bims-lifras 2022-08-28 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022‒08‒28
fourteen papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Presentation, diagnosis, and management of the Li-Fraumeni syndrome.
Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.
A Four-Year-Old Female With a Rare P53 Gene Mutation Diagnosed With Li-Fraumeni Syndrome and Concomitant Metastatic Rhabdomyosarcoma: A Case Report.
Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer.
Familial and hereditary gastric cancer, an overview.
Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort.
Mismatch Repair Screening of Gastrointestinal Cancers: The Impact on Lynch Syndrome Detection and Immunotherapy.
Rare germline ATM variants of uncertain significance in chronic lymphocytic leukaemia and other cancers.
Hereditary pancreatic cancer.
Mutational and splicing landscape in a cohort of 43,000 patients tested for hereditary cancer.
Examining the Diagnostic Yield of Tumour Testing and Qualifying Germline Concordance for Hereditary Cancer Variants in Patients with High-Grade Serous Carcinoma.
A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma.
A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Pheochromocytoma and Paraganglioma.
Novel Germline PHD2 Variant in a Metastatic Pheochromocytoma and Chronic Myeloid Leukemia, but in the Absence of Polycythemia.

Proc (Bayl Univ Med Cent). 2022 ;35(5): 678-679

Presentation, diagnosis, and management of the Li-Fraumeni syndrome.

John Ogden, John Pippen.

  Li-Fraumeni syndrome is a hereditary cancer syndrome that results in a dramatically increased risk of developing cancer over a patient's lifetime. Proper understanding of this syndrome is important for physicians across all specialties, as it can result in earlier cancer diagnosis and treatment. Here, we present the case of a patient presenting with Li-Fraumeni syndrome and discuss the appropriate screening recommendations and management of patients with this disorder.

Keywords:  Cancer screening; Li-Fraumeni; TP53; genetic screening; germline mutation; hereditary cancer

DOI:  https://doi.org/10.1080/08998280.2022.2071100
Blood Adv. 2022 Aug 24. pii: bloodadvances.2022008172. [Epub ahead of print]

Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.

Caner Saygin, Gregory W Roloff, Christopher N Hahn, Rakchha Chhetri, Saar I Gill, Hany Elmariah, Chetasi Talati, Emma Nunley, Guimin Gao, Aelin Kim, Michael R Bishop, Satyajit Kosuri, Soma Das, Deepak Singhal, Parvathy Venugopal, Claire Christine Homan, Anna L Brown, Hamish S Scott, Devendra K Hiwase, Lucy A Godley.

There is increasing recognition that pathogenic germline variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germline predisposition variants have different post-transplant outcomes compared to those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germline variants (DGVs) and 34% underwent HSCT. DGVs in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germline DDX41 variants had a higher incidence of severe (stage 3-4) acute graft versus host disease (GVHD) (38%) compared to recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germline variants (9%) (p= 0.002). Importantly, the use of post-transplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germline DDX41-associated myeloid neoplasms (0% vs 53%, p=0.03). Based on these results, we advocate the use of post-transplant cyclophosphamide when individuals with deleterious germline DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.

DOI: https://doi.org/10.1182/bloodadvances.2022008172
Cureus. 2022 Jul;14(7): e27009

A Four-Year-Old Female With a Rare P53 Gene Mutation Diagnosed With Li-Fraumeni Syndrome and Concomitant Metastatic Rhabdomyosarcoma: A Case Report.

Umberto M Donato, Sebastian Donato, Andrew Galligan.

  Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder that often results from mutations that impair the functions of the tumor suppressor gene p53. LFS is categorized as a hereditary cancer predisposition syndrome in which patients frequently suffer from an elevated degree of onset and incidence of neoplastic malignancies. Among the different pathogenic variants of LFS, TP53 is one of the most frequently encountered ones. A four-year-old female is reported in this vignette, with a rare c.375+1G>T pathogenic variant in the TP53 gene consistent with an LFS diagnosis. To our knowledge, this is the first reported "germline" example of this variant in the literature. Initially, the patient presented to the emergency department due to concerns of progressive swelling and firmness of a mass in the patient's right abdomen. Further imaging and analysis revealed a rhabdomyosarcoma of the pelvis secondary to LFS. In addition to this, the patient's brother and mother both were positive for the same LFS mutation allowing us to make a definitive LFS diagnosis. Our patient then underwent neoadjuvant chemotherapy, radiotherapy, and eventually a resection of the main neoplastic lesion. Among pediatric LFS patients, the risk of suffering secondary and/or multiple cancers is pathologically elevated. That said, it is crucial to perform genetic analysis tests for pediatric oncology patients, especially those patients with hereditary predisposition to cancers. Considering the poor prognosis of most TP53 mutations, it is of utmost importance to implement prompt and systematic care for patients diagnosed with LFS.

Keywords:  genetic syndromes; li-fraumeni syndrome; radiation and clinical oncology; rhabdomyosarcoma (rms); tumor suppressor protein p53

DOI:  https://doi.org/10.7759/cureus.27009
Front Oncol. 2022 ;12 873395

Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer.

Thais Baccili Cury Megid, Mateus C Barros-Filho, Janina Pontes Pisani, Maria Isabel Achatz.

  Hereditary breast cancer (BC) corresponds to 5% of all BC and a larger parcel of early-onset disease. The incorporation of next-generation sequencing (NGS) techniques reduced the cost of molecular testing and allowed the inclusion of additional cancer predisposition genes in panels that are more comprehensive. This enabled the identification of germline pathogenic variants in carriers and the introduction of risk-reducing strategies. It also resulted in the identification of the co-occurrence of more than one germline pathogenic variant in BC genes in some families. This is a rare event, and there are few reports on its impact on cancer risk. We conducted a single-institution retrospective study in which 1,156 women with early onset BC and/or a family history of cancer were tested by a germline multi-gene hereditary cancer panel. Germline pathogenic variants in high- and/or moderate-penetrance BC genes were identified in 19.5% of the individuals (n = 226). The most frequent variants were found in TP53 (69 of 226; 55 of them represented by p.R337H), BRCA1 (47 of 226), and BRCA2 (41 of 226). Double heterozygous (DH) variants were detected in 14 cases, representing 1.2% of all individuals assessed. There were no significant differences in age of BC onset and risk for bilateral BC in DH carriers when compared with those with one germline variant.

Keywords:  NGS; breast cancer; double heterozygous variants; germline panels; hereditary breast cancer

DOI:  https://doi.org/10.3389/fonc.2022.873395
Best Pract Res Clin Gastroenterol. 2022 Jun-Aug;58-59:pii: S1521-6918(22)00018-X. [Epub ahead of print]58-59 101800

Familial and hereditary gastric cancer, an overview.

Fátima Carneiro.

  There are three major hereditable syndromes that affect primarily the stomach: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and familial intestinal gastric cancer (FIGC). HDGC is caused by germline mutations in CDH1 gene that occur in 10-40% of HDGC families and, in a minority of cases, by mutations in CTNNA1 gene. GAPPS is caused by germline mutations in the promoter 1B of APC gene, and the genetic cause of FIGC is not fully elucidated. Gastric cancer can also be observed as part of other inherited cancer disorders, namely in familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and hereditary breast and ovarian cancer syndrome. In this article, the state of the art of familial gastric cancer regarding the clinical, molecular and pathology features is reviewed, as well as the practical aspects for a correct diagnosis and clinical management.

Keywords:  APC; Alpha-E-catenin (CTNNA1); E-cadherin (CDH1); Familial gastric cancer; Familial intestinal gastric cancer (FIGC); GAPPS; Genetic counseling; Genetic testing; Hereditary diffuse gastric cancer (HDGC); Hereditary gastric cancer; Prophylactic gastrectomy; Surveillance endoscopy

DOI:  https://doi.org/10.1016/j.bpg.2022.101800
Acta Neuropathol Commun. 2022 Aug 25. 10(1): 123

Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort.

Jon Foss-Skiftesvik, Ulrik Kristoffer Stoltze, Thomas van Overeem Hansen, Lise Barlebo Ahlborn, Erik Sørensen, Sisse Rye Ostrowski, Solvej Margrete Aldringer Kullegaard, Adrian Otamendi Laspiur, Linea Cecilie Melchior, David Scheie, Bjarne Winther Kristensen, Jane Skjøth-Rasmussen, Kjeld Schmiegelow, Karin Wadt, René Mathiasen.

  Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene.

Keywords:  DNA methylation profiling; Genetic susceptibility; Genomics; Molecular classification; Pediatrics

DOI:  https://doi.org/10.1186/s40478-022-01429-1
J Gastrointest Cancer. 2022 Aug 26.

Mismatch Repair Screening of Gastrointestinal Cancers: The Impact on Lynch Syndrome Detection and Immunotherapy.

Openshaw M R, Williams J, Foo T, Moss C, Wotherspoon A, Starling N, Kemp Z.

  INTRODUCTION: Mismatch repair immunohistochemistry (MMR IHC) or microsatellite instability (MSI) testing is now routinely performed in patients with colorectal cancer (CRC) to select those requiring Lynch syndrome testing. MMR IHC is also carried out on CRC and upper gastrointestinal (GI) cancers to select patients for immunotherapy. We review the Royal Marsden Hospital's pathway of molecular to germline testing for Lynch syndrome in the context of NICE guidance and the National Test Directory.METHODS: We conducted (i) a retrospective audit of adherence to NICE guidance DG27 for patients diagnosed with CRC March 2017-August 2018 and (ii) a retrospective service evaluation of MMR IHC/Lynch syndrome testing in patients diagnosed with upper GI cancers January 2019-2020.
RESULTS: Of 394 patients with CRC, 346 (87.8%) had MMR IHC testing. Thirty-eight of 346 (10.9%) were MMR deficient (MMR-D) and 5 (1.4%) were found to have pathogenic germline variants causing Lynch syndrome. Of 405 patients with upper GI cancers, 221 (54.6%) had MMR IHC testing. Ten of 221 (4.5%) were MMR-D and 1 (0.5%) had a pathogenic germline variant causing Lynch syndrome.
DISCUSSION: This study highlights the small but significant number of patients, with CRC or upper GI cancers, which were caused by Lynch syndrome. It also highlights weaknesses in our testing pathway that limit access to germline testing. As MMR testing increases, it is important that clinicians are aware that patients with MMR-D tumours require reflex somatic testing or referral for germline testing. We have incorporated the guidelines into a pathway for use in clinics and multidisciplinary teams.

Keywords:  Colorectal cancer; Gastrointestinal cancer; Immunotherapy; Lynch syndrome; Microsatellite instability; Mismatch repair

DOI:  https://doi.org/10.1007/s12029-022-00859-3
Br J Haematol. 2022 Aug 26.

Rare germline ATM variants of uncertain significance in chronic lymphocytic leukaemia and other cancers.

Anna Petrackova, Jakub Savara, Peter Turcsanyi, Petr Gajdos, Tomas Papajik, Eva Kriegova.

  Germline pathogenic ATM (ataxia-telangiectasia mutated) variants are associated with the risk of multiple cancers; however, genetic testing reveals a large number of ATM variants of uncertain significance (VUS). Here, we studied germline ATM variants occurring in a real-world cohort of 336 patients with chronic lymphocytic leukaemia (CLL) and public cancer whole-exome/genome-sequencing datasets (445 CLL, 75 mantle cell lymphoma, 216 metastatic breast cancer, 140 lung cancer patients). We found that two-thirds of rare germline ATM variants are pathogenic (18%-50%) or VUS-predicted pathogenic (50%-82%), depending on cancer type and reaching a prevalence of up to 8%, and one-third are VUS-predicted benign. Patients with both pathogenic and VUS-predicted pathogenic variants, all heterozygous, mostly missense, are more predisposed to biallelic ATM inactivation by acquiring deletion (del)11q than patients without these variants, similar to patients with somatic ATM variants. A functional assay of ATM activity in primary CLL cells proved that VUS-predicted pathogenic ATM variants partially reduce ATM activity and concurrent del(11q) leads to complete loss of ATM activity. The rare germline variants were associated with reduced progression-free survival in CLL on novel agents, comparable to somatic ATM or TP53 disruptions. Our results highlight the need to determine the pathogenicity of VUS in clinically relevant genes such as ATM.

Keywords:  11q deletion; CLL; VUS; ataxia-telangiectasia mutated gene; diagnostic next-generation sequencing; rare germline variants; variants of uncertain significance

DOI:  https://doi.org/10.1111/bjh.18419
Best Pract Res Clin Gastroenterol. 2022 Jun-Aug;58-59:pii: S1521-6918(21)00067-6. [Epub ahead of print]58-59 101783

Hereditary pancreatic cancer.

Derk C F Klatte, Michael B Wallace, Matthias Löhr, Marco J Bruno, Monique E van Leerdam.

  Pancreatic cancer is one of the deadliest malignancies. Therefore, there is an urgent need to detect pancreatic cancer in an earlier stage to improve outcomes. A variety of hereditary cancer syndromes have been associated with an increased risk of developing pancreatic cancer, and these individuals may benefit from surveillance programs. Surveillance programs have shown potential to improve outcomes, but have important risks such as overtreatment. In this review we will discuss the definitions and epidemiology of hereditary pancreatic cancer, recommendations for genetic testing and participation in surveillance. Important aspects are differences in surveillance strategies, target lesions, and potential benefits and harms of surveillance. Lastly we will highlight future directions for research and improvement of care for individuals at high-risk of pancreatic cancer.

Keywords:  Familial pancreatic cancer; Hereditary pancreatic cancer; High-risk individuals; Pancreatic ductal adenocarcinoma; Surveillance

DOI:  https://doi.org/10.1016/j.bpg.2021.101783
NPJ Genom Med. 2022 Aug 25. 7(1): 49

Mutational and splicing landscape in a cohort of 43,000 patients tested for hereditary cancer.

Carolyn Horton, Ashley Cass, Blair R Conner, Lily Hoang, Heather Zimmermann, Nelly Abualkheir, David Burks, Dajun Qian, Bhuvan Molparia, Huy Vuong, Holly LaDuca, Jessica Grzybowski, Kate Durda, Robert Pilarski, Jessica Profato, Katherine Clayback, Martin Mahoney, Courtney Schroeder, Wilfredo Torres-Martinez, Aaron Elliott, Elizabeth C Chao, Rachid Karam.

DNA germline genetic testing can identify individuals with cancer susceptibility. However, DNA sequencing alone is limited in its detection and classification of mRNA splicing variants, particularly those located far from coding sequences. Here we address the limitations of splicing variant identification and interpretation by pairing DNA and RNA sequencing and describe the mutational and splicing landscape in a clinical cohort of 43,524 individuals undergoing genetic testing for hereditary cancer predisposition.

DOI: https://doi.org/10.1038/s41525-022-00323-y
Genes (Basel). 2022 Aug 06. pii: 1398. [Epub ahead of print]13(8):

Examining the Diagnostic Yield of Tumour Testing and Qualifying Germline Concordance for Hereditary Cancer Variants in Patients with High-Grade Serous Carcinoma.

Emily A Goebel, Jennifer Kerkhof, Oleksandra Dzyubak, C Meg McLachlin, Jacob McGee, Bekim Sadikovic.

  Despite advances in treatment, prognosis for most patients with high-grade serous carcinoma (HGSC) remains poor. Genomic alterations in the homologous recombination (HR) pathway are used for cancer risk assessment and render tumours sensitive to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPi), which can be associated with more favourable outcomes. In addition to patients with tumours containing BRCA1 or BRCA2 pathologic variants, there is emerging evidence that patients with tumours harbouring pathologic variants in other HR genes may also benefit from PARPi therapy. The objective of this study is to assess the feasibility of primary-tumour testing by examining the concordance of variant detection between germline and tumour-variant status using a custom hereditary cancer gene panel (HCP). From April 2019 to November 2020, HCP variant testing was performed on 146 HGSC formalin-fixed, paraffin-embedded tissue samples using next-generation sequencing. Of those, 78 patients also underwent HCP germline testing using blood samples. A pathogenic variant was detected in 41.1% (60/146) of tumours tested, with 68.3% (41/60) having either a BRCA1 or BRCA2 variant (n = 36), or BRCA1/2 plus a second variant (n = 5), and 31.2% (19/60) carrying a pathogenic variant in another HCP gene. The overall variant rate among the paired germline and tumour samples was 43.6% (34/78), with the remaining 56% (44/78) having no pathogenic variant detected in the germline or tumour. The overall BRCA1/2 variant rate for paired samples was 33.3% (26/78), with germline variants detected in 11.5% (9/78). A non-BRCA1/2 germline variant in another HCP gene was detected in 9.0% (7/78). All germline variants were detected in the tumour, demonstrating 100% concordance. These data provide evidence supporting the feasibility of primary-tumour testing for detecting germline and somatic variants in HCP genes in patients with HGSC, which can be used to guide clinical decision-making, and may provide opportunity for improving patient triage and clinical genetic referral practices.

Keywords:  BRCA; molecular testing; ovarian carcinoma; solid tumour

DOI:  https://doi.org/10.3390/genes13081398
Genes (Basel). 2022 Jul 28. pii: 1355. [Epub ahead of print]13(8):

A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma.

Maria Kabbage, Jihenne Ben Aissa-Haj, Houcemeddine Othman, Amira Jaballah-Gabteni, Sarra Laarayedh, Sahar Elouej, Mouna Medhioub, Haifa Tounsi Kettiti, Amal Khsiba, Moufida Mahmoudi, Houda BelFekih, Afifa Maaloul, Hassen Touinsi, Lamine Hamzaoui, Emna Chelbi, Sonia Abdelhak, Mohamed Samir Boubaker, Mohamed Mousaddak Azzouz.

  Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case "JI-021", which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G>A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G>T. The structural prediction model of the MSH2 variant and electrostatic potential calculation showed for the first time that MSH2 c.728G>A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. It appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G>T FANCD2 variant was predicted to destabilize the protein structure. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights a putative impact on the binding with MLH1 by disrupting the electrostatic potential, suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine.

Keywords:  CDH1-negative case; DNA repair genes; HDGC; MSH2; genetic screening; lynch syndrome II; target gene sequencing

DOI:  https://doi.org/10.3390/genes13081355
Am J Surg Pathol. 2022 Aug 22.

A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Pheochromocytoma and Paraganglioma.

Talia L Fuchs, Catherine Luxford, Adele Clarkson, Amy Sheen, Loretta Sioson, Marianne Elston, Michael S Croxson, Trisha Dwight, Diana E Benn, Lyndal Tacon, Michael Field, Mahsa S Ahadi, Angela Chou, Roderick J Clifton-Bligh, Anthony J Gill.

Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)-tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk.

DOI: https://doi.org/10.1097/PAS.0000000000001945
Medicina (Kaunas). 2022 Aug 17. pii: 1113. [Epub ahead of print]58(8):

Novel Germline PHD2 Variant in a Metastatic Pheochromocytoma and Chronic Myeloid Leukemia, but in the Absence of Polycythemia.

Aldesia Provenzano, Massimiliano Chetta, Giuseppina De Filpo, Giulia Cantini, Andrea La Barbera, Gabriella Nesi, Raffaella Santi, Serena Martinelli, Elena Rapizzi, Michaela Luconi, Mario Maggi, Massimo Mannelli, Tonino Ercolino, Letizia Canu.

  BACKGROUND: Pheochromocytoma (Pheo) and paraganglioma (PGL) are rare tumors, mostly resulting from pathogenic variants of predisposing genes, with a genetic contribution that now stands at around 70%. Germline variants account for approximately 40%, while the remaining 30% is attributable to somatic variants.OBJECTIVE: This study aimed to describe a new PHD2 (EGLN1) variant in a patient affected by metastatic Pheo and chronic myeloid leukemia (CML) without polycythemia and to emphasize the need to adopt a comprehensive next-generation sequencing (NGS) panel.
METHODS: Genetic analysis was carried out by NGS. This analysis was initially performed using a panel of genes known for tumor predisposition (EGLN1, EPAS1, FH, KIF1Bβ, MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL), followed initially by SNP-CGH array, to exclude the presence of the pathogenic Copy Number Variants (CNVs) and the loss of heterozygosity (LOH) and subsequently by whole exome sequencing (WES) comparative sequence analysis of the DNA extracted from tumor fragments and peripheral blood.
RESULTS: We found a novel germline PHD2 (EGLN1) gene variant, c.153G>A, p.W51*, in a patient affected by metastatic Pheo and chronic myeloid leukemia (CML) in the absence of polycythemia.
CONCLUSIONS: According to the latest guidelines, it is mandatory to perform genetic analysis in all Pheo/PGL cases regardless of phenotype. In patients with metastatic disease and no evidence of polycythemia, we propose testing for PHD2 (EGLN1) gene variants. A possible correlation between PHD2 (EGLN1) pathogenic variants and CML clinical course should be considered.

Keywords:  PHD2 gene; PPRT; chronic myeloid leukemia; germline variants; metastatic pheochromocytoma; radiometabolic therapy

DOI:  https://doi.org/10.3390/medicina58081113