bims-lifras 2022-12-04 papers

Cureus. 2022 Oct;14(10): e30836

12-Year-Old Girl Diagnosed With Li-Fraumeni Syndrome and Concomitant Adrenocortical Carcinoma (ACC).

Umberto M Donato, Diego Torres, Andrew Galligan.

Adrenocortical carcinomas (ACC) are classical presentations of germline cancer predisposition syndromes such as the Li-Fraumeni syndrome (LFS). Li-Fraumeni syndrome is a multiple cancer syndrome caused by germline alterations of the tumor protein 53 (TP53) tumor suppressor gene and is often associated with ACC. If minor adrenocortical tumors (ACTs) are detected early, resection has proven to provide patients with better outcomes. However, non-functioning ACCs are particularly insidious since these patients present late and with distant metastases. We present the case of a 12-year-old female with a history of Li-Fraumeni syndrome (LFS) and a non-hormone-secreting ACC in the context of an exceedingly rare c.743G>A (p.Arg248Gln) p53 mutation.

Keywords: li-fraumeni; pediatric oncology surgeon; pediatric solid tumours; s: adrenocortical carcinoma (acc); tp53 mutations

DOI: https://doi.org/10.7759/cureus.30836

Oxf Med Case Reports. 2022 Nov;2022(11): omac124

Long-term response to olaparib in a patient with metastatic pancreatic cancer associated with hereditary breast and ovarian cancer syndrome.

Michiko Tsuneizumi, Shuzo Terada, Takeshi Usui, Kei Yamaguchi, Ryosuke Hayami, Ryoichi Matsunuma.

BRCA mutations are associated with an increased risk of pancreatic cancer (PC). Olaparib, an oral poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, has been approved for the treatment of metastatic PC with a germline BRCA mutation. In this report, we present the case of a metastatic PC harboring a germline BRCA2 mutation, and the daughter of the patient, who had bilateral breast cancers harboring the same germline mutation, suggesting that the PC was associated with hereditary breast and ovarian cancer syndrome. Although PC is an aggressive disease and has poor prognosis, olaparib was administered as maintenance therapy following modified FOLFIRINOX, providing clinical benefits for >12 months.

DOI: https://doi.org/10.1093/omcr/omac124

Virchows Arch. 2022 Nov 29.

The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia.

Martina Rudelius, Olga K Weinberg, Charlotte M Niemeyer, Akiko Shimamura, Katherine R Calvo.

Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200-1228, 2022).

Keywords: ANKRD26; CEBPA; DDX41; ETV6; GATA2; Germline predisposition to myeloid malignancy; Hematologic neoplasms; ICC; Juvenile myelomonocytic leukemia (JMML); Leukemia; Myelodysplastic syndrome (MDS); RUNX1; Refractory anemia of childhood (RCC); SAMD9; SAMD9L; TP53

DOI: https://doi.org/10.1007/s00428-022-03447-9

BMC Urol. 2022 Nov 30. 22(1): 196

The germline mutational landscape of genitourinary cancers and its indication for prognosis and risk.

Yong Yang, Guoying Zhang, Chen Hu, Wei Luo, Haiyang Jiang, Shaoyou Liu, Hong Yang.

BACKGROUND: Germline mutations represent a high risk of hereditary cancers in population. The landscape and characteristics of germline mutations in genitourinary cancer are largely unknown, and their correlation with patient prognosis has not been defined.
METHODS: Variant data and relevant clinical data of 10,389 cancer patients in The Cancer Genome Atlas (TCGA) database was downloaded. The subset of data of 206 genitourinary cancer patients containing bladder urothelial carcinoma (BLCA), kidney chromophobe carcinoma (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and prostate adenocarcinoma (PRAD) cancer with germline mutation information was filtered for further analysis. Variants were classified into pathogenic, likely pathogenic and non-pathogenic categories based on American College of Medical Genetics and Genomics (ACMG) guidelines. Genome Aggregation Database (gnomAD) database was used to assist risk analysis.
RESULTS: There were 48, 7, 44, 45 and 62 patients with germline mutations identified in BLCA, KICH, KIRC, KIRP and PRAD, respectively. Pathogenic germline mutations from 26 genes and likely pathogenic mutations from 33 genes were revealed. GJB2, MET, MUTYH and VHL mutations ranked top in kidney cancers, and ATM and CHEK2 mutations ranked top for bladder cancer, while ATM and BRCA1 mutations ranked top for prostate cancer. Frameshift, stop gained and missense mutations were the predominant mutation types. BLCA exhibited the highest ratio of stop gained mutations (22/48 = 45.8%). No difference in patient age was found among pathogenic, likely pathogenic and non-pathogenic groups for all cancer types. The number of male patients far overweight female patients whether PRAD was included (P = 0) or excluded (P < 0.001). Patients with pathogenic or likely pathogenic germline mutations exhibited significantly worse overall survival rate than the non-pathogenic group for all genitourinary cancers. More important, analyses assisted by gnomAD database revealed that pathogenic or likely pathogenic germline mutations significantly increased the risk for genitourinary cancer in population, with the odds ratio at 14.88 (95%CI 11.80-18.77) and 33.18 (95%CI 24.90-44.20), respectively.
CONCLUSIONS: The germline mutational status for genitourinary cancers has been comprehensively characterized. Pathogenic and likely pathogenic germline mutations increased the risk and indicated poor prognosis of genitourinary cancers.

Keywords: Bladder; Genitourinary cancer; Germline; Hereditary; Kidney; Mutation; Prognosis; Prostate

DOI: https://doi.org/10.1186/s12894-022-01141-1

Blood. 2022 Dec 01. pii: blood.2022017715. [Epub ahead of print]

DDX41-associated susceptibility to myeloid neoplasms.

Hideki Makishima, Teresa Venezia Bowman, Lucy A Godley.

Deleterious germline DDX41 variants confer risk for myeloid neoplasms (MNs), and less frequently to lymphoid malignancies, with autosomal dominant inheritance and an estimated prevalence of 3% among MNs. Germline DDX41 variants include truncating alleles that comprise about two thirds of all alleles; missense variants located preferentially within the DEAD box domain; and deletion variants. The identification of a truncating allele on tumor-based molecular profiling should prompt germline genetic testing, since virtually all such alleles are germline. Somatic mutation of the wild-type DDX41 allele occurs in about half of MNs with germline DDX41 alleles, typically in exons encoding the helicase domain and most frequently as R525H. Several aspects of deleterious germline DDX41 alleles are noteworthy: (i) Certain variants are common in particular populations; (ii) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people; (iii) Despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis; and (iv) Individuals with deleterious germline DDX41 variants develop acute severe graft versus host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive post-transplant cyclophosphamide, suggesting a pro-inflammatory milieu that stimulates donor-derived T-cells. Biochemical studies and animal models have identified DDX41's ability to interact with double stranded DNA and RNA:DNA hybrids with roles in mRNA splicing, rRNAs/snoRNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.

DOI: https://doi.org/10.1182/blood.2022017715

JCO Precis Oncol. 2022 Nov;6 e2200460

Germline Variants in DNA Damage Repair Genes and HOXB13 Among Black Patients With Early-Onset Prostate Cancer.

Matthew R Trendowski, Christopher Sample, Tara Baird, Azita Sadeghpour, David Moon, Julie J Ruterbusch, Jennifer L Beebe-Dimmer, Kathleen A Cooney.

PURPOSE: Genetic studies of prostate cancer susceptibility have predominantly focused on non-Hispanic White men, despite the observation that Black men are more likely to develop prostate cancer and die from the disease. Therefore, we sought to identify genetic variants in Black patients diagnosed with early-onset prostate cancer.
METHODS: Whole-exome sequencing of germline DNA from a population-based cohort of Black men diagnosed with prostate cancer at age 62 years or younger was performed. Analysis was focused on a panel of DNA damage repair (DDR) genes and HOXB13. All discovered variants were ranked according to their pathogenic potential based upon REVEL score, evidence from existing literature, and prevalence in the cohort. Logistic regression was used to investigate associations between mutation status and relevant clinical characteristics.
RESULTS: Among 743 Black prostate cancer patients, we identified 26 unique pathogenic (P) or likely pathogenic (LP) variants in 14 genes (including HOXB13, BRCA1/2, BRIP1, ATM, CHEK2, and PALB2) among 30 men, or approximately 4.0% of the patient population. We also identified 33 unique variants of unknown significance in 16 genes among 39 men. Because of the rarity of these variants in the population, most associations between clinical characteristics did not achieve statistical significance. However, our results suggest that carriers for P or LP (P/LP) variants were more likely to have a first-degree relative diagnosed with DDR gene-associated cancer, have a higher prostate-specific antigen at time of diagnosis, and be diagnosed with metastatic disease.
CONCLUSION: Variants in DDR genes and HOXB13 may be important cancer risk factors for Black men diagnosed with early-onset prostate cancer, and are more frequently observed in men with a family history of cancer.

DOI: https://doi.org/10.1200/PO.22.00460

Front Endocrinol (Lausanne). 2022 ;13 1024108

Case report: Two sisters with a germline CHEK2 variant and distinct endocrine neoplasias.

Raphaelle D Vallera, Yanli Ding, Kimmo J Hatanpaa, Justin A Bishop, Sasan Mirfakhraee, Abdel A Alli, Sergei G Tevosian, Mouna Tabebi, Oliver Gimm, Peter Söderkvist, Cynthia Estrada-Zuniga, Patricia L M Dahia, Hans K Ghayee.

Genetic testing has become the standard of care for many disease states. As a result, physicians treating patients who have tumors often rely on germline genetic testing results for making clinical decisions. Cases of two sisters carrying a germline CHEK2 variant are highlighted whereby possible other genetic drivers were discovered on tumor analysis. CHEK2 (also referred to as CHK2) loss of function has been firmly associated with breast cancer development. In this case report, two siblings with a germline CHEK2 mutation also had distinct endocrine tumors. Pituitary adenoma and pancreatic neuroendocrine tumor (PNET) was found in the first sibling and pheochromocytoma (PCC) discovered in the second sibling. Although pituitary adenomas, PNETs, and PCC have been associated with NF1 gene mutations, the second sister with a PCC did have proven germline CHEK2 with a pathogenic somatic NF1 mutation. We highlight the clinical point that unless the tumor is sequenced, the real driver mutation that is causing the patient's tumor may remain unknown.

Keywords: CHEK2; NF1; PCC; PNET; germline; somatic; tumor

DOI: https://doi.org/10.3389/fendo.2022.1024108

J Med Genet. 2022 Nov 28. pii: jmg-2022-108790. [Epub ahead of print]

Differential involvement of germline pathogenic variants in breast cancer genes between DCIS and low-grade invasive cancers.

D Gareth Evans, Siva Sithambaram, Elke Maria van Veen, George J Burghel, Helene Schlecht, Elaine F Harkness, Helen Byers, Jamie M Ellingford, Ashu Gandhi, Sacha J Howell, Anthony Howell, Claire Forde, Fiona Lalloo, William G Newman, Miriam Jane Smith, Emma Roisin Woodward.

PURPOSE: To investigate frequency of germline pathogenic variants (PVs) in women with ductal carcinoma in situ (DCIS) and grade 1 invasive breast cancer (G1BC).
METHODS: We undertook BRCA1/2 analysis in 311 women with DCIS and 392 with G1BC and extended panel testing (non-BRCA1/2) in 176/311 with DCIS and 156/392 with G1BC. We investigated PV detection by age at diagnosis, Manchester Score (MS), DCIS grade and receptor status.
RESULTS: 30/311 (9.6%) with DCIS and 16/392 with G1BC (4.1%) had a BRCA1/2 PV (p=0.003), and 24/176-(13.6%) and 7/156-(4.5%), respectively, a non-BRCA1/2 PV (p=0.004). Increasing MS was associated with increased likelihood of BRCA1/2 PV in both DCIS and G1BC, although the 10% threshold was not predictive for G1GB. 13/32 (40.6%) DCIS and 0/17 with G1BC <40 years had a non-BRCA1/2 PV (p<0.001). 0/16 DCIS G1 had a PV. For G2 and G3 DCIS, PV rates were 10/98 (BRCA1/2) and 9/90 (non-BRCA1/2), and 8/47 (BRCA1/2) and 8/45 (non-BRCA1/2), respectively. 6/9 BRCA1 and 3/26 BRCA2-associated DCIS were oestrogen receptor negative-(p=0.003). G1BC population testing showed no increased PV rate (OR=1.16, 95% CI 0.28 to 4.80).
CONCLUSION: DCIS is more likely to be associated with both BRCA1/2 and non-BRCA1/2 PVs than G1BC. Extended panel testing ought to be offered in young-onset DCIS where PV detection rates are highest.

Keywords: Genetics, Medical

DOI: https://doi.org/10.1136/jmg-2022-108790

Lancet Oncol. 2022 Nov 24. pii: S1470-2045(22)00643-X. [Epub ahead of print]

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.

José Garcia-Pelaez, Rita Barbosa-Matos, Silvana Lobo, Alexandre Dias, Luzia Garrido, Sérgio Castedo, Sónia Sousa, Hugo Pinheiro, Liliana Sousa, Rita Monteiro, Joaquin J Maqueda, Susana Fernandes, Fátima Carneiro, Nádia Pinto, Carolina Lemos, Carla Pinto, Manuel R Teixeira, Stefan Aretz, Svetlana Bajalica-Lagercrantz, Judith Balmaña, Ana Blatnik, Patrick R Benusiglio, Maud Blanluet, Vicent Bours, Hilde Brems, Joan Brunet, Daniele Calistri, Gabriel Capellá, Sergio Carrera, Chrystelle Colas, Karin Dahan, Robin de Putter, Camille Desseignés, Elena Domínguez-Garrido, Conceição Egas, D Gareth Evans, Damien Feret, Eleanor Fewings, Rebecca C Fitzgerald, Florence Coulet, María Garcia-Barcina, Maurizio Genuardi, Lisa Golmard, Karl Hackmann, Helen Hanson, Elke Holinski-Feder, Robert Hüneburg, Mateja Krajc, Kristina Lagerstedt-Robinson, Conxi Lázaro, Marjolijn J L Ligtenberg, Cristina Martínez-Bouzas, Sonia Merino, Geneviève Michils, Srdjan Novaković, Ana Patiño-García, Guglielmina Nadia Ranzani, Evelin Schröck, Inês Silva, Catarina Silveira, José L Soto, Isabel Spier, Verena Steinke-Lange, Gianluca Tedaldi, María-Isabel Tejada, Emma R Woodward, Marc Tischkowitz, Nicoline Hoogerbrugge, Carla Oliveira.

BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing.
METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test.
FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004).
INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria.
FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

DOI: https://doi.org/10.1016/S1470-2045(22)00643-X

PLoS One. 2022 ;17(12): e0278108

Kidney tumors associated with germline mutations of FH and SDHB show a CpG island methylator phenotype (CIMP).

Christopher J Ricketts, J Keith Killian, Cathy D Vocke, Yonghong Wang, Maria J Merino, Paul S Meltzer, W Marston Linehan.

Germline mutations within the Krebs cycle enzyme genes fumarate hydratase (FH) or succinate dehydrogenase (SDHB, SDHC, SDHD) are associated with an increased risk of aggressive and early metastasizing variants of renal cell carcinoma (RCC). These RCCs express significantly increased levels of intracellular fumarate or succinate that inhibit 2-oxoglutarate-dependent dioxygenases, such as the TET enzymes that regulate DNA methylation. This study evaluated the genome-wide methylation profiles of 34 RCCs from patients with RCC susceptibility syndromes and 11 associated normal samples using the Illumina HumanMethylation450 BeadChip. All the HLRCC (FH mutated) and SDHB-RCC (SDHB mutated) tumors demonstrated a distinct CpG island methylator phenotype (CIMP). HLRCC tumors demonstrated an extensive and relatively uniform level of hypermethylation that showed some correlation with tumor size. SDHB-RCC demonstrated a lesser and more varied pattern of hypermethylation that overlapped in part with the HLRCC hypermethylation. Combined methylation and mRNA expression analysis of the HLRCC tumors demonstrated hypermethylation and transcription downregulation of genes associated with the HIF pathway, HIF3A and CITED4, the WNT pathway, SFRP1, and epithelial-to-mesenchymal transition and MYC expression, OVOL1. These observations were confirmed in the TCGA CIMP-RCC tumors. A selected panel of probes could identify the CIMP tumors and differentiate between HLRCC and SDHB-RCC tumors. This panel accurately detected all CIMP-RCC tumors within the TCGA RCC cohort, identifying them as HLRCC -like, and could potentially be used to create a liquid biopsy-based screening tool. The CIMP signature in these aggressive tumors could provide both a useful biomarker for diagnosis and a target for novel therapies.

DOI: https://doi.org/10.1371/journal.pone.0278108