bims-lifras 2022-11-06 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–11–06
eleven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service.
The Frequency of Germline BRCA and Non-BRCA HR-Gene-Variants in a Cohort of Pancreatic Cancer Patients.
Somatic Inactivation of Breast Cancer Predisposition Genes in Tumours Associated with Pathogenic Germline Variants.
Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia.
Germline DDX41 mutations define a unique subtype of myeloid neoplasms.
Congenital medulloblastoma in two brothers with SUFU-mutated Gorlin-Goltz syndrome: Case reports and literature review.
Pancreatoblastoma in Elderly Adults: Report of Two Patients.
Prognostic impact of germline BRCA1/2 pathogenic variants in breast cancer.
Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.
The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.
Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility.

Sci Rep. 2022 Nov 03. 12(1): 18629

Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service.

Bruna Palma Matta, Renan Gomes, Daniel Mattos, Renata Olicio, Caroline Macedo Nascimento, Gerson Moura Ferreira, Ayslan Castro Brant, Mariana Boroni, Carolina Furtado, Valdirene Lima, Miguel Ângelo Martins Moreira, Anna Cláudia Evangelista Dos Santos.

Several studies have demonstrated the cost-effectiveness of genetic testing for surveillance and treatment of carriers of germline pathogenic variants associated with hereditary breast/ovarian cancer syndrome (HBOC). In Brazil, seventy percent of the population is assisted by the public Unified Health System (SUS), where genetic testing is still unavailable. And few studies were performed regarding the prevalence of HBOC pathogenic variants in this context. Here, we estimated the prevalence of germline pathogenic variants in BRCA1, BRCA2 and TP53 genes in Brazilian patients suspected of HBOC and referred to public healthcare service. Predictive power of risk prediction models for detecting mutation carriers was also evaluated. We found that 41 out of 257 tested patients (15.9%) were carriers of pathogenic variants in the analyzed genes. Most frequent pathogenic variant was the founder Brazilian mutation TP53 c.1010G > A (p.Arg337His), adding to the accumulated evidence that supports inclusion of TP53 in routine testing of Brazilian HBOC patients. Surprisingly, BRCA1 c.5266dupC (p.Gln1756fs), a frequently reported pathogenic variant in Brazilian HBOC patients, was not observed. Regarding the use of predictive models, we found that familial history of cancer might be used to improve selection or prioritization of patients for genetic testing, especially in a context of limited resources.

DOI: https://doi.org/10.1038/s41598-022-23012-3
Dig Dis Sci. 2022 Oct 31.

The Frequency of Germline BRCA and Non-BRCA HR-Gene-Variants in a Cohort of Pancreatic Cancer Patients.

M Baz, V Gondran-Teiller, B Bressac, O Cabaret, A Fievet, M Dimaria, V Goldbarg, C Colas, M N Bonnet-Dupeyron, J Tinat, M Lebrun, V Mari, J M Limacher, C Corsini, E Ginglinger, J C Saurin, A Brahimi, C Rouzier, S Giraud, H Schuster, A Hollebecque, V Boige, E Cauchin, D Malka, O Caron, E Rouleau.

  Germline DNA alterations affecting homologous recombination pathway genes have been associated with pancreatic cancer (PC) risk. BRCA2 is the most studied gene and affects the management of PC patients and their families. Even though recent reports have suggested a similar role of germline ATM pathogenic variants (PV) in familial PC, there is still a disagreement between experts on how it could affect patient management given the lack of proper PC risk estimates. We retrospectively analyzed the germline data of 257 PC patients among whom nearly 50% were sporadic cases. We showed similar frequencies of BRCA2 (4.9%) and ATM (4.4%) PV or likely pathogenic variants, which were not related to familial history. Based on our findings and that of the literature, we suggest including ATM gene among the panel of genes analyzed in PC patients pending the publication of prospective studies.

Keywords:  Germline DNA; Hereditary cancer; Homologous recombination pathway; Next generation sequencing; Pancreatic cancer

DOI:  https://doi.org/10.1007/s10620-022-07733-z
J Natl Cancer Inst. 2022 Oct 31. pii: djac196. [Epub ahead of print]

Somatic Inactivation of Breast Cancer Predisposition Genes in Tumours Associated with Pathogenic Germline Variants.

Belle W X Lim, Na Li, Sakshi Mahale, Simone Mcinerny, Magnus Zethoven, Simone M Rowley, Joanne Huynh, Theresa Wang, Jue Er Amanda Lee, Mia Friedman, Lisa Devereux, Rodney J Scott, Erica K Sloan, Paul A James, Ian G Campbell.

BACKGROUND: Breast cancers (BC) that arise in individuals heterozygous for a germline pathogenic variant in a susceptibility gene, such as BRCA1/2, PALB2 and RAD51C, have been shown to exhibit bi-allelic loss in the respective genes, and be associated with triple-negative (TN) BC and distinctive somatic mutational signatures. Tumour sequencing thus presents an orthogonal approach to assess the role of candidate genes in BC development.
METHODS: Exome sequencing was performed on paired normal-breast tumour DNA from 124 carriers of germline loss-of-function (LoF) or missense (MS) mutations carriers in 15 known and candidate BC predisposition genes identified in the BEACCON case-control study. Bi-allelic inactivation and association with tumour genome features including mutational signatures and homologous recombination deficiency (HRD) score were investigated.
RESULTS: BARD1-carrying TN BC (4/5) displayed bi-allelic loss and associated high HRD scores and mutational signature 3, as did a RAD51D-carrying TN BC and ovarian cancer. Bi-allelic loss was less frequent in BRIP1 BCs (4/13) and had low HRD scores. In contrast to other established BC genes, BCs from carriers of CHEK2 LoF (6/17) or MS (2/20) carriers had low rates of bi-allelic loss. Exploratory analysis of BC from carriers of LoF mutations in candidate genes such as BLM, FANCM, PARP2 and RAD50 found little evidence of bi-allelic inactivation.
CONCLUSIONS: BARD1 and RAD51D behave as classic BRCA-like genes with bi-allelic inactivation but this was not observed for any of the candidate genes. However, as demonstrated for CHEK2, the absence of bi-allelic inactivation does not provide definitive evidence against the gene's involvement in BC predisposition.

DOI: https://doi.org/10.1093/jnci/djac196
J Clin Oncol. 2022 Oct 31. JCO2200269

Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia.

Benjamin L Lampson, Aditi Gupta, Svitlana Tyekucheva, Kiyomi Mashima, Anna Petráčková, Zixu Wang, Natalia Wojciechowska, Conner J Shaughnessy, Peter O Baker, Stacey M Fernandes, Samantha Shupe, John-Hanson Machado, Rayan Fardoun, Annette S Kim, Jennifer R Brown.

PURPOSE: Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia-mutated (ATM) gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline ATM variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL.
METHODS: We identified 3,128 patients (including 825 patients with CLL) in our hematologic malignancy clinic who had received clinical-grade sequencing of the entire coding region of ATM. We ascertained the comparative frequencies of germline ATM variants in categories of hematologic neoplasms, and, in patients with CLL, we determined whether these variants affected CLL-associated characteristics such as somatic 11q deletion.
RESULTS: Rare germline ATM variants are present in 24% of patients with CLL, significantly greater than that in patients with other lymphoid malignancies (16% prevalence), myeloid disease (15%), or no hematologic neoplasm (14%). Patients with CLL with germline ATM variants are younger at diagnosis and twice as likely to have 11q deletion. The ATM variant p.L2307F is present in 3% of patients with CLL, is associated with a three-fold increase in rates of somatic 11q deletion, and is a hypomorph in cell-based assays.
CONCLUSION: Germline ATM variants cluster within CLL and affect the phenotype of CLL that develops, implying that some of these variants (such as ATM p.L2307F) have functional significance and should not be ignored. Further studies are needed to determine whether these variants affect the response to therapy or account for some of the inherited risk of CLL.

DOI: https://doi.org/10.1200/JCO.22.00269
Blood. 2022 Nov 02. pii: blood.2022018221. [Epub ahead of print]

Germline DDX41 mutations define a unique subtype of myeloid neoplasms.

Hideki Makishima, Ryunosuke Saiki, Yasuhito Nannya, Sophia Claire Korotev, Carmelo Gurnari, June Takeda, Yukihide Momozawa, Steven Best, Pramila Krishnamurthy, Tetsuichi Yoshizato, Yoshiko Atsuta, Yusuke Shiozawa, Yuka Iijima-Yamashita, Kenichi Yoshida, Yuichi Shiraishi, Yasunobu Nagata, Nobuyuki Kakiuchi, Makoto Onizuka, Kenichi Chiba, Hiroko Tanaka, Ayana Kon, Yotaro Ochi, Masahiro Marshall Nakagawa, Rurika Okuda, Takuto Mori, Akinori Yoda, Hidehiro Itonaga, Yasushi Miyazaki, Masashi Sanada, Takayuki Ishikawa, Shigeru Chiba, Hisashi Tsurumi, Senji Kasahara, Carsten Müller-Tidow, Akifumi Takaori-Kondo, Kazuma Ohyashiki, Toru Kiguchi, Fumihiko Matsuda, Joop H Jansen, Chantana Polprasert, Piers Blombery, Yoichiro Kamatani, Satoru Miyano, Luca Malcovati, Torsten Haferlach, Michiaki Kubo, Mario Cazzola, Austin G Kulasekararaj, Lucy A Godley, Jaroslaw P Maciejewski, Seishi Ogawa.

Germline DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here, enrolling a total of 346 patients with DDX41 pathogenic/likely pathogenic (P/LP) germline variants and/or somatic mutations from 9,082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients, we performed a comprehensive characterization of DDX41-mutated MNs. P/LP DDX41 germline variants explained ~80% of known germline predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n=4,461) compared to a Japanese general population (n=20,238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs. 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years old but rapidly increased to 49% by 90 years of age. DDX41-mutated MDS patients rapidly progressed to AML, which was, however, confined to those having truncating variants. Co-mutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and -WT cases, where none of the co-mutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multi-hit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System (IPSS-R/M). Our findings establish that DDX41-mutated MDS defines a unique subtype of MNs that is distinct from other MNs.

DOI: https://doi.org/10.1182/blood.2022018221
Front Oncol. 2022 ;12 988798

Congenital medulloblastoma in two brothers with SUFU-mutated Gorlin-Goltz syndrome: Case reports and literature review.

Yufan Chen, Haibo Zhang, Yang Zhao, Jie Ma.

   Background: Congenital medulloblastoma is very rare, and many cases involve germline mutations that can lead to inherited syndromes. Here, we first report two brothers with congenital medulloblastoma who were diagnosed with Gorlin-Goltz syndrome caused by SUFU mutation.
Clinical presentation: Medulloblastoma was detected in two brothers at 2 and 3 months of age, with very similar imaging features. Genetic testing revealed that both children and their mother carried SUFU gene germline mutations, and both brothers were diagnosed with Gorlin-Goltz syndrome.
Conclusion: Gorlin-Goltz syndrome-associated congenital medulloblastoma with SUFU germline mutation is very rare. Pathological types mostly involve desmoplastic/nodular or extensive nodularity; chemotherapy is the main treatment, and studies revealing prognostic data are scarce.

Keywords:  Gorlin-Goltz syndrome; congenital medulloblastoma; infantile; stem cell transplantation; sufu

DOI:  https://doi.org/10.3389/fonc.2022.988798
Int J Surg Pathol. 2022 Oct 30. 10668969221133347

Pancreatoblastoma in Elderly Adults: Report of Two Patients.

Ozlem Kulak, Arsen Osipov, Andrew E Hendifar, Nicholas N Nissen, Brian K Cox, Ralph H Hruban, Danielle A Hutchings.

  Introduction. Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas, which often shows multiple lines of differentiation, but is defined by neoplastic cells with acinar differentiation and characteristic squamoid nests. Pediatric patients are most commonly affected, and although a subset is known to occur in adults, the diagnosis is rarely considered in elderly adults. Methods. The clinicopathologic features of two cases of pancreatoblastoma in elderly patients were examined. Results. Two patients (age 80 and 81 years) presented with pancreatoblastoma, including one with early-stage pancreatic disease and one with liver metastasis. Biopsies and one pancreatic resection specimen showed characteristic histomorphologic features, including prominent acinar differentiation and abundant squamoid nests. Both cases had complete loss of SMAD4 (DPC4) immunolabeling. Next generation sequencing was performed on one case and revealed copy number loss of chromosome 11p and 9p21 (CDKN2A/B) and pathogenic or likely pathogenic variants in APC, SMAD4, and PIK3CA. The APC and SMAD4 variants occurred at allele frequencies suggestive of germline mutations, raising the possibility that this patient may have an inherited cancer predisposition syndrome. Conclusions. We present two cases which extend the upper age limit for reported pancreatoblastoma, including one with genetic findings suggestive of an inherited cancer predisposition syndrome.

Keywords:  SMAD4; adult pancreatoblastoma; elderly adult; germline mutation; pancreatoblastoma

DOI:  https://doi.org/10.1177/10668969221133347
Breast Cancer Res Treat. 2022 Nov 04.

Prognostic impact of germline BRCA1/2 pathogenic variants in breast cancer.

Giovanni Corso, Antonia Girardi, Mariarosaria Calvello, Sara Gandini, Aurora Gaeta, Monica Marabelli, Francesca Magnoni, Paolo Veronesi, Aliana Guerrieri-Gonzaga, Bernardo Bonanni.

   PURPOSE: This study investigates the impact of different subtypes of pathogenic BRCA variants on the prognosis and on the survival of breast cancer (BC) patients.
METHODS: Associations between BRCA1/2 pathogenic variants (PVs) mutations, clinicopathological features, locoregional tumor reappearance, and survival data were analyzed. The Gray's test was used to test difference of the cumulative incidence of local relapse between missense/splicing and other mutations, taking into of competing events. The multivariate proportional hazard model was used to assess the independent association between type of mutation and local relapse, after adjustment for other prognostic factors and clinicopathological characteristics.
RESULTS: Out of 482 patients, 285 presented 98 different BRCA1 PVs and 201 harbored 103 different BRCA2 PVs. Missense mutations were found in 46 BC patients (9.5%), splicing mutations in 42 (8.6%), deletions in 206 (42.4%), insertions in 73 (15%), indel mutations in 6 (1.2%), nonsense mutations in 86 (17.7%), and large rearrangements in 27 (5.6%). Kalbfleisch and Prentice cumulative incidence curves analysis showed a significantly lower locoregional recurrence incidence in the missense/splicing group (Gray-test P-value = 0.011). We found that the risk of local relapse was 58% less likely in women carrying missense/splicing variants than in those with other PV subtypes (HR 95% CI 0.42 [0.21-0.82]; P-value = 0.0108). No significant differences were observed in overall survival (OS) in all groups.
CONCLUSIONS: Having been found to be associated with a lower risk of BC reappearance, germline BRCA1/2 PVs of the missense/splicing subtypes can be used as prognostic predictors and are likely to improve BC patients' management.

Keywords:  BRCA1; BRCA2; Breast cancer prognosis; Germline mutations; Hereditary breast cancer

DOI:  https://doi.org/10.1007/s10549-022-06776-0
J Endocrinol Invest. 2022 Nov 05.

Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.

I Mazarico-Altisent, I Capel, N Baena, M R Bella-Cueto, S Barcons, X Guirao, L Albert, A Cano, R Pareja, A Caixàs, M Rigla.

   PURPOSE: CDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1 mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT).
METHODS: During genetic screening for familial hyperparathyroidism, three novel CDKIs germline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples.
RESULTS: DNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1B in cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3.
CONCLUSION: Germline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.

Keywords:  Cyclin dependent kinase inhibitors; Multiple endocrine neoplasia type 1; Multiple endocrine neoplasia type 4; Parathyroid; Primary hyperparathyroidism

DOI:  https://doi.org/10.1007/s40618-022-01948-7
J Med Genet. 2022 Nov 01. pii: jmedgenet-2022-108741. [Epub ahead of print]

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

Sue Philpott, Maria Raikou, Ranjit Manchanda, Michelle Lockley, Naveena Singh, Malcolm Scott, D Gareth Evans, Julian Adlard, Munaza Ahmed, Richard Edmondson, Emma Roisin Woodward, Athena Lamnisos, Janos Balega, Angela F Brady, Aarti Sharma, Louise Izatt, Anjana Kulkarni, Vishakha Tripathi, Joyce S Solomons, Kevin Hayes, Helen Hanson, Katie Snape, Lucy Side, Steve Skates, Alistair McGuire, Adam N Rosenthal.

   BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO).
METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation.
RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY.
CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

Keywords:  Costs and Cost Analysis; Early Diagnosis; Economics; Genetic Predisposition to Disease; Women's Health

DOI:  https://doi.org/10.1136/jmg-2022-108741
Sci Adv. 2022 Nov 04. 8(44): eabq5914

Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility.

Carolina Villarroya-Beltri, Ana Osorio, Raúl Torres-Ruiz, David Gómez-Sánchez, Marianna Trakala, Agustin Sánchez-Belmonte, Fátima Mercadillo, Begoña Hurtado, Borja Pitarch, Almudena Hernández-Núñez, Antonio Gómez-Caturla, Daniel Rueda, José Perea, Sandra Rodríguez-Perales, Marcos Malumbres, Miguel Urioste.

Germline mutations leading to aneuploidy are rare, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, encoding the spindle assembly checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias. Functional studies demonstrated lack of full-length protein and deficient SAC response, resulting in ~30 to 40% of aneuploid blood cells. Single-cell RNA analysis identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFκB signaling both in aneuploid and euploid cells, suggesting a non-cell autonomous response. MAD1L1 mutations resulted in specific clonal expansions of γδ T cells with chromosome 18 gains and enhanced cytotoxic profile as well as intermediate B cells with chromosome 12 gains and transcriptomic signatures characteristic of leukemia cells. These data point to MAD1L1 mutations as the cause of a new variant of mosaic variegated aneuploidy with systemic inflammation and unprecedented tumor susceptibility.

DOI: https://doi.org/10.1126/sciadv.abq5914