bims-lifras 2021-08-29 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021‒08‒29
ten papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor.
B-cell acute lymphoblastic leukemia in patients with germline RUNX1 mutations.
Germline PALB2 Mutation in High-Risk Chinese Breast and/or Ovarian Cancer Patients.
Germline mutations in Black patients with ovarian, fallopian tube and primary peritoneal carcinomas.
Cancer predisposition and germline CTNNA1 variants.
A novel germline BRCA2 mutation in a Chinese patient with prostate cancer sensitive to platinum chemotherapy: a case report.
Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma.
Treatment Options for Germline BRCA-Mutated Metastatic Pancreatic Adenocarcinoma.
Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants.
Clinical Quality in Cancer Research: Strategy to Assess Data Integrity of Germline Variants Inferred from Tumor-Only Testing Sequencing Data.

World J Surg Oncol. 2021 Aug 27. 19(1): 254

A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor.

Juraj Prejac, Natalija Dedić Plavetić, Kristina Gotovac Jerčić, Fran Borovečki.

  BACKGROUND: Li-Fraumeni is a rare autosomal dominant cancer predisposition syndrome. The basis is a germline mutation of TP53 gene which encodes tumor suppressor protein resulting in early onset of tumors, most often breast cancer, soft tissue sarcomas, brain tumors, adrenocortical carcinomas, and leukemia.CASE REPORT: We present a case of a young woman with a positive family history for cancer diagnosed with malignant solitary fibrous tumor and luminal B-like invasive breast cancer. Breast cancer and sarcomas account for the majority of tumors associated with Li-Fraumeni syndrome, yet solitary fibrous tumor is a rare clinical entity with no established guidelines for treatment. Even though both primary tumors were successfully resected, the sarcoma relapsed in the form of lung metastases. The NGS analysis revealed single nucleotide variant (c.1101-1G>A) in TP53 gene, affecting the acceptor splice site at intron 10. Until now, only one case of this genetic variant has been documented with conflicting interpretations of pathogenicity.
CONCLUSIONS: The knowledge of TP53 mutation status is essential since the management of these patients requires different approach to avoid excessive toxicity due to the risk of developing secondary malignancy. Using the clinical criteria to screen for affected individuals facilitates appropriate early genetic counseling of patients and their families. Following the American College of Medical Genetics criteria, we believe that the reported single nucleotide variant (c.1101-1G>A) in TP53 gene should be considered pathogenic.

Keywords:  Invasive breast cancer; Li-Fraumeni syndrome; Malignant solitary fibrous tumor; Splice-site mutation; TP53

DOI:  https://doi.org/10.1186/s12957-021-02370-8
Blood Adv. 2021 Aug 24. 5(16): 3199-3202

B-cell acute lymphoblastic leukemia in patients with germline RUNX1 mutations.

Kathryn A Six, Ulrike Gerdemann, Anna L Brown, Andrew E Place, Alan B Cantor, Matthew A Kutny, Serine Avagyan.

Germline RUNX1 mutations underlie a syndrome, RUNX1-familial platelet disorder (RUNX1-FPD), characterized by bleeding symptoms that result from quantitative and/or qualitative defect in platelets and a significantly increased risk for developing hematologic malignancies. Myeloid neoplasms are the most commonly diagnosed hematologic malignancies, followed by lymphoid malignancies of T-cell origin. Here, we describe the first 2 cases of B-cell acute lymphoblastic leukemia (B-ALL) in patients with confirmed germline RUNX1 mutations. While 1 of the patients had a known diagnosis of RUNX1-FPD with a RUNX1 p.P240Hfs mutation, the other was the index patient of a kindred with a novel RUNX1 variant, RUNX1 c.587C>T (p.T196I), noted on a targeted genetic testing of the B-ALL diagnostic sample. We discuss the clinical course, treatment approaches, and the outcome for the 2 patients. Additionally, we describe transient resolution of the mild thrombocytopenia and bleeding symptoms during therapy, as well as the finding of clonal hematopoiesis with a TET2 mutant clone in 1 of the patients. It is critical to consider testing for germline RUNX1 mutations in patients presenting with B-ALL who have a personal or family history of thrombocytopenia, bleeding symptoms, or RUNX1 variants identified on genetic testing at diagnosis.

DOI: https://doi.org/10.1182/bloodadvances.2021004653
Cancers (Basel). 2021 Aug 20. pii: 4195. [Epub ahead of print]13(16):

Germline PALB2 Mutation in High-Risk Chinese Breast and/or Ovarian Cancer Patients.

Ava Kwong, Vivian Y Shin, Cecilia Y S Ho, Aleena Khalid, Chun Hang Au, Karen K L Chan, Hextan Y S Ngan, Tsun-Leung Chan, Edmond S K Ma.

  The prevalence of the PALB2 mutation in breast cancer varies across different ethnic groups; hence, it is of intense interest to evaluate the cancer risk and clinical association of the PALB2 mutation in Chinese breast and/or ovarian cancer patients. We performed sequencing with a 6-gene test panel (BRCA1, BRCA2, TP53, PTEN, PALB2, and CDH1) to identify the prevalence of the PALB2 germline mutation among 2631 patients with breast and/or ovarian cancer. In this cohort, 39 mutations were identified with 24 types of mutation variants, where the majority of the mutations were frame-shift mutations and resulted in early termination. We also identified seven novel PALB2 mutations. Most of the PALB2 mutation carriers had breast cancer (36, 92.3%) and were more likely to have family history of breast cancer (19, 48.7%). The majority of the breast tumors were invasive ductal carcinoma (NOS type) (34, 81.0%) and hormonal positive (ER: 32, 84.2%; PR: 23, 60.5%). Pathogenic mutations of PALB2 were found in 39 probands with a mutation frequency of 1.6% and 1% in breast cancer and ovarian cancer patients, respectively. PALB2 mutation carriers were more likely have hormonal positive tumors and were likely to have familial aggregation of breast cancer.

Keywords:  Chinese; PALB2 mutation; breast cancer risk; hereditary breast cancer

DOI:  https://doi.org/10.3390/cancers13164195
Gynecol Oncol. 2021 Aug 24. pii: S0090-8258(21)01315-9. [Epub ahead of print]

Germline mutations in Black patients with ovarian, fallopian tube and primary peritoneal carcinomas.

Sahana Somasegar, Arielle S Weiss, Barbara M Norquist, Nithisha Khasnavis, Marc Radke, Enna Manhardt, Christopher Pennil, Kathryn P Pennington, Mark A Eckert, Agnieszka Chryplewicz, Ernst Lengyel, Elizabeth M Swisher.

OBJECTIVE: Routine genetic testing for ovarian cancer and identification of germline mutations can help improve early detection of cancer as well as guide treatment. Knowledge of genetic counseling and referral rates for genetic testing has been lower for Black patients, compared to White patients. We aimed to describe the demographics and presence of germline mutations in Black individuals with ovarian, fallopian tube or peritoneal carcinoma at two large academic institutions.METHODS: Fifty-one Black patients with invasive epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were identified via institutional tissue banks over a 20-year time-period. Germline DNA was sequenced using BROCA, a targeted capture and parallel sequencing assay that identified pathogenic germline mutations in ovarian carcinoma susceptibility genes.
RESULTS: Germline mutations in ovarian cancer susceptibility genes were found in 25.5% of women, most commonly BRCA1 and BRCA2. This mutation frequency mirrors those previously described among predominantly White populations. Our data suggests there may be an advantage in survival among those with germline mutations, although this was not statistically significant.
CONCLUSIONS: Given similar frequencies of germline mutations between Black and White patients with ovarian cancer, we conclude that there are not major differences in the genetic predisposition to ovarian carcinoma. Equitable access to genomic advancements including germline and tumor sequencing would facilitate equal access to PARP inhibitors, the standard of care for patients with BRCA mutated advanced ovarian cancer.

DOI: https://doi.org/10.1016/j.ygyno.2021.08.017
Eur J Med Genet. 2021 Aug 21. pii: S1769-7212(21)00182-8. [Epub ahead of print]64(10): 104316

Cancer predisposition and germline CTNNA1 variants.

Silvana Lobo, Patrick R Benusiglio, Florence Coulet, Lise Boussemart, Lisa Golmard, Isabel Spier, Robert Hüneburg, Stefan Aretz, Chrystelle Colas, Carla Oliveira.

  Hereditary Diffuse Gastric Cancer (HDGC) is a cancer predisposing syndrome mainly caused by germline inactivating variants in CDH1, encoding E-cadherin. Early-onset diffuse gastric cancer (DGC) and/or invasive lobular breast cancer (LBC) are the main phenotypes in CDH1-associated HDGC. CTNNA1, encoding for α-E-catenin, and E-cadherin-partner in the adherens junction complex, has been recently classified as a HDGC predisposing gene. Nevertheless, little is known about CTNNA1 tumor spectrum in variant carriers and variant-type associated causality. Herein, we systematically reviewed the literature searching for CTNNA1 germline variants carriers, further categorized them according to HDGC clinical criteria (HDGC vs non-HDGC), collected phenotypes, classified variants molecularly and according to CDH1 ACMG/AMP guidelines and performed genotype-phenotype analysis. We found 41 families carrying CTNNA1 germline variants encompassing in total 105 probands and relatives. All probands from 13 HDGC families presented DGC and their average age of onset was 40 ± 17 years; 10/13 (77%) HDGC families carried a pathogenic (P) variant. Most probands from 28 non-HDGC families developed unspecified-BC, as well as most of their relatives; 4/28 (14%) carried a P variant, 16/28 (57%) carried a likely pathogenic (LP) variant, 7/28 (25%) carried variants of unknown significance (VUS) and 1/28 (4%) carried a likely benign variant. Regardless of clinical criteria, 97% (32/33) of probands and relatives from P variant-carrier families had DGC/unspecified-GC. In LP variant-carrier families, 82% (28/34) of probands and relatives had unspecified-BC. Only 2/105 individuals had LBC. A cluster of frameshift and nonsense variants was found in CTNNA1 last exon of non-HDGC families and classified as VUS. In conclusion, current available data confirms an association of CTNNA1 P variants with early-onset DGC, but not with LBC. We demonstrate that in ascertained cohorts, CTNNA1 P variants explain <2% of HDGC families and support the use of ACMG/AMP CDH1 specific variant curation guidelines, while no specific guidelines are developed for CTNNA1 variant classification. Moreover, we demonstrated that truncating variants at the CTNNA1 NMD-incompetent last exon have limited deleteriousness, and that CTNNA1 LP variants have lower actionability than CDH1 LP variants. Current knowledge supports considering only CTNNA1 P variants as clinically actionable in HDGC carrying families.

Keywords:  CDH1; CTNNA1; Hereditary diffuse gastric cancer; Pathogenic variants; Variant classification

DOI:  https://doi.org/10.1016/j.ejmg.2021.104316
BMC Urol. 2021 Aug 23. 21(1): 114

A novel germline BRCA2 mutation in a Chinese patient with prostate cancer sensitive to platinum chemotherapy: a case report.

Lijuan Jiang, Zunguang Bai, Shoulun Zhu, Tingting Zhao, Yining Yang, Zhiyong Li, Dong Chen, Zhiming Wu, Yanjun Wang, Fangjian Zhou, Yonghong Li.

  BACKGROUND: Germline BRCA2 mutation is associated with an aggressive prostate cancer phenotype and indicates higher risk for hereditary cancer. Recently, numerous studies have attempted to identify the genomic landscape of prostate cancer to better understand the genomic drivers of this disease and look for the molecular targets to guide treatment selection.CASE PRESENTATION: We report a 67-year-old patient diagnosed with prostate cancer who experienced rapid disease progression after androgen deprivation therapy and subsequent docetaxel treatment. The patient had a strong family history of malignancy as his mother was diagnosed with breast cancer and his father was died of lung cancer. Next generation sequencing demonstrated a novel pathogenic germline BRCA2 mutation (p.Gly2181Glufs*10) in the patient. His mother with breast cancer and his son were found to have the same BRCA2 mutation. The patient experienced impressive and durable responses to carboplatin treatment.
CONCLUSIONS: This case demonstrated that the carboplatin could have a dramatic antitumor effect on patients with prostate cancer with germline BRCA2 mutations and family history will help to ensure that patients and their families can be provided with proper genetic counseling.

Keywords:  BRCA2; Family history; Platinum chemotherapy; Prostate cancer

DOI:  https://doi.org/10.1186/s12894-021-00879-4
Cancers (Basel). 2021 Aug 09. pii: 4014. [Epub ahead of print]13(16):

Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma.

Masato Yonamine, Koichiro Wasano, Yuichi Aita, Takehito Sugasawa, Katsutoshi Takahashi, Yasushi Kawakami, Hitoshi Shimano, Hiroyuki Nishiyama, Hisato Hara, Mitsuhide Naruse, Takahiro Okamoto, Tadashi Matsuda, Shinji Kosugi, Kazuhiko Horiguchi, Akiyo Tanabe, Atsushi Watanabe, Noriko Kimura, Eijiro Nakamura, Akihiro Sakurai, Kiyoto Shiga, Kazuhiro Takekoshi.

  The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype-phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.

Keywords:  Japanese; SDHB; SDHD; VHL; genetics; germline variants; paraganglioma; pheochromocytoma

DOI:  https://doi.org/10.3390/cancers13164014
J Adv Pract Oncol. 2021 Jul;12(5): 488-491

Treatment Options for Germline BRCA-Mutated Metastatic Pancreatic Adenocarcinoma.

Doreen Grzelak.

Pancreatic cancer is the fourth leading cause of death from cancer in both men and women. Pancreatic cancer is typically diagnosed at an advanced stage and has an overall 5-year survival of approximately 9.3%. The National Comprehensive Cancer Network recommends both germline testing (testing cells such as blood or skin that do not have cancer) as well as somatic testing (testing cells with cancer) for pathogenic variants that may increase the risk of pancreatic cancer. In December 2019, the U.S. Food & Drug Administration approved the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib for maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma in individuals who have completed at least 16 weeks of progression-free treatment with first-line platinum-based chemotherapy. This new therapy option has implications not only for treatment but also for the role of the oncology advanced practitioner as genetic testing becomes more prevalent in the care of patients with cancer.

DOI: https://doi.org/10.6004/jadpro.2021.12.5.4
Cancer Treat Rev. 2021 Jul 23. pii: S0305-7372(21)00110-9. [Epub ahead of print]100 102262

Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants.

Marina Macchini, Federico Centonze, Umberto Peretti, Giulia Orsi, Anna Maria Militello, Maria Maddalena Valente, Stefano Cascinu, Michele Reni.

  Personalized treatments and predictive biomarkers of pancreatic cancer (PDAC) are still lacking. Recently germline mutations in BRCA 1 and 2 genes, leading to homologous repair deficiency, have emerged as new targets for more specific and effective therapies, exploiting the increased susceptibility to platinum salts and PARP inhibitors. In addition to BRCA, pathogenic variants in PALB2 and in other genes involved in the DNA damage response pathway (DDR) represent potential targets, as well as their respective somatic alterations. This enlarged molecularly-selected population sharing the BRCAness phenotype, is expected to show a higher sensibility to a number of DNA damaging agents and DDR inhibitors. However, the possibility of new therapeutic opportunities for DDR defective PDAC patients has to face the lack of solid evidence about the proper type and timing of targeted-treatments, the potential combination strategies and most importantly, the lack of informations on the functional impact of each specific pathogenic variant on the DDR pathway. This review summarizes the current and near-future options for the clinical management of PDAC patients harboring a DDR deficiency, analyzing the state of the art of the indications of platinum salts and other cytotoxic agents in the advanced and early stage PDAC, the development of PARP inhibitors and the rational for new combinations with immunotherapy and cycle checkpoint inhibitors, as well as the strategy to overcome the development of resistance over treatments.

Keywords:  BRCA/BRCAness; DNA damage response; Drug resistance; PARP inhibitors; Pancreatic adenocarcinoma; Platinum

DOI:  https://doi.org/10.1016/j.ctrv.2021.102262
Pharmaceut Med. 2021 Aug 26.

Clinical Quality in Cancer Research: Strategy to Assess Data Integrity of Germline Variants Inferred from Tumor-Only Testing Sequencing Data.

Timothé Ménard, Donato Rolo, Björn Koneswarakantha.

In the majority of cancers, pathogenic variants are only found at the level of the tumor; however, an unusual number of cancers and/or diagnoses at an early age in a single family may suggest a genetic predisposition. Predisposition plays a major role in about 5-10% of adult cancers and in certain childhood tumors. As access to genomic testing for cancer patients continues to expand, the identification of potential germline pathogenic variants (PGPVs) through tumor-DNA sequencing is also increasing. Statistical methods have been developed to infer the presence of a PGPV without the need of a matched normal sample. These methods are mainly used for exploratory research, for example in real-world clinico-genomic databases/platforms (CGDB). These databases are being developed to support many applications, such as targeted drug development, clinical trial optimization, and postmarketing studies. To ensure the integrity of data used for research, a quality management system should be established, and quality oversight activities should be conducted to assess and mitigate clinical quality risks (for patient safety and data integrity). As opposed to well-defined 'good practice' quality guidelines (GxP) areas such as good clinical practice, there are no comprehensive instructions on how to assess the clinical quality of statistically derived variables from sequencing data such as PGPVs. In this article, we aim to share our strategy and propose a possible set of tactics to assess the PGPV quality and to ensure data integrity in exploratory research.

DOI: https://doi.org/10.1007/s40290-021-00399-4