bims-lifras 2022-06-26 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–06–26
thirteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Rare germline deleterious variants increase susceptibility for lung cancer.
An appraisal of genetic testing for prostate cancer susceptibility.
Prevalence of Pathogenic Germline BRCA1/2 Variants and Their Association with Clinical Characteristics in Patients with Epithelial Ovarian Cancer in a Rural Area of Japan.
Germline Mutations in Patients With Early-Onset Prostate Cancer.
Predicting the likelihood of a BRCA1/2 pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer.
BRCA1, BRCA2, TP53, PIK3CA, PTEN and AKT1 genes mutations in Burkina Faso breast cancer patients: prevalence, spectrum and novel variant.
Enrichment of cancer-predisposing germline variants in adult and pediatric patients with acute lymphoblastic leukemia.
RAD51B Harbors Germline Mutations Associated With Pancreatic Ductal Adenocarcinoma.
A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations.
A Scoring Model and Protocol to Adapt Universal Screening for Lynch Syndrome to Identify Germline Pathogenic Variants by Next Generation Sequencing from Colorectal Cancer Patients and Cascade Screening.
Fumarate hydratase is a novel gene for familial non-medullary thyroid cancer.
Precursor B-cell Acute Lymphoblastic Leukemia in a pediatric patient with Bainbridge-Ropers Syndrome.
Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62.

Hum Mol Genet. 2022 Jun 18. pii: ddac123. [Epub ahead of print]

Rare germline deleterious variants increase susceptibility for lung cancer.

Jian Sang, Tongwu Zhang, Jung Kim, Mengying Li, Angela C Pesatori, Dario Consonni, Lei Song, Jia Liu, Wei Zhao, Phuc H Hoang, Dave S Campbell, James Feng, Monica E D'Arcy, Naoise Synnott, Yingxi Chen, Zeni Wu, Bin Zhu, Xiaohong R Yang, Kevin M Brown, Jiyeon Choi, Jianxin Shi, Maria Teresa Landi.

Although multiple common susceptibility loci for lung cancer (LC) have been identified by genome-wide association studies (GWAS), they can explain only a small portion of heritability. The etiological contribution of rare deleterious variants (RDVs) to LC risk is not fully characterized and may account for part of the missing heritability. Here, we sequenced the whole exomes of 2777 participants from the Environment and Genetics in Lung cancer Etiology (EAGLE) study, a homogenous population including 1461 LC cases and 1316 controls. In single variant analyses, we identified a new RDV, rs77187983 (EHBP1, Odds Ratio [OR] = 3.13, 95% confidence interval [CI] = 1.34-7.30, P = 0.008) and replicated two previously reported RDVs, rs11571833 (BRCA2, OR = 2.18; 95% CI = 1.25-3.81, P = 0.006) and rs752672077 (MPZL2, OR = 3.70, 95% CI = 1.04-13.15, P = 0.044). In gene-based analyses, we confirmed BRCA2 (P = 0.007) and ATM (P = 0.014) associations with LC risk and identified TRIB3 (P = 0.009), involved in maintaining genome stability and DNA repair, as a new candidate susceptibility gene. Furthermore, cases were enriched with RDVs in homologous recombination repair (carrier frequency [CF] = 22.9% vs. 19.5%, P = 0.017) and Fanconi anemia (CF = 12.5% vs. 10.2%, P = 0.036) pathways. Our results were not significant after multiple testing correction but were enriched in cases vs. controls from large scale public biobank resources, including TCGA, FinnGen, and UK Biobank. Our study identifies novel candidate genes and highlights the importance of RDVs in DNA repair related genes for LC susceptibility. These findings improve our understanding of LC heritability and may contribute to the development of risk stratification and prevention strategies.

DOI: https://doi.org/10.1093/hmg/ddac123
NPJ Precis Oncol. 2022 Jun 22. 6(1): 43

An appraisal of genetic testing for prostate cancer susceptibility.

Amy Finch, Roderick Clark, Danny Vesprini, Justin Lorentz, Raymond H Kim, Emily Thain, Neil Fleshner, Mohammad R Akbari, Cezary Cybulski, Steven A Narod.

Most criteria for genetic testing for prostate cancer susceptibility require a prior diagnosis of prostate cancer, in particular cases with metastatic disease are selected. Advances in the field are expected to improve outcomes through tailored treatments for men with advanced prostate cancer with germline pathogenic variants, although these are not currently offered in the curative setting. A better understanding of the value of genetic testing for prostate cancer susceptibility in screening, for early detection and prevention is necessary. We review and summarize the literature describing germline pathogenic variants in genes associated with increased prostate cancer risk and aggressivity. Important questions include: what is our ability to screen for and prevent prostate cancer in a man with a germline pathogenic variant and how does knowledge of a germline pathogenic variant influence treatment of men with nonmetastatic disease, with hormone-resistant disease and with metastatic disease? The frequency of germline pathogenic variants in prostate cancer is well described, according to personal and family history of cancer and by stage and grade of disease. The role of these genes in aggressive prostate cancer is also discussed. It is timely to consider whether or not genetic testing should be offered to all men with prostate cancer. The goals of testing are to facilitate screening for early cancers in unaffected high-risk men and to prevent advanced disease in men with cancer.

DOI: https://doi.org/10.1038/s41698-022-00282-8
Genes (Basel). 2022 Jun 18. pii: 1085. [Epub ahead of print]13(6):

Prevalence of Pathogenic Germline BRCA1/2 Variants and Their Association with Clinical Characteristics in Patients with Epithelial Ovarian Cancer in a Rural Area of Japan.

Akiko Abe, Issei Imoto, Shoichiro Tange, Masato Nishimura, Takeshi Iwasa.

  The prevalence of germline BRCA1 or BRCA2 pathogenic variants (gBRCA1/2-PV) in patients with primary epithelial ovarian cancer (OC) in a rural area of Japan and their association with clinical characteristics, including treatment response and survival outcome, were investigated. A total of 123 unbiased patients with OC were tested for gBRCA1 and gBRCA2 using next-generation sequencing-based targeted amplicon sequencing. Clinical characteristics of OC patients with and without gBRCA1/2 status were compared. The overall prevalence of gBRCA1/2-PV was 15.4% (19 cases), with gBRCA2-PV (10.5%, 13 cases) being more common than gBRCA1-PV (4.9%, 6 cases). Among the observed gBRCA1/2-PV, several novel variants were included, suggesting that gBRCA1/2-PV unique to the local area exist. gBRCA1/2-PV was significantly more prevalent in OC patients at an older age, with high-grade serous carcinoma, with advanced-stage tumors, and with a family history of breast cancer or hereditary breast and ovarian cancer syndrome (HBOC)-associated cancers. Patients with advanced-stage OC with gBRCA1/2-PV showed a significantly lower recurrence rate and tended to have better progression-free and overall survival than those with wild-type gBRCA1/2. Genetic testing for gBRCA1/2 status in all OC patients is useful not only for diagnosing HBOC in patients and their relatives to assess the risk of HBOC-associated cancers, but also to estimate therapy response and outcomes in patients.

Keywords:  BRCA1/2; epithelial ovarian cancer; germline pathogenic variants; hereditary breast and ovarian cancer syndrome (HBOC)

DOI:  https://doi.org/10.3390/genes13061085
Front Oncol. 2022 ;12 826778

Germline Mutations in Patients With Early-Onset Prostate Cancer.

Tang Tang, Xintao Tan, Ze Wang, Shuo Wang, Yapeng Wang, Jing Xu, Xiajie Wei, Dianzheng Zhang, Qiuli Liu, Jun Jiang.

   Objective: To investigate the inherited mutations and their association with clinical features and treatment response in young-onset prostate cancer patients.
Method: Targeted gene sequencing on 139 tumor susceptibility genes was conducted with a total of 24 patients diagnosed with PCa under the age of 63 years old. Meanwhile, the related clinical information of those patients is collected and analyzed.
Results: Sixty-two germline mutations in 45 genes were verified in 22 patients. BRCA2 (20.8%) and GJB2 (20.8%) were found to be the most frequently mutated, followed by CHEK2, BRCA1, PALB2, CDKN2A, HOXB13, PPM1D, and RECQL (8.3% of each, 2/24). Of note, 58.3% (14/24) patients carry germline mutations in DNA repair genes (DRGs). Four families with HRR (homologous recombination repair)-related gene mutations were described and analyzed in detail. Two patients with BRCA2 mutation responded well to the combined treatment of androgen deprivation therapy (ADT) and radiotherapy/chemotherapy.
Conclusion: Mutations in DRGs are more prevalent in early-onset PCa with advanced clinical stages, and these patients had shorter progression-free survival. ADT Combined with either radiotherapy or chemotherapy may be effective in treating PCa caused by HRR-related gene mutations.

Keywords:  early-onset; germline mutations; homologous recombination associated genes; next-generation sequencing; prostate cancer

DOI:  https://doi.org/10.3389/fonc.2022.826778
J Clin Pathol. 2022 Jun 23. pii: jclinpath-2022-208369. [Epub ahead of print]

Predicting the likelihood of a BRCA1/2 pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer.

Robert D Morgan, George J Burghel, Nicola Flaum, Michael Bulman, Philip Smith, Andrew R Clamp, Jurjees Hasan, Claire Mitchell, Zena Salih, Emma R Woodward, Fiona Lalloo, Joseph Shaw, Sudha Desai, Emma J Crosbie, Richard J Edmondson, Helene Schlecht, Andrew J Wallace, Gordon C Jayson, D Gareth R Evans.

   AIMS: Clinical guidelines recommend testing both germline and tumour DNA for BRCA1/2 pathogenic variants (PVs) in non-mucinous high-grade epithelial ovarian cancer (NMEOC). In this study, we show that some tumour BRCA1/2 PVs are highly likely to be somatic based on certain clinical and variant characteristics, meaning it may not be necessary to test all NMEOC cases for germline BRCA1/2 PVs.
METHODS: An observational study that included all tumour BRCA1/2 PVs detected in cases of NMEOC in the Northwest of England between July 2017 and February 2022. All tumour BRCA1/2 PVs were compared with PVs recorded in a prospectively gathered pan-cancer germline BRCA1/2 (gBRCA) testing database for the same geographical region (gBRCA1 PVs=910 and gBRCA2 PVs=922). Tumour BRCA1/2 PVs were categorised as common (≥1%), uncommon (<1%) or absent from the germline database.
RESULTS: One hundred and thirteen tumour BRCA1/2 PVs were detected in 111 NMEOC cases. There were 69 germline and 44 somatic variants. The mean age at diagnosis for gBRCA and somatic BRCA1/2 (sBRCA) PVs was 56.9 and 68.5 years, respectively (Student's t-test p<0.0001). All sBRCA PVs were detected in non-familial cases. All tumour BRCA1/2 PVs with a variant allele frequency (VAF) <35% in non-familial cases were somatic variants. Eighty-one per cent of germline-tumour BRCA1/2 PVs were present (common=31, uncommon=25) in the gBRCA testing database, while 89% of somatic-tumour BRCA1/2 PVs were absent (n=39).
CONCLUSIONS: We predict the likelihood of a tumour BRCA1/2 PV being somatic is 99.8% in non-familial cases of NMEOC diagnosed aged ≥75, where the VAF is ≤30% and there is no regional germline commonality.

Keywords:  Biomarkers, Tumor; GENETICS; Ovarian Neoplasms

DOI:  https://doi.org/10.1136/jcp-2022-208369
Mol Genet Genomics. 2022 Jun 22.

BRCA1, BRCA2, TP53, PIK3CA, PTEN and AKT1 genes mutations in Burkina Faso breast cancer patients: prevalence, spectrum and novel variant.

Serge Yannick Ouedraogo, Abdou Azaque Zoure, Moutanou Modeste Judes Zeye, Touwendpoulimdé Isabelle Kiendrebeogo, Xi Zhou, Alexis Yobi Sawadogo, Jacques Simpore, Hanchun Chen.

  BRCA1 and BRCA2 are the two most commonly mutated tumor suppressor genes associated with hereditary breast cancer (BC). Also, mutations in TP53, PIK3CA, PTEN and AKT1 were observed at a high frequency in BC with their mutation spectrum exhibiting a subgroup particularity with enormous clinical significance in the prevention, classification and treatment of cancers. Unfortunately, the mutation spectrum of these genes is still unknown in most Sub-Saharan African population. Therefore, using samples from 133 unselected BC patients, we aimed to assess the contribution of these mutations by direct Sanger sequencing. The analysis revealed pathogenic germline variants on BRCA1 exon 11 (c.3331C > T, 0.75%) and BRCA2 exon 11 (c.5635G > T, c.6211delA; 1.5%). Five other pathogenic variants were identified in 61 of the 133 subjects (45.86%), with 39.09% for PIK3CA, 12.78% for TP53. Interestingly, a variant in PIK3CA found in high frequency in our population was different from the one usually found in other populations (c.1634A > C, 38.34%), and four patients carried mutations linked to Cowen Syndrome 5 c.[1634A > C;1658_1659delGTinsC]. A novel variant (c.312G > T) was found in TP53 gene at 12.78%. Overall, mutation carriers were found more in Her2 negative and in patients that underwent surgery and chemotherapy. No pathogenic variant was found in PTEN and AKT1. Our population displayed a high frequency of PIK3CA mutations with an unusual distribution and spectrum as well as a relatively low prevalence of BRCA mutations. Our results provided novel data on an unstudied population and may help in prevention, and the establishment of suitable therapeutic approaches for our population.

Keywords:  Breast cancer; Burkina Faso; Pathogenic variant; Prevention; Sanger sequencing

DOI:  https://doi.org/10.1007/s00438-022-01914-1
Sci Rep. 2022 Jun 23. 12(1): 10670

Enrichment of cancer-predisposing germline variants in adult and pediatric patients with acute lymphoblastic leukemia.

Suvi P M Douglas, Atte K Lahtinen, Jessica R Koski, Lilli Leimi, Mikko A I Keränen, Minna Koskenvuo, Caroline A Heckman, Kirsi Jahnukainen, Esa Pitkänen, Ulla Wartiovaara-Kautto, Outi Kilpivaara.

Despite recent progress in acute lymphoblastic leukemia (ALL) therapies, a significant subset of adult and pediatric ALL patients has a dismal prognosis. Better understanding of leukemogenesis and recognition of germline genetic changes may provide new tools for treating patients. Given that hematopoietic stem cell transplantation, often from a family member, is a major form of treatment in ALL, acknowledging the possibility of hereditary predisposition is of special importance. Reports of comprehensive germline analyses performed in adult ALL patients are scarce. Aiming at fulfilling this gap of knowledge, we investigated variants in 93 genes predisposing to hematologic malignancies and 70 other cancer-predisposing genes from exome data obtained from 61 adult and 87 pediatric ALL patients. Our results show that pathogenic (P) or likely pathogenic (LP) germline variants in genes associated with predisposition to ALL or other cancers are prevalent in ALL patients: 8% of adults and 11% of children. Comparison of P/LP germline variants in patients to population-matched controls (gnomAD Finns) revealed a 2.6-fold enrichment in ALL cases (CI 95% 1.5-4.2, p = 0.00071). Acknowledging inherited factors is crucial, especially when considering hematopoietic stem cell transplantation and planning post-therapy follow-up. Harmful germline variants may also predispose patients to excessive toxicity potentially compromising the outcome. We propose integrating germline genetics into precise ALL patient care and providing families genetic counseling.

DOI: https://doi.org/10.1038/s41598-022-14364-x
JCO Precis Oncol. 2022 Jun;6 e2100404

RAD51B Harbors Germline Mutations Associated With Pancreatic Ductal Adenocarcinoma.

Fanfan Xie, Ding Ding, Cong Lin, Dea Cunningham, Michael Wright, Ammar A Javed, Nilo Azad, Valerie Lee, Ross Donehower, Ana De Jesus-Acosta, Dung T Le, Michael Pishvaian, Eun Ji Shin, Anne Marie Lennon, Mouen Khashab, Vikesh Singh, Alison P Klein, Nicholas J Roberts, Amy Hacker-Prietz, Thomas McPhaul, Richard A Burkhart, William R Burns, Amol Narang, Atif Zaheer, Elliot K Fishman, Elizabeth D Thompson, Robert Anders, Jun Yu, Jin He, Christopher L Wolfgang, Lei Zheng, Dongbing Liu, Kui Wu, Daniel A Laheru.

PURPOSE: Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond BRCA1, BRCA2, ATM, and PALB2 may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC).
METHODS: We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores.
RESULTS: Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with BRCA2 mutations is associated with a high HRD score. However, another tumor with a CHEK2 mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a RAD51B gene mutation. All four RAD51B gene mutations were germline mutations. However, currently, RAD51B is not the gene panel for germline tests.
CONCLUSION: The finding in this study thus supports including RAD51B in the germline test of HR-DDR pathway genes.

DOI: https://doi.org/10.1200/PO.21.00404
PLoS Genet. 2022 Jun;18(6): e1010260

A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations.

Paula Martínez, Raúl Sánchez-Vázquez, Iole Ferrara-Romeo, Rosa Serrano, Juana M Flores, Maria A Blasco.

The shelterin protein POT1 has been found mutated in many different familial and sporadic cancers, however, no mouse models to understand the pathobiology of these mutations have been developed so far. To address the molecular mechanisms underlying the tumorigenic effects of POT1 mutant proteins in humans, we have generated a mouse model for the human POT1R117C mutation found in Li-Fraumeni-Like families with cases of cardiac angiosarcoma by introducing this mutation in the Pot1a endogenous locus, knock-in for Pot1aR117C. We find here that both mouse embryonic fibroblasts (MEFs) and tissues from Pot1a+/ki mice show longer telomeres than wild-type controls. Longer telomeres in Pot1a+/ki MEFs are dependent on telomerase activity as they are not found in double mutant Pot1a+/ki Tert-/- telomerase-deficient MEFs. By using complementation assays we further show that POT1a pR117C exerts dominant-negative effects at telomeres. As in human Li-Fraumeni patients, heterozygous Pot1a+/ki mice spontaneously develop a high incidence of angiosarcomas, including cardiac angiosarcomas, and this is associated to the presence of abnormally long telomeres in endothelial cells as well as in the tumors. The Pot1a+/R117C mouse model constitutes a useful tool to understand human cancers initiated by POT1 mutations.

DOI: https://doi.org/10.1371/journal.pgen.1010260
Cancers (Basel). 2022 Jun 12. pii: 2901. [Epub ahead of print]14(12):

A Scoring Model and Protocol to Adapt Universal Screening for Lynch Syndrome to Identify Germline Pathogenic Variants by Next Generation Sequencing from Colorectal Cancer Patients and Cascade Screening.

Ramadhani Chambuso, Barbara Robertson, Raj Ramesar.

  Identification of germline pathogenic variants (PV) predisposing to Lynch syndrome (LS) is an important step for effective use of cascade screening of extended at-risk lineages, leading to reduced morbidity and mortality due to colorectal cancer (CRC). As a general rule, however, next generation sequencing (NGS, either of gene panels or whole exomes) is relatively expensive and unaffordable for general clinical use. In resource-poor settings, performing NGS testing on an entire cohort of CRC patients, even if limited to those under 50 or 60 years of age, still places an enormous burden on limited resources. Although family history can be a good indicator for LS testing, identifying at-risk family members and offering cascade screening may not benefit many patients/probands without an obvious family history. This article presents a novel program called Modified Ascertainment and follow-up Program (MAP) with a scoring model for LS ascertainment and molecular screening by NGS with diagnosis confirmation of PV and cascade screening. The goal is to improve LS ascertainment in light of the growing burden of early-onset CRC, particularly in low- and middle-income countries. Through MAP, judiciously applied molecular genetics will improve identification of PV predisposing to LS and cascade screening.

Keywords:  Lynch syndrome; Lynch syndrome scoring model; cascade screening; colorectal cancer; germline pathogenic variants; modified ascertainment and follow up program; next generation sequencing

DOI:  https://doi.org/10.3390/cancers14122901
J Clin Endocrinol Metab. 2022 Jun 25. pii: dgac386. [Epub ahead of print]

Fumarate hydratase is a novel gene for familial non-medullary thyroid cancer.

Ali S Alzahrani, Meshael Alswailem, Balgees Alghamdi, Hindi Al-Hindi.

   CONTEXT: the majority of cases of epithelial cell-derived thyroid cancer are sporadic. Familial non-medullary thyroid cancer (FNMTC) occurs in about 5-9% of cases, either as a part of known syndromes such as Cowden syndrome or in the form of familial clustering of 2 or more affected family members. Hereditary Leiomyoma and renal cell cancer (HLRCC) syndrome is a rare familial cancer syndrome. The underlying etiology is heterozygous germline mutations of the fumarate hydratase gene (FH). In addition to extensive uterine and skin leiomyomas and renal cell cancer (RCC), other tumors may arise in this syndrome. However, thyroid cancer has never been described as part of HLRCC. Here, we describe a young woman who presented with an aggressive poorly differentiated thyroid cancer (PDTC) and was found to have HLRCC syndrome due to a novel heterozygous germline FH mutation.
RESULTS: A 44-year-old lady presented with a large lower neck mass that was found to be PDTC. During her evaluation, she was found to have extensive uterine leiomyomatosis and bilateral adrenal nodules. Whole exome and subsequent Sanger sequencing of leucocyte DNA revealed a novel monoallelic nonsense FH mutation (c.760C>T, p.Q254*). Sequencing of the thyroid tumor tissue showed a biallelic loss at the same mutation site (loss of heterozygosity) and immunohistochemistry of the PDTC showed loss of FH staining in the tumor tissue indicating the pathogenic role of this mutation in the development of PDTC in this patient.
CONCLUSION: Thyroid cancer is a novel feature of the FH-related HLRCC syndrome. This syndrome can be added to the rare genetic causes of syndromic FNMTC.

Keywords:  Fumarate hydratase; Leiomyoma; familial thyroid cancer; mutation; thyroid cancer

DOI:  https://doi.org/10.1210/clinem/dgac386
Pediatr Blood Cancer. 2022 Jun 22. e29873

Precursor B-cell Acute Lymphoblastic Leukemia in a pediatric patient with Bainbridge-Ropers Syndrome.

Leonora R Slatnick, Katie Angione, Lisa Hartman.



Keywords:  ASXL3; BRPS; cancer; germline ASXL3 mutation; malignancy

DOI:  https://doi.org/10.1002/pbc.29873
Sci Rep. 2022 Jun 20. 12(1): 10333

Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62.

Stephanie U Greer, Jiamin Chen, Margret H Ogmundsdottir, Carlos Ayala, Billy T Lau, Richard Glenn C Delacruz, Imelda T Sandoval, Sigrun Kristjansdottir, David A Jones, Derrick S Haslem, Robin Romero, Gail Fulde, John M Bell, Jon G Jonasson, Eirikur Steingrimsson, Hanlee P Ji, Lincoln D Nadauld.

Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development.

DOI: https://doi.org/10.1038/s41598-022-13569-4