bims-lifras 2023-03-12 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2023–03–12
twelve papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Hereditary acute myeloid leukemia associated with C-terminal CEBPA germline variants.
Unrelated hematopoietic stem cell transplantation for familial platelet disorder/acute myeloid leukemia with germline RUNX1 mutations.
Frequency of actionable germline pathogenic variants identified through tumor next-generation sequencing in a gynecologic cancer cohort.
Evaluating Germline Testing Panels in Southern African Males With Advanced Prostate Cancer.
Are population level familial risks and germline genetics meeting each other?
Novel PRUNE2 Germline Mutations in Aggressive and Benign Parathyroid Neoplasms.
Rare germline variants in pancreatic cancer and multiple primary cancers: an autopsy study.
The genetic era of childhood cancer: Identification of high-risk patients and germline sequencing approaches.
The Clinical Spectrum, Diagnosis, and Management of GATA2 Deficiency.
Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series.
BRCA1 and BRCA2 germline mutation analysis from a cohort of 1267 patients at high risk for breast cancer in Brazil.
New SAMD9L heterozygous mutation leading to myelodysplastic syndrome and acute myeloid leukemia: A case report and review of the literature.

Fam Cancer. 2023 Mar 06.

Hereditary acute myeloid leukemia associated with C-terminal CEBPA germline variants.

Amye M Harrigan, Amy M Trottier.

  Acute myeloid leukemia with germline CEBPA mutation is a subtype of acute myeloid leukemia that is associated with a favorable prognosis. Most of the reported cases of acute myeloid leukemia with CEBPA germline variants involve a germline variant in the N-terminus and a somatic variant in the C-terminus. There are only a few reported cases where the CEBPA germline variant has been identified in the C-terminus and the somatic variant in the N-terminus. This case report and review of the literature illustrates that, although acute myeloid leukemia with CEBPA N- or C-terminal germline variants have certain similarities such as atypically young age at diagnosis, frequent relapse, and favourable overall prognosis, there are also significant differences such as lower life-time penetrance of acute myeloid leukemia and shorter time to relapse for germline C-terminal cases. These findings add important information on the natural history and clinical outcomes of acute myeloid leukemia with germline CEBPA C-terminal variants and these findings should be considered in the management of patients and their family members.

Keywords:  Acute myeloid leukemia; C-terminal; CEBPA; Germline; Hereditary

DOI:  https://doi.org/10.1007/s10689-023-00329-0
Int J Hematol. 2023 Mar 10.

Unrelated hematopoietic stem cell transplantation for familial platelet disorder/acute myeloid leukemia with germline RUNX1 mutations.

Kazunori Toratani, Mizuki Watanabe, Junya Kanda, Tomomi Oka, Mizuki Hyuga, Yasuyuki Arai, Makoto Iwasaki, Maki Sakurada, Yasuhito Nannya, Seishi Ogawa, Takahiro Yamada, Akifumi Takaori-Kondo.

  Germline mutations in RUNX1 result in rare autosomal-dominant familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). As genetic analysis is becoming increasingly prevalent, the diagnosis rate of FPD/AML is expected to increase. In this report, we present two pedigrees, one diagnosed molecularly and another highly suspected to be FPD/AML, whose members both received allogeneic hematopoietic stem cell transplantation (HSCT). Both pedigrees had a family history of thrombocytopenia, platelet dysfunction, and hematological malignancies. One family inherited a frameshift mutation (p.P240fs) of RUNX1, a known pathogenic variant. Another family inherited a point mutation (p.G168R) in the runt-homology domain, the clinical significance of which is uncertain at this point. As this mutation was completely absent from all population databases and had a relatively high REVEL score of 0.947, we thought that it would be dangerous to ignore its possible pathogenicity. Consequently, we avoided choosing HSCT donors from relatives of both families and performed HSCT from unrelated donors. In conclusion, our experience with two families of FPD/AML highlights the importance of searching for gene mutations associated with germline predisposition and indicates the necessity of developing a donor coordination system for FPD/AML patients, as well as a support system for families.

Keywords:  Acute myeloid leukemia; Familial platelet disorder; Genetic pedigree; Germline; Myelodysplastic syndrome; RUNX1 mutation

DOI:  https://doi.org/10.1007/s12185-023-03575-1
Int J Gynecol Cancer. 2023 Mar 08. pii: ijgc-2022-004142. [Epub ahead of print]

Frequency of actionable germline pathogenic variants identified through tumor next-generation sequencing in a gynecologic cancer cohort.

Hannah Karpel, Elizabeth Manderski, Bhavana Pothuri.

   BACKGROUND: Tumor next-generation sequencing can identify potential germline pathogenic variants associated with cancer susceptibility.
OBJECTIVE: To describe the frequency of tumor sequencing results that met European Society of Medical Oncology (ESMO) recommendations for further germline genetic testing, and the frequency of germline variants among a cohort with gynecologic cancer.
METHODS: Patients with gynecologic cancer who underwent tumor sequencing between September 2019 and February 2022 in a large healthcare system in New York City were retrospectively identified. Eligible patients with suspected germline pathogenic variants on tumor sequencing were identified based on ESMO guidelines. Logistic regression was used to explore variables associated with referral and completion of germline testing.
RESULTS: Of 358 patients with gynecologic cancers who underwent tumor sequencing, 81 (22.6%) had ≥1 suspected germline variant according to ESMO guidelines. Of the 81 patients with qualifying tumor sequencing results, 56 (69.1%) received germline testing: 41/46 (89.1%) eligible patients with ovarian cancer and 15/33 (45.5%) with endometrial cancer. In the endometrial cancer cohort, 11/33 (33.3%) eligible patients were not referred for germline testing and the majority of these patients had tumor variants in genes commonly known to cause hereditary cancer. Of the 56 patients who underwent germline testing, 40 (71.4%) had pathogenic germline variants. In multivariable analysis, race/ethnicity other than non-Hispanic white was associated with lower odds of germline testing referral and completion (OR=0.1, 95% CI 0.01 to 0.5 and OR=0.2, 95% CI 0.04 to 0.6, respectively).
CONCLUSION: Given the high rate of pathogenic germline variant detection and the importance of identifying such variants for both patients and their family, it is imperative that eligible patients undergo germline testing. Additional education for providers on multidisciplinary guidelines and development of clinical pathways to ensure germline testing of suspected pathogenic variants identified on tumor sequencing is warranted, especially in light of the racial/ethnic inequity observed.

Keywords:  Cervical Cancer; Ovarian Cancer; Uterine Cancer

DOI:  https://doi.org/10.1136/ijgc-2022-004142
J Natl Compr Canc Netw. 2023 Mar;21(3): 289-296.e3

Evaluating Germline Testing Panels in Southern African Males With Advanced Prostate Cancer.

Kazzem Gheybi, Jue Jiang, Shingai B A Mutambirwa, Pamela X Y Soh, Zsofia Kote-Jarai, Weerachai Jaratlerdsiri, Rosalind A Eeles, M S Riana Bornman, Vanessa M Hayes.

   BACKGROUND: Germline testing for prostate cancer is on the increase, with clinical implications for risk assessment, treatment, and management. Regardless of family history, NCCN recommends germline testing for patients with metastatic, regional, very-high-risk localized, and high-risk localized prostate cancer. Although African ancestry is a significant risk factor for aggressive prostate cancer, due to a lack of available data no testing criteria have been established for ethnic minorities.
PATIENTS AND METHODS: Through deep sequencing, we interrogated the 20 most common germline testing panel genes in 113 Black South African males presenting with largely advanced prostate cancer. Bioinformatic tools were then used to identify the pathogenicity of the variants.
RESULTS: After we identified 39 predicted deleterious variants (16 genes), further computational annotation classified 17 variants as potentially oncogenic (12 genes; 17.7% of patients). Rare pathogenic variants included CHEK2 Arg95Ter, BRCA2 Trp31Arg, ATM Arg3047Ter (2 patients), and TP53 Arg282Trp. Notable oncogenic variants of unknown pathogenicity included novel BRCA2 Leu3038Ile in a patient with early-onset disease, whereas patients with FANCA Arg504Cys and RAD51C Arg260Gln reported a family history of prostate cancer. Overall, rare pathogenic and early-onset or familial-associated oncogenic variants were identified in 6.9% (5/72) and 9.2% (8/87) of patients presenting with a Gleason score ≥8 or ≥4 + 3 prostate cancer, respectively.
CONCLUSIONS: In this first-of-its-kind study of southern African males, we provide support of African inclusion for advanced, early-onset, and familial prostate cancer genetic testing, indicating clinical value for 30% of current gene panels. Recognizing current panel limitations highlights an urgent need to establish testing guidelines for men of African ancestry. We provide a rationale for considering lowering the pathologic diagnostic inclusion criteria and call for further genome-wide interrogation to ensure the best possible African-relevant prostate cancer gene panel.

Keywords:  African ancestry; Germline testing; advanced disease; pathogenic variants; prostate cancer

DOI:  https://doi.org/10.6004/jnccn.2022.7097
Hered Cancer Clin Pract. 2023 Mar 08. 21(1): 3

Are population level familial risks and germline genetics meeting each other?

Kari Hemminki, Xinjun Li, Asta Försti, Charis Eng.

  Large amounts of germline sequencing data have recently become available and we sought to compare these results with population-based family history data. Family studies are able to describe aggregation of any defined cancers in families. The Swedish Family-Cancer Database is the largest of its kind in the world, covering the Swedish families through nearly a century with all cancers in family members since the start of national cancer registration in 1958. The database allows estimation of familial risks, ages of cancer onset and the proportion of familial cancer in different family constellations. Here, we review the proportion of familial cancer for all common cancers and specify them based on the number of affected individuals. With the exception of a few cancers, age of onset of familial cancer is not different from all cancers combined. The highest proportions of familial cancer were found for prostate (26.4%), breast (17.5%) and colorectal (15.7%) cancers, but the proportions of high-risk families with multiple affected individuals were only 2.8%, 1% and 0.9%, respectively. A large sequencing study on female breast cancer found that BRCA1 and BRCA2 mutations could account for 2% of the cases (subtracting the proportions in healthy individuals) and that all germline mutations accounted for 5.6% of the cases. Early age of onset was a distinct feature of only BRCA mutations. In heritable colorectal cancer, Lynch syndrome genes dominate. Large studies on penetrance in Lynch syndrome have shown an approximately linear increase in risk from 40-50 years up to age 80 years. Interesting novel data revealed a strong modification of familial risk by unknown factors. High-risk germline genetics of prostate cancer is characterized by BRCA and other DNA repair genes. HOXB13 encodes a transcription factor which contributes to germline risk of prostate cancer. A strong interaction was shown with a polymorphism in the CIP2A gene. The emerging germline landscape of common cancers can be reasonably accommodated by family data on these cancers as to high-risk proportions and age of onset.

Keywords:  Familial proportion; Familial risk; Family-Cancer Database; High-risk families; Nation-wide study

DOI:  https://doi.org/10.1186/s13053-023-00247-3
Cancers (Basel). 2023 Feb 23. pii: 1405. [Epub ahead of print]15(5):

Novel PRUNE2 Germline Mutations in Aggressive and Benign Parathyroid Neoplasms.

Sara Storvall, Eeva Ryhänen, Auli Karhu, Camilla Schalin-Jäntti.

  Parathyroid tumors are mostly sporadic but can also occur in familial forms, including different kinds of genetic syndromes with varying phenotypes and penetrance. Recently, somatic mutations of the tumor suppressor gene PRUNE2 were found to be frequent in parathyroid cancer (PC). The germline mutation status of PRUNE2 was investigated in a large cohort of patients with parathyroid tumors from the genetically homogenous Finnish population, 15 of which had PC, 16 atypical parathyroid tumors (APT), and 6 benign parathyroid adenomas (PA). Mutations in previously established hyperparathyroidism-related genes were screened with a targeted gene panel analysis. Nine PRUNE2 germline mutations with a minor allele frequency (MAF) of <0.05 were found in our cohort. Five of these were predicted to be potentially damaging and were identified in two patients with PC, two with APT, and three with PA. The mutational status was not associated with the tumor group nor related to the clinical picture or severity of the disease. Still, the frequent finding of rare germline mutations of PRUNE2 may point to the gene playing a role in the pathogenesis of parathyroid neoplasms.

Keywords:  PRUNE2; germline; mutation; parathyroid carcinoma; primary hyperparathyroidism; whole-exome sequencing

DOI:  https://doi.org/10.3390/cancers15051405
Eur J Cancer Prev. 2023 Mar 02.

Rare germline variants in pancreatic cancer and multiple primary cancers: an autopsy study.

Hiroo Fujitani, Hidetaka Eguchi, Yuta Kochi, Tomio Arai, Masaaki Muramatsu, Yasushi Okazaki.

BACKGROUND: There is a lack of information on rare germline variants of pancreatic cancer-predisposing genes. Risk genes for multiple primary cancers may overlap with those for pancreatic cancer.
METHODS: A retrospective study of autopsy cases with a negative family history in the Japanese single nucleotide polymorphism for geriatric research database examined rare germline variants in the protein-coding regions of 61 genes. Targeted sequencing of these genes was performed and classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. Polyphen-2, SIFT and LoFtool algorithms were used to predict damage to protein function.
RESULTS: Of the 189 subjects used (90 cancer and 99 non-cancer controls), 72 patients had pancreatic cancer (23 had multiple primary cancers) and 18 had no pancreatic cancer in multiple primary cancers. APC, BRCA2, BUB1B, ENG and MSH6 were associated with cancer predisposition, and pathogenic/likely pathogenic (P/LP) variants occurred in 6% [pancreatic cancer (4/72); all-cancer (5/90)] and 54% (49/90) carried only variants of uncertain significance (VUS) among cancer patients. Of these VUS, in pancreatic cancer patients, four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2), and POLQ in men were significantly associated (odds ratio = 3.83; P = 0.025; P = 0.027, respectively). The most abundant predictor of functionally damaging variants was POLQ.
CONCLUSIONS: The frequency of P/LP variants in patients with sporadic pancreatic cancer suggests the need for genetic evaluation of individuals with no family history. VUS of MMR genes (MLH1, MSH2, MSH6 and PMS2) and POLQ may be useful in predicting genetic trends in the potential risk of pancreatic cancer, especially in individuals lacking P/LP.

DOI: https://doi.org/10.1097/CEJ.0000000000000787
Ann Hum Genet. 2023 Mar 10.

The genetic era of childhood cancer: Identification of high-risk patients and germline sequencing approaches.

Oscar Alonso-Luna, Gabriela E Mercado-Celis, Jorge Melendez-Zajgla, Marta Zapata-Tarres, Elvia Mendoza-Caamal.

  Childhood cancer is a leading cause of death by disease in children ages 5-14, for which there are no preventive strategies. Due to early-age of diagnosis and short period of exposure to environmental factors, increasing evidence suggests childhood cancer could have strong association with germline alterations in predisposition cancer genes but, their frequency and distribution are largely unknown. Several efforts have been made to develop tools to identify children with increased risk of cancer who may benefit from genetic testing but their validation and application on a large scale is necessary. Research on genetic bases of childhood cancer is ongoing, in which several approaches for the identification of genetic variants related to cancer predisposition have been used. In this paper, we discuss the updated efforts, strategies, molecular mechanisms and clinical implications for germline predisposition gene alterations and the characterization of risk variants in childhood cancer.

Keywords:  cancer prevention; childhood cancer; genetic predisposition

DOI:  https://doi.org/10.1111/ahg.12502
Cancers (Basel). 2023 Mar 03. pii: 1590. [Epub ahead of print]15(5):

The Clinical Spectrum, Diagnosis, and Management of GATA2 Deficiency.

Marta Santiago, Alessandro Liquori, Esperanza Such, Ángel Zúñiga, José Cervera.

  Hereditary myeloid malignancy syndromes (HMMSs) are rare but are becoming increasingly significant in clinical practice. One of the most well-known syndromes within this group is GATA2 deficiency. The GATA2 gene encodes a zinc finger transcription factor essential for normal hematopoiesis. Insufficient expression and function of this gene as a result of germinal mutations underlie distinct clinical presentations, including childhood myelodysplastic syndrome and acute myeloid leukemia, in which the acquisition of additional molecular somatic abnormalities can lead to variable outcomes. The only curative treatment for this syndrome is allogeneic hematopoietic stem cell transplantation, which should be performed before irreversible organ damage happens. In this review, we will examine the structural characteristics of the GATA2 gene, its physiological and pathological functions, how GATA2 genetic mutations contribute to myeloid neoplasms, and other potential clinical manifestations. Finally, we will provide an overview of current therapeutic options, including recent transplantation strategies.

Keywords:  GATA2 deficiency; GATA2 haploinsufficiency; germline mutation; predisposition to myeloid neoplasms

DOI:  https://doi.org/10.3390/cancers15051590
JAAD Int. 2023 Jun;11 43-51

Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series.

Alisa M Goldstein, Richard Qin, Emily Y Chu, David E Elder, Daniela Massi, David J Adams, Paul W Harms, Carla Daniela Robles-Espinoza, Julia A Newton-Bishop, D Timothy Bishop, Mark Harland, Elizabeth A Holland, Anne E Cust, Helen Schmid, Graham J Mann, Susana Puig, Miriam Potrony, Llucia Alos, Eduardo Nagore, David Millán-Esteban, Nicholas K Hayward, Natasa Broit, Jane M Palmer, Vaishnavi Nathan, Elizabeth G Berry, Esteban Astiazaran-Symonds, Xiaohong R Yang, Margaret A Tucker, Maria Teresa Landi, Ruth M Pfeiffer, Michael R Sargen.

   Background: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation.
Objective: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology.
Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist.
Results: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P < .001) had increased odds of spitzoid morphology.
Limitations: Findings may not be generalizable to nonfamilial melanoma cases.
Conclusion: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.

Keywords:  ACD; CI, confidence interval; GPV, germline pathogenic variant; OR, odds ratio; POT1; TERF2IP; TERT; TMG, telomere maintenance gene; familial melanoma; melanoma; spitz melanoma; spitzoid melanoma

DOI:  https://doi.org/10.1016/j.jdin.2023.01.013
Breast Cancer Res Treat. 2023 Mar 07.

BRCA1 and BRCA2 germline mutation analysis from a cohort of 1267 patients at high risk for breast cancer in Brazil.

Patricia Mazzonetto, Fernanda Milanezi, Mariana D'Andrea, Silvia Martins, Priscilla M Monfredini, Juliana Dos Santos Silva, Eduardo Perrone, Darine Villela, Beatriz Schnabel, Viviane Nakano, Edenir Inez Palmero, Esteban Braggio, Thereza L Cavalcanti, Gustavo Guida, Michele P Migliavacca, Cristovam Scapulatempo-Neto, Ilana Zalcberg.

  We determined the frequency and mutational spectrum of BRCA1 and BRCA2 in a series of patients at high risk for developing breast cancer from Brazil. A total of 1267 patients were referred for BRCA genetic testing, and no obligation of fulfilling criteria of mutation probability methods for molecular screening was applied. Germline deleterious mutations in BRCA1/2 (i.e., pathogenic/likely pathogenic variants) were identified in 156 out of 1267 patients (12%). We confirm recurrent mutations in BRCA1/2, but we also report three novel mutations in BRCA2, not previously reported in any public databases or other studies. Variants of unknown significance (VUS) represent only 2% in this dataset and most of them were detected in BRCA2. The overall mutation prevalence in BRCA1/2 was higher in patients diagnosed with cancer at age > 35 years old, and with family history of cancer. The present data expand our knowledge of BRCA1/2 germline mutational spectrum, and it is a valuable clinical resource for genetic counseling and cancer management programs in the country.

Keywords:  BRCA1; BRCA2; Brazilian population; Genetic testing; Germline mutation; Hereditary breast and ovarian cancer

DOI:  https://doi.org/10.1007/s10549-023-06892-5
Cancer Rep (Hoboken). 2023 Mar 07. e1797

New SAMD9L heterozygous mutation leading to myelodysplastic syndrome and acute myeloid leukemia: A case report and review of the literature.

Dania A Monagel.

   BACKGROUND: SAMD9L mutation is linked to the development of myeloid neoplasm. The mutation has a wide range of clinical presentations involving neurological, immunological, and hematological manifestations. Until now, limited data regarding different variants of this genetic mutation existed. Here we present a 6-year-old girl who presented with acute myeloid leukemia/myelodysplastic changes and who carries a new germline variant mutation in the SAMD9L gene.
CASE PRESENTATION: A 6-year-old girl who presented initially as a case of immune thrombocytopenic purpura (ITP) was later diagnosed with acute myeloid leukemia and myelodysplastic changes. In addition, she was found to have a new germline variant mutation in the SAMD9L gene (other known pathogenic variants known to cause ataxia pancytopenia syndrome). She was treated with chemotherapy followed by haplo identical transplant from her unaffected father. She is alive 30 months post-transplant and in complete remission with full donor chimerism. Her initial brain MRI showed mild prominence of the anterior (superior) vermis folia, suggesting mild atrophy. Ongoing surveillance for accompanied neurological manifestation is ongoing, although the patient is asymptomatic.
CONCLUSION: For SAMD-9L-related disorder, a careful approach must be taken when a patient presents with a suspicious clinical feature even without a well-known genetic mutation giving the diverse presentation across affected members within the same family. In addition, other associated abnormalities should be monitored long-term.

Keywords:  SAMD9L; acute myeloid leukemia; myelodysplastic syndrome; pediatric; transplant

DOI:  https://doi.org/10.1002/cnr2.1797