における調査区の設置および林分調査を行った。クスノキ見本林の調査区（400m2）では，胸高断面積合計の91% をクスノキが占めた。37 本のクスノキの平均胸高直径は42.0cm で，稚樹は見られなかった。外国産ヒノキ見本林では，コウヨウザンが18 本，ランダイスギが７本生残していた。それぞれ平均胸高直径は33.4cm，32.0cm，平均樹高は19.7m，20.6m であった。ヒノキ見本林は，立木密度が425 本/ha, 胸高断面積合計が64.2m2/ha，平均胸高直径が43.7cm，平均樹高が25.6m であった。高田外国産樹種見本林には，胸高周囲長15cm 以上の樹木が75 種2955 本生育していた。これは1935 年の見本林整備当時と比較すると，樹種数で七分の一以下，個体数で約半分程度であった。The ninth Kasuya Research Forest Management Plan (2015-2024) designated the model forests with characteristic standstructure and species composition in the Research Forest. We surveyed the stands of Cinnamomum camphola model forest, foreignCupressaceae species model forest, Chamaecyparis obtusa model forest, and Takada foreign tree species model forest. In themonitoring plot (400m2) of the C. camphola model forest, 91% of the basal area was composed by C. camphola. The mean diameter atbreast height (DBH) of 37 C. camphola trees was 42.0cm. There was no C. camphola sapling in the plot. In the foreign Cupressaceaespecies model forest, 18 Cunninghamia lanceolate trees and 7 Cunninghamia konishii trees survived. The mean DBHs and meanheights of the two species were 33.4 cm and 32.0 cm, and 19.7m and 20.6m, respectively. In the Chamaecyparis obtusa model forest,the tree density, basal area, mean DBH and mean height were 425 tree / ha, 64.2m2/ha, 43.7cm and 25.6m, respectively. In the Takadaforeign tree species model forest, there were 75 species of 2955 trees larger than 15cm in girth at breast height. These values are lessthan one seventh for species number and less than one half for the tree number comparing with those in 1935 when the model forestwas established