bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–03–10
eight papers selected by
Joanna Zawacka, Karolinska Institutet
  1. Multiple Primary Cancers With Hematologic Malignancies and Germline Predisposition: A Case Series.
  2. Comprehensive germline profiling of patients with breast cancer: initial experience from a Familial Cancer Clinic.
  3. Germline variants of DNA repair and immune genes in lymphoma from lymphoma-cancer families.
  4. Clinical features and management of germline CEBPA-mutated carriers.
  5. Germline Genetic NBN Variation and Predisposition to B-cell Acute Lymphoblastic Leukemia in Children.
  6. Editorial: Advances in predisposition to bone marrow failure and hematopoietic neoplasms.
  7. Bilateral fumarate hydratase deficient renal cell carcinoma in a patient with hereditary leiomyomatosis and renal cell cancer syndrome.
  8. The Role of Demographic and Clinical Factors in Germline Mutation Testing for Patients with Primary Hyperparathyroidism.
  1. Ann Lab Med. 2024 Mar 07.
    Multiple Primary Cancers With Hematologic Malignancies and Germline Predisposition: A Case Series.
    Jiwon Yun, Dong Soon Lee, Sungyoung Lee, Hongseok Yun.
      The term "multiple primary (MP) cancers" refers to the existence of more than one cancer in the same patient. The combination of MP cancers with hematological malignancies is relatively uncommon. In this study, we present five patients diagnosed with MP cancers concomitant with hematological malignancies. We comprehensively analyzed their clinical characteristics, cytogenetic profiles, and germline and somatic variants. As first primaries, two patients had solid cancer not followed by cytotoxic therapy and three had hematologic cancer, followed by cytotoxic therapy. The second primaries were all hematologic malignancies that did not meet the criteria for therapy-related myeloid neoplasm. Notably, two (40%) out of the five patients harbored pathogenic potential/presumed germline variants in cancer predisposition genes. Therefore, germline variant testing should be considered when MP cancers with hematological malignancies require consideration for related donor stem cell transplantation.
    Keywords:  Germline predisposition; Hematologic neoplasms; High-throughput nucleotide sequencing; Multiple primary neoplasms
    DOI:  https://doi.org/10.3343/alm.2023.0444
  2. Ecancermedicalscience. 2024 ;18 1670
    Comprehensive germline profiling of patients with breast cancer: initial experience from a Familial Cancer Clinic.
    Raja Pramanik, Sindhura Chitikela, S V S Deo, Ajay Gogia, Atul Batra, Akash Kumar, Ritu Gupta, Deepshi Thakral, Vedam L Ramprasad, Sandeep Mathur, D N Sharma, Aparna Sharma, Ashutosh Mishra, Babul Bansal.
       Introduction: Breast cancer is the most common cancer among Indian females. There is limited data on germline profiling of breast cancer patients from India.
    Objective: The objective of the current study was to analyse the frequency and spectrum of germline variant profiles and clinicopathological characteristics of breast cancer patients referred to our Familial Cancer Clinic (FCC).
    Materials and methods: It is a single-centre audit of patients with a confirmed diagnosis of breast carcinoma referred to our FCC from January 2017 to 2020. All patients underwent pretest counselling. Genetic testing was done by multigene panel testing by next-generation sequencing along with reflex multiplication ligation-dependent probe amplification for BRCA1 and 2. The variants were classified based on American College of Medical Genetics guidelines. Demographic and clinicopathological details were extracted from the case record files.
    Results: One hundred and fifty-five patients were referred to the FCC and underwent pretest counselling. A total of 99 (63.9%) patients underwent genetic testing. Among them, 62 patients (62/99 = 62.6%) had a germline variant. A pathogenic/likely pathogenic (P/LP) germline variant was identified in 41 (41.4%) of the patients who underwent testing. Additional variants of unknown significance (VUS) were identified in seven patients who also carried a P/LP variant. VUS alone was detected in 21 patients (21/99 = 21.2%). Among the P/LP pathogenic variants (PV), BRCA 1 PV were seen in 27 patients (65.8%), BRCA 2 variants in 7 patients (17.1%), ATM variants in 3 patients (7.3%) and RAD51, TP53, CHEK2 and HMMR in 1 patient each. Variants were significantly more common in patients with a family history (FH) of malignancy than those without FH (58.5% versus 29.5%; p = 0.013). Age and triple-negative histology were not found to be significantly associated with the occurrence of P/LP PVs.
    Conclusion: We report a 41% P/LP variant rate in our selected cohort of breast cancer patients, with variants in BRCA constituting 83% and non-BRCA gene variants constituting 17%.
    Keywords:  India; breast cancer; germline variant; next-generation sequencing
    DOI:  https://doi.org/10.3332/ecancer.2024.1670
  3. Int J Cancer. 2024 Mar 06.
    Germline variants of DNA repair and immune genes in lymphoma from lymphoma-cancer families.
    Xiaogan Wang, Lijuan Deng, Lingyan Ping, Yunfei Shi, Haojie Wang, Feier Feng, Xin Leng, Yahan Tang, Yan Xie, Zhitao Ying, Weiping Liu, Jun Zhu, Yuqin Song.
      The genetic predisposition to lymphoma is not fully understood. We identified 13 lymphoma-cancer families (2011-2021), in which 27 individuals developed lymphomas and 26 individuals had cancers. Notably, male is the predominant gender in lymphoma patients, whereas female is the predominant gender in cancer patients (p = .019; OR = 4.72, 95% CI, 1.30-14.33). We collected samples from 18 lymphoma patients, and detected germline variants through exome sequencing. We found that germline protein truncating variants (PTVs) were enriched in DNA repair and immune genes. Totally, we identified 31 heterozygous germline mutations (including 12 PTVs) of 25 DNA repair genes and 19 heterozygous germline variants (including 7 PTVs) of 14 immune genes. PTVs of ATM and PNKP were found in two families, respectively. We performed whole genome sequencing of diffuse large B cell lymphomas (DLBCLs), translocations at IGH locus and activation of oncogenes (BCL6 and MYC) were verified, and homologous recombination deficiency was detected. In DLBCLs with germline PTVs of ATM, deletion and insertion in CD58 were further revealed. Thus, in lymphoma-cancer families, we identified germline defects of both DNA repair and immune genes in lymphoma patients.
    Keywords:  germline variant; lymphoma; lymphoma-cancer family
    DOI:  https://doi.org/10.1002/ijc.34892
  4. Leuk Res. 2024 Feb 03. pii: S0145-2126(24)00019-5. [Epub ahead of print]138 107453
    Clinical features and management of germline CEBPA-mutated carriers.
    Lili Pan, Yining Li, Huiying Gao, Xiaolin Lai, Yuanhua Cai, Zhixiang Chen, Xiaofan Li, Shao-Yuan Wang.
      Familial acute myeloid leukemia (AML) pedigrees with germline CCAAT/enhancer-binding protein-α (CEBPA) mutation have been rarely reported due to insufficient knowledge of their clinical features. Here, we report two Chinese families with multiple AML cases carrying germline CEBPA mutations, one of which had 11 cases spanning four consecutive generations. Additionally, we collected clinical data of 57 AML patients from 22 families with germline CEBPA mutations, with 58.3% of them harboring double CEBPA mutations. The first mutation frequently occurred at the N-terminal of CEBP/α (78.6%), resulting in an exclusive expression of p30 of CEBPA (CEBPAp30). The second mutation was mostly found at the C-terminal of CEBP/α (CEBPAothers). Germline CEBPAp30 carriers had higher incidences of AML (80.36% vs. 42.86%) and earlier onset of AML (18 vs. 38.5 years old) compared to germline CEBPAothers carriers. Despite the high rates of relapse, most familial AML cases exhibited favorable overall survival (OS), with germline CEBPAp30 carriers having better survival outcomes (>25 years vs. 11 years for CEBPAothers carriers). Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.
    Keywords:  AML; CEBPA; Familial AML
    DOI:  https://doi.org/10.1016/j.leukres.2024.107453
  5. Blood. 2024 Mar 06. pii: blood.2023023336. [Epub ahead of print]
    Germline Genetic NBN Variation and Predisposition to B-cell Acute Lymphoblastic Leukemia in Children.
    Carolin S Escherich, Wenan Chen, Yizhen Li, Wenjian Yang, Rina Nishii, Zhenhua Li, Elizabeth A Raetz, Meenakshi Devidas, Gang Wu, Kim E Nichols, Hiroto Inaba, Ching-Hon Pui, Sima Jeha, Bruce Matthew Camitta, Eric C Larsen, Stephen P Hunger, Mignon L Loh, Jun J Yang.
      Biallelic mutation in the DNA-damage repair gene NBN is the genetic cause of Nijmegen Breakage Syndrome, which is associated with predisposition to lymphoid malignancies. Heterozygous carriers of germline NBN variants may also be at risk for leukemia development, although this is much less characterized. Sequencing 4,325 pediatric B-ALL patients, we systematically examined the frequency of germline NBN variants and identified 25 unique, putatively damaging NBN coding variants in 50 patients. Compared with the frequency of NBN variants in gnomAD non-cancer controls (189 unique, putatively damaging NBN coding variants in 472 of 118,479 individuals) we found significant overrepresentation in pediatric B-ALL (p=0.004, OR=1.8). Most B-ALL-risk variants were missense and cluster within the NBN N-terminal domains. Using two functional assays, we verified 14 of 25 variants with severe loss-of-function phenotypes and thus classified these as non-functional or partially functional. Finally, we found that germline NBN variant carriers, all of which were identified as heterozygous genotypes, showed similar survival outcomes relative to those with WT status. Taken together, our findings provide novel insights into the genetic predisposition to B-ALL, and the impact of NBN variants on protein function and suggest that heterozygous NBN variant carriers may safely receive B-ALL therapy.
    DOI:  https://doi.org/10.1182/blood.2023023336
  6. Front Oncol. 2024 ;14 1377974
    Editorial: Advances in predisposition to bone marrow failure and hematopoietic neoplasms.
    Sushree S Sahoo, Sherif Abdelhamed, Makiko Mochizuki-Kashio, Lara Wahlster.
      
    Keywords:  Hematopoietic neoplasms; bone marrow failure; diagnosis; genetics; germline predisposition; pathomechanism; therapy
    DOI:  https://doi.org/10.3389/fonc.2024.1377974
  7. IJU Case Rep. 2024 Mar;7(2): 144-147
    Bilateral fumarate hydratase deficient renal cell carcinoma in a patient with hereditary leiomyomatosis and renal cell cancer syndrome.
    Akihiro Ono, Masaki Nakamura, Takuya Takada, Sakiko Miura, Ibuki Tsuru, Taro Izumi, Masashi Kusakabe, Sachiko Mitarai, Yoji Nagashima, Haruki Kume, Teppei Morikawa, Yoshiyuki Shiga.
       Introduction: Patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome have high risks of uterine and cutaneous leiomyomas and renal cell carcinoma (RCC), which are caused by germline mutation of the fumarate hydratase (FH) gene. RCC lesions are mostly high-grade tumors with a poor prognosis.
    Case presentation: A 37-year-old man who had previously undergone treatment for a left RCC was referred to our hospital with a diagnosis of right RCC. Robot-assisted partial nephrectomy was performed, and the pathological diagnosis revealed fumarate hydratase (FH)-deficient RCC. The left RCC, which was originally diagnosed as mucinous tubular and spindle cell carcinoma, was reviewed and diagnosed as FH-deficient RCC. The patient's father and uncle both died of RCC, and the father's tumor was also immunohistochemically proven to be FH-deficient RCC.
    Conclusion: HLRCC-related RCC should be considered in a differential diagnosis of young patients with a family history of RCC.
    Keywords:  fumarate hydratase; hereditary leiomyomatosis and cancer; nephrectomy; renal cell; renal cell carcinoma
    DOI:  https://doi.org/10.1002/iju5.12688
  8. Ann Surg Oncol. 2024 Mar 08.
    The Role of Demographic and Clinical Factors in Germline Mutation Testing for Patients with Primary Hyperparathyroidism.
    Patrick T Hangge, Sophie Dream, Tina W F Yen, Kara Doffek, Samantha M Stachowiak, Joseph Shaker, Douglas B Evans, Tracy S Wang.
       INTRODUCTION: Guidelines recommending genetic counseling in primary hyperparathyroidism (PHPT) vary. To further delineate current recommendations, this study examined genetic counseling referral patterns and rates of mutations in surgical patients with PHPT.
    PATIENTS AND METHODS: A single-institution review was performed of adult patients who underwent parathyroidectomy for presumed sporadic PHPT. Genetic testing indications of hypercalcemia onset ≤ 40 years, multigland disease (MGD), family history (FHx) of PHPT, or other clinical indications suspicious for a PHPT-related endocrinopathy were examined by demographics and mutation detection rates.
    RESULTS: Genetic counseling was performed in 237 (37.9%) of 625 patients. Counseling was discussed but not performed in 121 (19.4%) patients. No evidence was noted of genetic referral discussion in the remaining 267 (42.7%). Of these groups, patients who received genetic counseling were youngest, p < 0.001 [median age 55.3 (IQR 43.2, 66.7) years]. The majority of patients with indications of age ≤ 40 years (65.7%), FHx (78.0%), and other clinical indications (70.7%) underwent genetic counseling, while most with MGD (57.0%) did not. Eight mutations were detected in 227 patients (3.5%). Mutations included: MEN1 (n = 2), CDC-73 (n = 4), and CASR (n = 2). Detection was most common in patients with FHx (4/71, 5.6%), then age ≤ 40 years (3/66, 4.5%), and other clinical indications (3/80, 3.8%). No mutations were identified in 48 patients tested solely for MGD.
    CONCLUSIONS: Most patients with onset of hypercalcemia age ≤ 40 years, positive FHx, or other clinical concerns underwent genetic counseling, while most with MGD did not. As no germline mutations were identified in patients with MGD alone, further investigation of MGD as a sole indication for genetic counseling may be warranted.
    Keywords:  Age; Family history; Genetic testing; Germline mutations; Guidelines; Indications; Multigland disease; Primary hyperparathyroidism
    DOI:  https://doi.org/10.1245/s10434-024-15104-3
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