bims-lifras 2023-02-05 papers

Issue of 2023–02–05
twelve papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Mol Med. 2023 01 30. 29(1): 14

Evaluation of inherited germline mutations in cancer susceptibility genes among pancreatic cancer patients: a single-center study.

Francesca Tavano, Domenica Gioffreda, Andrea Fontana, Orazio Palmieri, Annamaria Gentile, Tiziana Latiano, Anna Latiano, Tiziana Pia Latiano, Matteo Scaramuzzi, Evaristo Maiello, Francesca Bazzocchi, Francesco Perri.

BACKGROUND: Germline mutations in cancer susceptibility genes were identified in pancreatic cancer (PanC) patients with a sporadic disease and in those unselected for family cancer history.
METHODS: With the aim to determine the prevalence of germline predisposition genes mutations in PanC, and to evaluate whether they were associated with the presence of PanC, we profiled a custom AmpliSeq panel of 27 cancer susceptibility genes in 47 PanC patients and 51 control subjects by using the Ion Torrent PGM system.
RESULTS: Multigene panel testing identified a total of 31 variants in 27 PanC (57.4%), including variants with pathogenic/likely pathogenic effect, those of uncertain significance, and variants whose clinical significance remains currently undefined. Five patients carried more than one variant in the same gene or in different genes. Eight patients (17.0%) had at least one pathogenic/likely pathogenic variant in four main genes: CFTR (10.6%), BRCA2 (8.5%), ATM and CHEK2 (2.1%). Pathogenic/likely pathogenic mutation were identified in patients with positive PanC family history (20%) or in patients without first-degree relatives affected by PanC (13.6%). All the BRCA2 mutation carriers were unselected PanC patients. The presence of mutations in BRCA2 was significantly associated with an increased occurrence of PanC and with positive family history for endometrial cancer (p = 0.018).
CONCLUSIONS: This study confirmed the potential remarkable contribution of BRCA2 in assessing the presence of PanC. Overall our findings supported the recommendation of offering the germline testing to all the PanC patients with the intent to reduce the number of underdiagnosed carriers of mutations in predisposition genes, and not to preclude their relatives from the opportunity to benefit from surveillance programs.

Keywords: Cancer family history; Genetic testing; Germline variants; Next Generation Sequencing; Pancreatic cancer; Prevalence

DOI: https://doi.org/10.1186/s10020-023-00600-1

medRxiv. 2023 Jan 19. pii: 2023.01.18.23284664. [Epub ahead of print]

Integrative Analysis of Germline Rare Variants in Clear and Non-Clear Cell Renal Cell Carcinoma.

Seunghun Han, Sabrina Y Camp, Hoyin Chu, Ryan Collins, Riaz Gillani, Jihye Park, Ziad Bakouny, Cora A Ricker, Brendan Reardon, Nicholas Moore, Eric Kofman, Chris Labaki, David Braun, Toni K Choueiri, Saud H AlDubayan, Eliezer M Van Allen.

IMPORTANCE: RCC encompasses a set of histologically distinct cancers with a high estimated genetic heritability, of which only a portion is currently explained. Previous rare germline variant studies in RCC have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification that may significantly impact the interpretation and discovery of certain candidate risk genes.
OBJECTIVE: To evaluate the enrichment of germline PVs in established cancer-predisposing genes (CPGs) in clear cell and non-clear cell RCC patients compared to cancer-free controls using approaches that account for population stratification and to identify unconventional types of germline RCC risk variants that confer an increased risk of developing RCC.
DESIGN SETTING AND PARTICIPANTS: In 1,436 unselected RCC patients with sufficient data quality, we systematically identified rare germline PVs, cryptic splice variants, and copy number variants (CNVs). From this unselected cohort, 1,356 patients were ancestry-matched with 16,512 cancer-free controls, and gene-level enrichment of rare germline PVs were assessed in 143 CPGs, followed by an investigation of somatic events in matching tumor samples.
MAIN OUTCOMES AND MEASURES: Gene-level burden of rare germline PVs, identification of secondary somatic events accompanying the germline PVs, and characterization of less-explored types of rare germline PVs in RCC patients.
RESULTS: In clear cell RCC (n = 976 patients), patients exhibited significantly higher prevalence of PVs in VHL compared to controls (OR: 39.1, 95% CI: 7.01-218.07, p-value:4.95e-05, q-value:0.00584). In non-clear cell RCC (n = 380 patients), patients carried enriched burden of PVs in FH (OR: 77.9, 95% CI: 18.68-324.97, p-value:1.55e-08, q-value: 1.83e-06) and MET (OR: 1.98e11, 95% CI: 0-inf, p-value: 2.07e-05, q-value: 3.50e-07). In a CHEK2 -focused analysis with European cases and controls, clear cell RCC patients (n=906 European patients) harbored nominal enrichment of the previously reported low-penetrance CHEK2 variants, p.Ile157Thr (OR:1.84, 95% CI: 1.00-3.36, p-value:0.049) and p.Ser428Phe (OR:5.20, 95% CI: 1.00-26.40, p-value:0.045) while non-clear cell RCC patients (n=295 European patients) exhibited nominal enrichment of CHEK2 LOF germline PVs (OR: 3.51, 95% CI: 1.10-11.10, p-value: 0.033). RCC patients with germline PVs in FH, MET, and VHL exhibited significantly earlier age of cancer onset compared to patients without any germline PVs in CPGs (Mean: 46.0 vs 60.2 years old, Tukey adjusted p-value < 0.0001), and more than half had secondary somatic events affecting the same gene (n=10/15, 66.7%, 95% CI: 38.7-87.0%). Conversely, patients with rare germline PVs in CHEK2 exhibited a similar age of disease onset to patients without any identified germline PVs in CPGs (Mean: 60.1 vs 60.2 years old, Tukey adjusted p-value: 0.99), and only 30.4% of the patients carried secondary somatic events in CHEK2 (n=7/23, 95% CI: 14.1-53.0%). Finally, rare pathogenic germline cryptic splice variants underexplored in RCC were identified in SDHA and TSC1 , and rare pathogenic germline CNVs were found in 18 patients, including CNVs in FH, SDHA , and VHL .
CONCLUSIONS AND RELEVANCE: This systematic analysis supports the existing link between several RCC risk genes and elevated RCC risk manifesting in earlier age of RCC onset. Our analysis calls for caution when assessing the role of germline PVs in CHEK2 due to the burden of founder variants with varying population frequency in different ancestry groups. It also broadens the definition of the RCC germline landscape of pathogenicity to incorporate previously understudied types of germline variants, such as cryptic splice variants and CNVs.
KEY Points:
Question: Can we improve the assessment of germline genetic risk determinants for clear cell and non-clear cell renal cell carcinoma (RCC) with approaches that are aware to population-stratification and RCC histological subtypes?
Findings: In this systematic case-control study of 1,356 RCC patients and 16,512 ancestry-matched cancer-free controls strictly controlling for population stratification, clear-cell RCC patients exhibited a significantly higher prevalence of rare germline pathogenic variants (PVs) in VHL , and non-clear cell RCC patients carried significantly more rare germline PVs in FH and MET . European clear-cell RCC patients harbored a nominally significant enrichment of two low-penetrance CHEK2 variants (p.Ser428Phe and p.Ile157Thr) while European non-clear RCC patients carried a nominally significant enrichment of rare germline loss-of-function (LOF) variants in CHEK2 . Subsequent somatic analyses identified secondary somatic events in genes significantly enriched for germline PVs ( VHL, FH, MET ), and these variant carriers presented with earlier age of disease onset, but CHEK2 germline variant carriers harbored relatively fewer somatic events in CHEK2 and did not present with earlier age of onset. Finally, we identified 6 RCC patients with rare germline cryptic splice and copy number variants that impacted known kidney cancer risk genes, increasing the diagnostic yield of pathogenic variants in RCC risk genes from 2.1% to 2.5%.
Meaning: Clear and non-clear RCCs have distinct germline pathogenic variant enrichment patterns and somatic variants. Accurate risk assessment of CHEK2 in RCC requires careful adjustment for population stratification. In addition, previously underappreciated forms of germline variants may explain a portion of the missing heritability in RCC.

DOI: https://doi.org/10.1101/2023.01.18.23284664

Singapore Med J. 2023 Jan;64(1): 37-44

Understanding cancer predisposition in Singapore: What's next.

Jianbang Chiang, Tarryn Shaw, Joanne Ngeow.

Knowledge of an underlying genetic predisposition to cancer allows the use of personalised prognostic, preventive and therapeutic strategies for the patient and carries clinical implications for family members. Despite great progress, we identified six challenging areas in the management of patients with hereditary cancer predisposition syndromes and suggest recommendations to aid in their resolution. These include the potential for finding unexpected germline variants through somatic tumour testing, optimal risk management of patients with hereditary conditions involving moderate-penetrance genes, role of polygenic risk score in an under-represented Asian population, management of variants of uncertain significance, clinical trials in patients with germline pathogenic variants and technology in genetic counselling. Addressing these barriers will aid the next step forward in precision medicine in Singapore. All stakeholders in healthcare should be empowered with genetic knowledge to fully leverage the potential of novel genomic insights and implement them to provide better care for our patients.

Keywords: Cancer genetics; Singapore; genetic testing; precision medicine

DOI: https://doi.org/10.4103/singaporemedj.SMJ-2021-468

Gan To Kagaku Ryoho. 2022 Dec;49(13): 1947-1949

[Report of Multidisciplinary Treatment for Sisters with Li-Fraumeni Syndrome].

Okihide Suzuki, Kunihiko Amano, Noriyasu Chika, Takafumi Yamano, Hidetaka Eguchi, Hideo Nakashima, Soichi Ooya, Yasushi Okazaki, Erito Mochiki, Takeo Takahashi, Hideyuki Ishida.

Li-Fraumeni syndrome(LFS)is a hereditary cancer disorder caused by germline variant in TP53 and characterized by various malignancies. Multidisciplinary treatment is needed for tumors of LFS, however, radiation therapy is a relative contraindication because of frequent development of secondary malignancy such as sarcoma in the irradiated field. Case 1: A 22- year-old woman who was diagnosed with LFS by genetic test when she developed upper rectal cancer. Her rectal tumor with marked bilateral lateral lymph node dissection was successfully removed by low anterior resection with extensive lateral lymph node dissection. She underwent resection for ovarian metastasis followed by chemotherapy and radiotherapy but subsequently died by the disease 32 months postoperatively. Case 2(elder sister of Case 1): A brain tumor was identified in the left high frontal lobe to the parietal lobe because of consciousness disorder, after the genetic diagnosis of LFS. The brain tumor was successfully resected. Histological examination revealed diffuse astrocytoma(WHO grade Ⅱ). Local recurrence was observed 46 months later, and radiation therapy was performed. Six months have passed since radiation therapy, no exacerbation of local recurrence has been observed.

Br J Haematol. 2023 Jan 30.

Are the current guidelines for identification of myelodysplastic syndrome with germline predisposition strong enough?

Oriol Calvete, Julia Mestre, Arda Durmaz, Carmelo Gurnari, Jaroslaw P Maciejewski, Francesc Solé.

Keywords: Variant allele frequency (VAF); current guidelines; genetic predisposition; germline variants; myelodysplastic syndrome (MDS)

DOI: https://doi.org/10.1111/bjh.18676

Hered Cancer Clin Pract. 2023 Jan 28. 21(1): 2

Germline heterozygous exons 8-11 pathogenic BARD1 gene deletion reported for the first time in a family with suspicion of a hereditary colorectal cancer syndrome: more than an incidental finding?

Sergio Carrera, Ana Belén Rodríguez-Martínez, Intza Garin, Esther Sarasola, Cristina Martínez, Hiart Maortua, Almudena Callejo, Abigail Ruiz de Lobera, Alberto Muñoz, Nagore Miñambres, Pablo Jiménez-Labaig.

BACKGROUND: Colorectal cancer (CRC) is a highly prevalent disease in developed countries. Inherited Mendelian causes account for approximately 5% of CRC cases, with Lynch syndrome and familial adenomatous polyposis being the most prevalent forms. Scientific efforts are focused on the discovery of new candidate genes associated with CRC and new associations of phenotypes with well-established cancer-related genes. BRCA1-associated ring domain (BARD1) gene deleterious germline variants are associated with a moderate increase in the relative risk of breast cancer, but their association with other neoplasms, such as CRC, remains unclear.
CASE PRESENTATION: We present the case of a 49-year-old male diagnosed with rectal adenocarcinoma whose maternal family fulfilled Amsterdam clinical criteria for Lynch syndrome. Genetic test confirmed the presence in heterozygosis of a germline pathogenic deletion of exons 8-11 in BARD1 gene. The predictive genetic study of the family revealed the presence of this pathogenic variant in his deceased cancer affected relatives, confirming co-segregation of the deletion with the disease.
CONCLUSIONS: To the best of our knowledge, this is the first published work in which this BARD1 deletion is detected in a family with familial colorectal cancer type X (FCCTX) syndrome, in which the clinical criteria for Lynch syndrome without alteration of the DNA mismatch repair (MMR) system are fulfilled. Whether this incidental germline finding is the cause of familial colorectal aggregation remains to be elucidated in scientific forums. Patients should be carefully assessed in specific cancer genetic counseling units to account for hypothetical casual findings in other genes, in principle unrelated to the initial clinical suspicion, but with potential impact on their health.

Keywords: Amsterdam clinical criteria; BARD1; Cancer genetic counseling; Colorectal cancer; Deletion; Familial colorectal cancer type X syndrome; Hereditary; Pathogenic variant

DOI: https://doi.org/10.1186/s13053-023-00246-4

Cancer Sci. 2023 Jan 30.

Genetically Engineered Mouse Models for Hereditary Cancer Syndromes.

Kajal Biswas, Altaf Mohammed, Shyam K Sharan, Robert H Shoemaker.

Advances in molecular diagnostics have led to improved diagnosis and molecular understanding of hereditary cancers in the clinic. Improving the management, treatment, and potential prevention of cancers in carriers of predisposing mutations requires preclinical experimental models that reflect the key pathogenic features of the specific syndrome associated with the mutations. Numerous genetically engineered mouse models of hereditary cancer have been developed. In this review we describe the models of Lynch Syndrome and hereditary breast and ovarian cancer syndrome, the two most common hereditary cancer predisposition syndromes. We focus on Lynch Syndrome models as illustrative of the potential for using mouse models to devise improved approaches to prevention of cancer in a high-risk population.

Keywords: Cancer genetics; Disease model; GEM (Genetically Engineered Mice); Hereditary cancers; Mouse models

DOI: https://doi.org/10.1111/cas.15737

Fam Cancer. 2023 Jan 31.

Characteristics of familial pancreatic cancer families with additional colorectal carcinoma.

Bettina Lehman, Elvira Matthäi, Norman Gercke, Ulrike W Denzer, Jens Figiel, Timo Hess, Emily P Slater, Detlef K Bartsch.

Familial pancreatic cancer (FPC) is a rare hereditary tumor entity with broad phenotypic heterogeneity, including colorectal carcinoma (CRC) in some families. The underlying factors for this co-occurrence are still not well evaluated. FPC families in the National Case Collection of Familial Pancreatic Cancer with an additional occurrence of CRC were analyzed regarding the phenotype, genotype and recommendation for a clinical screening program. The total cohort of 272 FPC families included 30 (11%) families with at least one CRC case. The proportion of affected family members with PDAC was 16.1% (73/451) compared to 9.3% of family members with CRC (42/451, p < 0.01). Females were affected with PDAC in 49% (36/73) and CRC in 38% (16/42). The median age of PDAC was 63 compared to 66 years in CRC, whereas 8 (26.6%) of families had an early onset of PDAC and 2 (6.7%) of CRC. Seventeen families had 2 or more affected generations with PDAC and 6 families with CRC. Eleven (9.6%) of affected patients had both PDAC and CRC. Potentially causative germline mutations (2 ATM, 1 CDKN2a, 1 MLH1, 1 PALB2) were detected in 5 of 18 (27.7%) analyzed cases. These findings provide a step forward to include the phenotypic and genotypic characteristics of FPC-CRC families for the genetic counseling and management of these families. Nevertheless, results need to be verified in a larger patient cohort beforehand.

Keywords: Colorectal cancer; Familial pancreatic cancer; Genotype; Mutations; Phenotype

DOI: https://doi.org/10.1007/s10689-023-00328-1

Discov Oncol. 2023 Jan 31. 14(1): 14

Hereditary diffuse gastric cancer in a Japanese family with CDH1 mutation three case reports.

Futoshi Muranaka, Emiko Kise, Shigeo Tokumaru, Masato Kitazawa, Yusuke Miyagawa, Tomoaki Suga, Takeshi Uehara, Mai Iwaya, Shota Kobayashi, Midori Sato, Daisuke Gomi, Hidetaka Yamada, Haruhiko Sugimura, Tomoki Kosho, Yuji Soejima, Tomonobu Koizumi.

BACKGROUND: Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1-3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan.
METHOD: In this study we report the clinical courses of three cases with HDGC from a single Japanese family.
RESULTS: The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy.
CONCLUSION: It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.

Keywords: CDH1 mutations; E-cadherin; Esophagogastroduodenoscopy; Hereditary Diffuse Gastric Cancer; Random and target biopsies; Signet ring cell carcinoma; Total prophylactic gastrectomy

DOI: https://doi.org/10.1007/s12672-023-00623-4

Mol Genet Genomic Med. 2023 Feb 02. e2126

New pathogenic variants in ARMC5 gene in a series of Italian patients affected by primary bilateral macronodular adrenocortical hyperplasia (PBMAH).

Mara Giacché, Alessandra Panarotto, Luigi Mori, Pietro Luigi Poliani, Roberto Lanzi, Marco Schiavo Lena, Maurizio Castellano.

BACKGROUND: To perform genetic screening for ARMC5 gene germline pathogenic variants in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH).
SUBJECTS AND METHODS: In a group of 10 PBMAH patients, we performed complete sequencing of the coding region of the ARMC5 gene and MLPA analysis for large deletion detection. In subjects with the ARMC5 variant, we searched ARMC5 gene somatic variants on tumor samples.
RESULTS: Among 10 PBMAH patients, we identified four ARMC5 germline variants (40%). One variant, c:174dupC p.Glu59Argfs*44, was already known; one variant p.Gly323Asp, was already reported and classified as likely disease-causing VUS (class 3-4); two variants p.Leu596Arg and p.Arg811Pro, were never reported before. For p.Gly323Asp and p.Arg811Pro, we identified second deleterious variants at the somatic level, enforcing the possible pathogenic effect of germline variants.
CONCLUSIONS: Our results underscore the importance of performing genetic testing also in sporadic PBMAH patients and broaden the spectrum of molecular variants involved in PBMAH syndrome.

Keywords: ARMC5-gene; Cushing syndrome; PBMAH; meningioma

DOI: https://doi.org/10.1002/mgg3.2126

Gynecol Oncol. 2023 Jan 30. pii: S0090-8258(22)02012-1. [Epub ahead of print]170 234-240

Beyond BRCA: Patterns of risk-reducing surgery for non-BRCA, homologous recombination repair pathway gene variant carriers.

Sarah S Lee, Hannah C Karpel, Cheongeun Oh, Julia Smith, Bhavana Pothuri.

OBJECTIVE: The real-world management of patients with non-BRCA, homologous recombination repair pathway variants with increased or uncertain risks of ovarian cancer is unknown. The objective was to determine the adoption of risk-reducing salpingo-oophorectomy (RRSO) for carriers of variants with increased or uncertain risks of ovarian cancer beyond BRCA.
METHODS: This was a retrospective cohort study of patients at three hospitals with non-BRCA, homologous recombination repair pathway variants with increased risk (BRIP1, RAD51C, RAD51D) and uncertain risk (ATM, BARD1, NBN, PALB2) of ovarian cancer. Outcomes of interest were adoption of RRSO and factors associated with adoption of RRSO. Wilcoxon rank-sum, chi-square, and logistic regression were performed with p < 0.05.
RESULTS: Of 318 patients, 76 (24%) had pathogenic variants with increased risks of ovarian cancer (BRIP1, 45; RAD51C, 20; RAD51D, 11), and 242 (76%) had variants with uncertain risks of ovarian cancer (ATM, 145; PALB2, 69; NBN, 23; BARD1, 5). Of 64 patients eligible for RRSO by National Comprehensive Cancer Network (NCCN) criteria or family history, 31 (48%) underwent RRSO. Among eligible patients who did not undergo RRSO, 24 (73%) were not referred for gynecologic oncology consultation. Older age at testing (adjusted odds ratio [aOR] 1.08, 95% confidence interval [CI] 1.03-1.13) and referral to gynecologic oncology (aOR 33.48, CI 8.10-138.39) were associated with increased adoption of RRSO when adjusting for personal and family history of breast and ovarian cancer.
CONCLUSION: Half of RRSO-eligible patients by NCCN criteria beyond BRCA did not undergo RRSO. Opportunities exist for improving education to increase referrals to facilitate RRSO for these patients.

Keywords: Cancer predisposition; Genetic testing; Ovarian cancer; Risk-reducing surgery

DOI: https://doi.org/10.1016/j.ygyno.2022.12.012

Gastroenterology. 2023 Jan 27. pii: S0016-5085(23)00057-4. [Epub ahead of print]

Clinical Spectrum and Science Behind the Hamartomatous Polyposis Syndromes.

Lamis Yehia, Brandie Heald, Charis Eng.

The hamartomatous polyposis syndromes are a set of clinically distinct disorders characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumor syndrome. Although each of the syndromes has distinct phenotypes, the hamartomatous polyps can be challenging to differentiate histologically. Additionally, each of these syndromes is associated with increased lifetime risks of gene-specific and organ-specific cancers, including those outside of the gastrointestinal tract. Germline pathogenic variants can be identified in a subset of individuals with these syndromes, which facilitates molecular diagnosis and subsequent gene-enabled management in the setting of genetic counseling. While the malignant potential of hamartomatous polyps remains elusive, timely recognition of these syndromes is important and enables pre-symptomatic cancer surveillance and management prior to symptom exacerbation. Presently, there are no standard agents to prevent the development of polyps and cancers in the hamartomatous polyposis syndromes.

Keywords: Hamartoma; cancer risk; hereditary cancer syndrome; polyposis

DOI: https://doi.org/10.1053/j.gastro.2023.01.026