bims-lifras 2021-11-14 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–11–14
fourteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Germline GATA1s generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype.
Germline DNA damage repair gene mutations in pancreatic cancer patients with personal/family histories of pancreas/breast/ovarian/prostate cancer in a Japanese population.
Genetic spectrum in a Canadian cohort of apparently sporadic pheochromocytomas and paragangliomas: New data on multigene panel retesting over time.
Survey of Germline Variants in Cancer-Associated Genes in Young Adults with Colorectal Cancer.
Clinical heterogeneity and reduced penetrance in DICER1 syndrome: a report of three families.
Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care.
Radiation-Associated Sarcoma of the Breast in a Patient With a Germline Tumor Protein p53 Mutation.
Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial.
Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood.
Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies.
Constructing germline research cohorts from the discarded reads of clinical tumor sequences.
Hematologic Complications with Age in Shwachman-Diamond Syndrome.
Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia.
NKX2.1 (TTF1) germline mutation associated with pulmonary fibrosis and lung cancer.

Blood. 2021 Nov 10. pii: blood.2021011463. [Epub ahead of print]

Germline GATA1s generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype.

Henrik Hasle, Ronald M Kline, Eigil Kjeldsen, Nik F Nik-Abdul-Rashid, Deepa Bhojwani, Jeffrey M Verboon, Stephanie P DiTroia, Katherine R Chao, Klas Raaschou-Jensen, Josefine Palle, C Michel Zwaan, Charlotte Guldborg Nyvold, Vijay G Sankaran, Alan B Cantor.

Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s generating mutations result in congenital anemia in males. We report on two unrelated families harboring germline GATA1s generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy or tetrasomy 21. The leukemia characteristics overlapped those of myeloid leukemia of Down syndrome including age of onset of less than 4 years, unique immunophenotype, complex karyotype, gene expression pattern, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is unique functional cooperatively between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s generating mutations should be included among those associated with familial myelodysplastic syndrome and leukemia predisposition.

DOI: https://doi.org/10.1182/blood.2021011463
Ann Gastroenterol Surg. 2021 Nov;5(6): 853-864

Germline DNA damage repair gene mutations in pancreatic cancer patients with personal/family histories of pancreas/breast/ovarian/prostate cancer in a Japanese population.

Tatsuo Hata, Masamichi Mizuma, Fuyuhiko Motoi, Masaharu Ishida, Hideo Ohtsuka, Kei Nakagawa, Takanori Morikawa, Toru Furukawa, Michiaki Unno.

   Aim: Cancer patients with personal/family histories of pancreatic/breast/ovarian/prostate cancer are associated with a higher likelihood of harboring DNA damage repair (DDR)-related germline mutations. Here, we aimed to obtain a better understanding of DDR-related germline mutations in Japanese pancreatic ductal adenocarcinoma (PDAC) patients with personal and/or family histories of BRCA-related cancers of the pancreas, breast, ovary, and prostate.
Methods: We performed next-generation sequencing (NGS) and evaluated germline mutations in nine DDR-related genes (BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2) in PDAC patients with personal and/or family histories.
Results: Of 196 patients with PDAC, 39 (19.9%) fulfilled the criteria for at least one family history of pancreatic/breast/ovarian/prostate cancer in first-degree relatives (sibling-sibling or parent-child) or the personal history of these malignancies. Targeted NGS revealed that four (10.2%) of 39 patients with personal/family histories harbored deleterious germline mutations-two in BRCA2, one in ATM, and one in MLH1. Both the BRCA2 variants showed frameshift mutations due to short insertion/deletions. In the 39 patients undergoing NGS, a similar distribution of the clinicopathological characteristics was observed between those with deleterious mutations/variants of unknown significance (VUSs) and with benign/wild types. Patients with deleterious germline mutations/VUSs in DDR-related genes showed a significantly more favorable prognosis than those with benign mutations/wild-type genes (hazard ratio: 0.160, P = .040).
Conclusions: A significant fraction of PDAC patients with personal/family histories of BRCA-related cancers harbored deleterious germline mutations in DDR-related genes. DDR-related germline gene mutations might be a favorable prognostic factor in patients with pancreatic cancer.

Keywords:  familial pancreatic cancer; germline mutation; homologous recombination repair; mismatch repair; next‐generation sequencing

DOI:  https://doi.org/10.1002/ags3.12482
Clin Endocrinol (Oxf). 2021 Nov 08.

Genetic spectrum in a Canadian cohort of apparently sporadic pheochromocytomas and paragangliomas: New data on multigene panel retesting over time.

Stéfanie Parisien-La Salle, Nadine Dumas, Karine Bédard, Judith Jolin, Jessica Moramarco, André Lacroix, Isabelle Lévesque, Nelly Burnichon, Anne-Paule Gimenez-Roqueplo, Isabelle Bourdeau.

   OBJECTIVE: Pheochromocytomas (PHEOs) and paragangliomas (PGLs), collectively known as PPGLs, are tumours with high heritability. The prevalence of germline mutations in apparently sporadic PPGLs varies depending on the study population. The objective of this study was to determine the spectrum of germline mutations in a cohort of patients with apparently sporadic PPGLs over time.
DESIGN: We performed a retrospective review of patients with apparently sporadic PPGLs who underwent genetic testing at our referral centre from 2005 to 2020.
PATIENTS: We included patients with apparently sporadic PPGLs who underwent genetic testing at our referral center.
MEASUREMENTS: Genetic analysis included sequential gene sequencing by Sanger method or next generation sequencing (NGS) with a multigene panel.
RESULTS: The prevalence of germline mutations was 26.2% (43/164); 40.0% (30/75) in PGLs and 14.6% (13/89) in PHEOs. We identified four novel pathogenic variants (two SDHB and two SDHD). Patients carrying germline mutations were younger (38.7 vs. 49.7 years old) than patients with no identified germline mutations. From 2015 to 2020, we performed NGS with a multigene panel on 12 patients for whom the initial genetic analysis was negative. Germline mutations in previously untested genes were found in four (33.3%) of these patients (two MAX and two SDHA), representing 9.3% (4/43) of the mutation carriers.
CONCLUSION: The prevalence of germline mutations in our cohort of patients with apparently sporadic PPGLs was 26.2%. Genetic re-evaluation over time using multigene sequencing by NGS assay in a subgroup of patients leads to an increase in the detection of mutations.

Keywords:  mutations; paraganglioma; pheochromocytoma; variant of uncertain significance

DOI:  https://doi.org/10.1111/cen.14618
Genes Chromosomes Cancer. 2021 Nov 11.

Survey of Germline Variants in Cancer-Associated Genes in Young Adults with Colorectal Cancer.

Reger R Mikaeel, Joanne P Young, Yun Li, Eric Smith, Mehgan Horsnell, Wendy Uylaki, Gonzalo Tapia Rico, Nicola K Poplawski, Jennifer E Hardingham, Yoko Tomita, Amanda R Townsend, Jinghua Feng, Arne Zibat, Silke Kaulfuß, Christian Müller, Gökhan Yigit, Bernd Wollnik, Timothy J Price.

  Colorectal cancer (CRC) incidence in young adults is rising. Identifying genetic risk factors is fundamental for the clinical management of patients and their families. This study aimed to identify clinically significant germline variants among young adults with CRC. Whole-exome sequencing data of blood-derived DNA from 133 unrelated young CRC patients (<55 years of age) underwent comprehensive analysis of 133 cancer-predisposition/implicated genes. All patient tumours were evaluated for mismatch repair deficiency (dMMR). Among 133 patients (ages 16-54 years), 15% (20/133) had clinically actionable pathogenic or likely pathogenic (P/LP) variants in at least 1 well established cancer-predisposing gene: dMMR genes (6), MUTYH [bi-allelic (2), mono-allelic (3)], RNF43 (1), BMPR1A (1), BRCA2 (4), ATM (1), RAD51C (1) and BRIP1(1). Five patients (4%) had variants in genes implicated in cancer but where the significance of germline variants in CRC risk is uncertain: GATA2 (1), ERCC2 (mono-allelic) (1), ERCC4 (mono-allelic) (1), CFTR (2). Fourteen (11%) had dMMR tumours. Eighteen (14%) reported a first-degree relative with CRC, but only 3 of these carried P/LP variants. Three patients with variants in polyposis-associated genes showed no polyposis (1 each in MUTYH (bi-allelic), RNF43, and BMPR1A). Approximately 1 in 5 young adults in our series carried at least 1 P/LP variant in a cancer-predisposing/implicated gene; 80% of these variants are currently considered clinically actionable in a familial cancer setting. Family history and phenotype have limitations for genetic risk prediction, therefore multigene panel testing and genetic counselling are warranted for all young adults with CRC regardless of those two factors.

Keywords:  BRCA2; Mismatch repair; Young-onset CRC, Whole-exome sequencing

DOI:  https://doi.org/10.1002/gcc.23011
Tumori. 2021 Nov 11. 3008916211058788

Clinical heterogeneity and reduced penetrance in DICER1 syndrome: a report of three families.

Jacopo Azzollini, Andrea Ferrari, Alessandra Stracuzzi, Stefano Chiaravalli, Monica Terenziani, Filippo Spreafico, Maurizia Grasso, Paola Collini, Valeria Pensotti, Maura Massimino, Eloisa Arbustini, Siranoush Manoukian.

   INTRODUCTION: DICER1 syndrome is characterized by increased susceptibility to malignancies, mostly occurring in childhood. The range of phenotypic effects of DICER1 variants is under investigation, and the syndrome's phenotypic spectrum is steadily widening. We report on three Italian families showing heterogeneous clinical presentation and reduced penetrance in family members.
CASE DESCRIPTIONS: Patient 1 is a 10-year-old girl with a Sertoli-Leydig cell tumor. Although family history was unremarkable, genetic testing identified a DICER1 germline variant, inherited from her healthy father. Benign thyroid nodules were subsequently diagnosed in both the proband and her father. Patient 2 is an 8-month-old boy with type 1 pleuropulmonary blastoma. His sister developed a nephroblastoma at age 2 years. A DICER1 novel variant was identified in both siblings and their healthy father. Patient 3 is a 22-year-old man who developed a spinal extramedullary intradural mass diagnosed as rhabdomyosarcoma with a peculiar tubular, gland-like component. Tumor testing revealed two pathogenic DICER1 variants, one of which was confirmed to be germline and identified in his 17-year-old healthy brother and in his father, who showed multiple thyroid nodules.
CONCLUSIONS: Among our patients, three developed tumors most frequently associated with DICER1 syndrome (i.e. pleuropulmonary blastoma, nephroblastoma, and Sertoli-Leydig cell tumor). One developed a peculiar sarcoma of the spinal cord not previously described in DICER1 syndrome. Genetic testing in relatives highlighted the paternal origin and reduced penetrance in all families, with thyroid benign lesions as the most common features in otherwise unaffected individuals.

Keywords:  CNS sarcoma; DICER1 syndrome; pediatric cancer; spinal cord tumor; tumor predisposition syndrome

DOI:  https://doi.org/10.1177/03008916211058788
Cancers (Basel). 2021 Oct 24. pii: 5339. [Epub ahead of print]13(21):

Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care.

Pablo Gargallo, Silvestre Oltra, Yania Yáñez, Antonio Juan-Ribelles, Inés Calabria, Vanessa Segura, Marián Lázaro, Julia Balaguer, Teresa Tormo, Sandra Dolz, José María Fernández, Carolina Fuentes, Bárbara Torres, Mara Andrés, María Tasso, Victoria Castel, Jaime Font de Mora, Adela Cañete.

  Knowledge about genetic predisposition to pediatric cancer is constantly expanding. The categorization and clinical management of the best-known syndromes has been refined over the years. Meanwhile, new genes for pediatric cancer susceptibility are discovered every year. Our current work shares the results of genetically studying the germline of 170 pediatric patients diagnosed with cancer. Patients were prospectively recruited and studied using a custom panel, OncoNano V2. The well-categorized predisposing syndromes incidence was 9.4%. Likely pathogenic variants for predisposition to the patient's tumor were identified in an additional 5.9% of cases. Additionally, a high number of pathogenic variants associated with recessive diseases was detected, which required family genetic counseling as well. The clinical utility of the Jongmans MC tool was evaluated, showing a high sensitivity for detecting the best-known predisposing syndromes. Our study confirms that the Jongmans MC tool is appropriate for a rapid assessment of patients; however, the updated version of Ripperger T criteria would be more accurate. Meaningfully, based on our findings, up to 9.4% of patients would present genetic alterations predisposing to cancer. Notably, up to 20% of all patients carry germline pathogenic or likely pathogenic variants in genes related to cancer and, thereby, they also require expert genetic counseling. The most important consideration is that the detection rate of genetic causality outside Jongmans MC et al. criteria was very low.

Keywords:  genetic counseling; genetic predisposition; genetic syndrome; germline; hereditary cancer; pediatric oncology; working tool

DOI:  https://doi.org/10.3390/cancers13215339
Cureus. 2021 Oct;13(10): e18563

Radiation-Associated Sarcoma of the Breast in a Patient With a Germline Tumor Protein p53 Mutation.

Cheyenne Thompson, Muhammad O Hakim, Jorge Infante-Mendez, Susan Kesmodel, Neha Goel.

  Radiation-induced sarcoma of the breast is a rare complication that is primarily treated with surgical resection but in patients with advanced disease, a multimodality treatment approach is often required. This case report discusses a 37-year-old female with a history of a pT3N3M0, estrogen receptor (ER)+, progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)+, right breast cancer, and a germline tumor protein (TP) p53 mutation who underwent right modified radical mastectomy, adjuvant systemic therapy, and radiation therapy, and subsequently developed a radiation-induced sarcoma. The patient is a 37-year-old female who has a history of pT3N3M0, ER/PR+, HER2+, and right breast cancer diagnosed in 2014. At the time of diagnosis, she had locally advanced disease and underwent right modified radical mastectomy followed by adjuvant chemotherapy, radiation, delayed right breast implant-based reconstruction, and left breast augmentation with mastopexy. Upon completion of adjuvant chemotherapy, she was started on hormonal therapy. In February 2020, she underwent genetic testing given her early onset of breast cancer and was found to have a germline TP53 mutation. Routine MRI for breast implant evaluation showed two irregular enhancing masses with an additional satellite lesion in the right breast. Right breast ultrasound (US)-guided biopsy revealed two separate foci of high-grade pleomorphic fibroblastic/myofibroblastic sarcoma. Further staging workup with a whole-body MRI was negative for evidence of metastatic disease. Her case was discussed in multidisciplinary sarcoma tumor board and consensus was for surgical resection. She underwent radical resection of the right chest wall masses and subcutaneous tissue, removal of right breast implant and capsulectomy, and left breast mastectomy with left breast implant removal and capsulectomy. The final pathology revealed two separate foci of high-grade pleomorphic fibroblastic/myofibroblastic sarcoma, 1.2 cm and 1.1 cm in their greatest dimensions with negative margins. Her case was re-discussed in multidisciplinary sarcoma tumor board and due to T1 size of the tumors and the negative resection margins, close surveillance with annual whole-body MRI and quarterly chest MRI imaging was recommended. In patients with a germline TP53 mutation and breast cancer, the utilization of adjuvant radiotherapy should be considered cautiously given the increased risk of radiation-associated sarcoma.

Keywords:  adjuvant radiation therapy; germline tp53 mutation; li-fraumeni syndrome; myofibroblastic sarcoma; radiation-induced sarcoma

DOI:  https://doi.org/10.7759/cureus.18563
Gynecol Oncol. 2021 Nov 03. pii: S0090-8258(21)01420-7. [Epub ahead of print]

Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial.

Darren R Hodgson, Jessica S Brown, Simon P Dearden, Zhongwu Lai, Cathy E Elks, Tsveta Milenkova, Brian A Dougherty, Jerry S Lanchbury, Michael Perry, Kirsten M Timms, Elizabeth A Harrington, J Carl Barrett, Alexandra Leary, Eric Pujade-Lauraine.

   OBJECTIVE: Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor.
METHODS: Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined.
RESULTS: 289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off.
CONCLUSIONS: Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

Keywords:  LOH and marker studies; Mutation detection methods; Olaparib; Ovarian cancer

DOI:  https://doi.org/10.1016/j.ygyno.2021.10.002
Int J Mol Sci. 2021 Oct 26. pii: 11572. [Epub ahead of print]22(21):

Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood.

Pia Michler, Anne Schedel, Martha Witschas, Ulrike Anne Friedrich, Rabea Wagener, Juha Mehtonen, Triantafyllia Brozou, Maria Menzel, Carolin Walter, Dalileh Nabi, Glen Pearce, Miriam Erlacher, Gudrun Göhring, Martin Dugas, Merja Heinäniemi, Arndt Borkhardt, Friedrich Stölzel, Julia Hauer, Franziska Auer.

  While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene POT1, which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated POT1 display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional POT1 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisposition to myeloid malignancies in childhood.

Keywords:  POT1; acute myeloid leukemia; germline cancer predisposition; pediatric; shelterin complex; trio sequencing

DOI:  https://doi.org/10.3390/ijms222111572
Front Med. 2021 Nov 06.

Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies.

Daijing Nie, Jing Zhang, Fang Wang, Xvxin Li, Lili Liu, Wei Zhang, Panxiang Cao, Xue Chen, Yang Zhang, Jiaqi Chen, Xiaoli Ma, Xiaosu Zhou, Qisheng Wu, Ming Liu, Mingyue Liu, Wenjun Tian, Hongxing Liu.

  Whether Fanconi anemia (FA) heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting. We retrospectively analyzed rare possibly significant variations (PSVs) in the five most obligated FA genes, BRCA2, FANCA, FANCC, FANCD2, and FANCG, in 788 patients with aplastic anemia (AA) and hematologic malignancy. Sixty-eight variants were identified in 66 patients (8.38%). FANCA was the most frequently mutated gene (n = 29), followed by BRCA2 (n = 20). Compared with that of the ExAC East Asian dataset, the overall frequency of rare PSVs was higher in our cohort (P = 0.016). BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia (P = 0.038), and FANCA PSVs were significantly enriched in AA and AML subgroups (P = 0.020; P = 0.008). FA-PSV-positive MDS/AML patients had a higher tumor mutation burden, higher rate of cytogenetic abnormalities, less epigenetic regulation, and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients (P = 0.024, P = 0.029, P = 0.024, and P = 0.013). The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.

Keywords:  Fanconi anemia; aplastic anemia; germline predisposition; hematologic malignancy

DOI:  https://doi.org/10.1007/s11684-021-0841-x
Genome Med. 2021 11 08. 13(1): 179

Constructing germline research cohorts from the discarded reads of clinical tumor sequences.

Alexander Gusev, Stefan Groha, Kodi Taraszka, Yevgeniy R Semenov, Noah Zaitlen.

BACKGROUND: Hundreds of thousands of cancer patients have had targeted (panel) tumor sequencing to identify clinically meaningful mutations. In addition to improving patient outcomes, this activity has led to significant discoveries in basic and translational domains. However, the targeted nature of clinical tumor sequencing has a limited scope, especially for germline genetics. In this work, we assess the utility of discarded, off-target reads from tumor-only panel sequencing for the recovery of genome-wide germline genotypes through imputation.
METHODS: We developed a framework for inference of germline variants from tumor panel sequencing, including imputation, quality control, inference of genetic ancestry, germline polygenic risk scores, and HLA alleles. We benchmarked our framework on 833 individuals with tumor sequencing and matched germline SNP array data. We then applied our approach to a prospectively collected panel sequencing cohort of 25,889 tumors.
RESULTS: We demonstrate high to moderate accuracy of each inferred feature relative to direct germline SNP array genotyping: individual common variants were imputed with a mean accuracy (correlation) of 0.86, genetic ancestry was inferred with a correlation of > 0.98, polygenic risk scores were inferred with a correlation of > 0.90, and individual HLA alleles were inferred with a correlation of > 0.80. We demonstrate a minimal influence on the accuracy of somatic copy number alterations and other tumor features. We showcase the feasibility and utility of our framework by analyzing 25,889 tumors and identifying the relationships between genetic ancestry, polygenic risk, and tumor characteristics that could not be studied with conventional on-target tumor data.
CONCLUSIONS: We conclude that targeted tumor sequencing can be leveraged to build rich germline research cohorts from existing data and make our analysis pipeline publicly available to facilitate this effort.

DOI: https://doi.org/10.1186/s13073-021-00999-4
Blood Adv. 2021 Nov 10. pii: bloodadvances.2021005539. [Epub ahead of print]

Hematologic Complications with Age in Shwachman-Diamond Syndrome.

Elissa Furutani, Shanshan Liu, Ashley Galvin, Sarah Steltz, Maggie M Malsch, Sara Katharine Loveless, Leann Mount, Jordan Henry Larson, Kelan Queenan, Alison A Bertuch, Mark D Fleming, John M Gansner, Amy E Geddis, Rabi Hanna, Sioban B Keel, Bonnie W Lau, Jeffrey M Lipton, Robert Lorsbach, Taizo A Nakano, Adrianna Vlachos, Winfred C Wang, Stella M Davies, Edie Weller, Kasiani C Myers, Akiko Shimamura.

Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258+2T>C variant was present in all but one patient. To evaluate association of blood counts with age, a total of 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P<0.0001). Hemoglobin was also positively associated with age up to 18 years (P<0.0001) but thereafter the association was negative (P=0.0079). Platelet counts and marrow cellularity were negatively associated with age (P<0.0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 MDS and 10 AML) at a median age of 12.3 years (range 0.5-45.0) for MDS, and 28.4 years (range 14.4-47.3) for AML. A lymphoid malignancy developed in one patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths, 85%). These data inform surveillance of hematologic complications in SDS.

DOI: https://doi.org/10.1182/bloodadvances.2021005539
JAMA Netw Open. 2021 Nov 01. 4(11): e2132615

Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia.

Sounak Gupta, Lori A Erickson, Christine M Lohse, Wei Shen, Beth A Pitel, Shannon M Knight, Kevin C Halling, Loren Herrera-Hernandez, Stephen A Boorjian, R Houston Thompson, Bradley C Leibovich, Rafael E Jimenez, John C Cheville.

Importance: In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations.
Objective: To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort.
Design, Setting, and Participants: In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021.
Main Outcomes and Measures: Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel.
Results: Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history.
Conclusions and Relevance: In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.

DOI: https://doi.org/10.1001/jamanetworkopen.2021.32615
ERJ Open Res. 2021 Oct;pii: 00356-2021. [Epub ahead of print]7(4):

NKX2.1 (TTF1) germline mutation associated with pulmonary fibrosis and lung cancer.

Raphael Borie, Benoit Funalot, Ralph Epaud, Céline Delestrain, Aurélie Cazes, Valerie Gounant, Justine Frija, Marie-Pierre Debray, Gérard Zalcman, Bruno Crestani.

Germline surfactant-associated genes mutations are associated with ILD and increased risk of lung cancer https://bit.ly/3CkkXgD.

DOI: https://doi.org/10.1183/23120541.00356-2021