bims-lifras 2021-12-12 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–12–12
seven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Prevalence and spectrum of pathogenic variants among patients with multiple primary cancers evaluated by clinical characteristics.
Inherited TP53 Variants and Risk of Prostate Cancer.
Identification of the Unique Clinical and Genetic Features of Chinese Lung Cancer Patients With EGFR Germline Mutations in a Large-Scale Retrospective Study.
Prevalence and spectrum of germline cancer susceptibility gene variants and somatic second hits in colorectal cancer.
Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes.
Mismatch repair deficiency in early-onset duodenal, ampullary, and pancreatic carcinomas is a strong indicator for a hereditary defect.
Mechanisms of somatic transformation in inherited bone marrow failure syndromes.

Cancer. 2021 Dec 07.

Prevalence and spectrum of pathogenic variants among patients with multiple primary cancers evaluated by clinical characteristics.

Brittany L Bychkovsky, Min-Tzu Lo, Amal Yussuf, Carrie Horton, Marcy Richardson, Holly LaDuca, Judy E Garber, Huma Q Rana.

   BACKGROUND: Multiple primary cancers (MPCs) are a hallmark of cancer predisposition syndromes. Here the frequency of germline pathogenic variants (PVs) among patients with MPCs is reported.
METHODS: Patients with MPCs who underwent multigene panel testing from March 2012 to December 2016 were studied. Eligible patients had an analysis of 21 genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. The frequencies of PVs by sex, number of cancers, and age at diagnosis were compared with 2-sided χ2 tests or Fisher exact tests when the number was <10.
RESULTS: Among the 9714 patients analyzed, most were female (91.1%) and White (71.0%); the median age at testing was 63 years, and the median ages at first and second cancer diagnoses were 49 and 58 years, respectively. Overall, 1320 (13.6%) had PVs. The prevalence of PVs increased with the number of primary cancers (PCs): 13.1% with 2 PCs, 15.9% with 3 PCs, and 18.0% with ≥4 PCs (P = .00056). Differences in the prevalence of PVs by age at diagnosis were significant: 14.7% with 2 PCs at an age < 50 years, 15.8% with 1 PC at an age < 50 years, and 12.0% with all PCs at an age ≥ 50 years (P = 2.07E-05). PVs by the age at second cancer diagnosis were also significant: 14.7% at an age < 50 years, 13.9% at an age of 50 to 69 years, and 11.4% at an age ≥ 70 years (P for trend = .005).
CONCLUSIONS: Among patients with MPCs, there is a high frequency of germline PVs, with a higher frequency found among patients with a higher number of PCs. These findings suggest that genetic testing should be considered even among patients who are older at the diagnosis of an additional primary malignancy.

Keywords:  genetics; germline; multiple primary cancers; multiple tumors; mutations; pathogenic variants; testing

DOI:  https://doi.org/10.1002/cncr.34056
Eur Urol. 2021 Dec 01. pii: S0302-2838(21)02139-4. [Epub ahead of print]

Inherited TP53 Variants and Risk of Prostate Cancer.

Kara N Maxwell, Heather H Cheng, Jacquelyn Powers, Roman Gulati, Elisa M Ledet, Casey Morrison, Anh Le, Ryan Hausler, Jill Stopfer, Sophie Hyman, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Samantha E Greenberg, Lorraine Naylor, Mercy Laurino, Eric Q Konnick, Brian H Shirts, Saud H AlDubayan, Eliezer M Van Allen, Bastien Nguyen, Joseph Vijai, Wassim Abida, Maria I Carlo, Marianne Dubard-Gault, Daniel J Lee, Luke D Maese, Diana Mandelker, Bruce Montgomery, Michael J Morris, Piper Nicolosi, Robert L Nussbaum, Lauren E Schwartz, Zsofia Stadler, Judy E Garber, Kenneth Offit, Joshua D Schiffman, Peter S Nelson, Oliver Sartor, Michael F Walsh, Colin C Pritchard.

   BACKGROUND: Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53.
OBJECTIVE: To determine whether gTP53 predisposes to prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer.
RESULTS AND LIMITATIONS: We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis.
CONCLUSIONS: Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing.
PATIENT SUMMARY: Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

Keywords:  Attenuated; Genetic testing; Germline; Hypomorphic mutation; Inherited cancer syndrome; Li-Fraumeni syndrome; Pathogenic variant; Prostate cancer; Screening; TP53

DOI:  https://doi.org/10.1016/j.eururo.2021.10.036
Front Oncol. 2021 ;11 774156

Identification of the Unique Clinical and Genetic Features of Chinese Lung Cancer Patients With EGFR Germline Mutations in a Large-Scale Retrospective Study.

Xinqing Lin, Muyun Peng, Quanfang Chen, Mingming Yuan, Rongrong Chen, Haiyi Deng, Jiaxi Deng, Ouqi Liu, Yuqing Weng, Mingjiu Chen, Chengzhi Zhou.

   Background: Epidemiological surveys have suggested that lung cancer has inherited susceptibility and shows familial aggregation. However, the distribution and prevalence of epidermal growth factor receptor (EGFR) germline variants and their roles in lung cancer genetic predisposition in Chinese population remain to be elucidated.
Methods: In this study, EGFR germline and somatic variants were retrospectively reviewed from the next-generation sequencing results of 31,906 patients with lung cancer. Clinical information was also collected for patients with confirmed EGFR germline mutations.
Results: A total of 22 germline EGFR variants were identified in 64 patients with lung cancer, accounting for 0.2% of the total cases studied. Five patients were diagnosed as multiple primary carcinomas. Family history was documented in 31.3% (20/64) of patients, 55% of which were diagnosed as lung cancer. G863D was the most frequent EGFR germline mutation, followed by P848L, D1014N, and K757R. Somatic EGFR-sensitive mutations were identified in 51.6% of patients with germline EGFR mutations. The proportion of L858R mutation, exon 19 deletion, and rare sensitive mutation was 50%, 17.6%, and 32.4%, respectively. D1014N and T790M mutations were common in young patients. The family members of patients with P848L, R776H, V769M, and V774M mutations were more commonly diagnosed with cancers. A total of 19 patients were confirmed to have received EGFR tyrosine kinase inhibitors (TKIs), but the response to EGFR-TKIs differed among patients with different EGFR mutations.
Conclusion: Chinese patients with lung cancer harbored unique and dispersive EGFR germline mutations and showed unique clinical and genetic characteristics, with varied response patterns to EGFR-TKI treatment.

Keywords:  Chinese lung cancer patient; EGFR; genetic features; germline mutations; treatment

DOI:  https://doi.org/10.3389/fonc.2021.774156
Am J Cancer Res. 2021 ;11(11): 5571-5580

Prevalence and spectrum of germline cancer susceptibility gene variants and somatic second hits in colorectal cancer.

Haiyan Liao, Songhua Cai, Yuezong Bai, Bei Zhang, Yuling Sheng, Shuang Tong, Jinping Cai, Feilong Zhao, Xiaochen Zhao, Shiqing Chen, Cheng Zhang, Jing Gao.

Colorectal cancer (CRC) is one of the most heritable cancers, and genetic factors play an important role in the increased CRC risk. However, the well-established CRC-risk genes were limited for explaining the increased risk of CRC individuals. Germline mutations in DNA damage repair (DDR) genes have also been reported to be implicated in CRC heritability. Here, we aimed to determine the prevalence and significance of germline DDR and well-established CRC-risk gene variants in CRCs with paired somatic analyses. Next-generation sequencing (NGS) was performed on tumor tissues and paired white blood cells collected from 2160 Chinese patients with CRC using well-designed 381- or 733-cancer gene panel. Germline/somatic variations were identified and assessed for pathogenicity and likely pathogenicity. Of 2160 CRCs, 136 pathogenic germline mutations in 133 patients (133/2160, 6.1%) were identified in 21 genes, including 19 out of 32 examined DDR genes. Compared with non-carriers, individuals with germline variants were prone to a higher level of microsatellite instability (MSI) and tumor mutational burden (TMB), and an earlier age of onset. Somatic sequencing identified second hits in 24/133 (18%) patients with germline variants. Among the mismatch repair (MMR) genes with germline mutations, the second hit significantly increased MSI and TMB, particularly apparent in MSH6. All MMR germline variation carriers further with a second hit were all MSI-H and had an extraordinarily high level of TMB. Collectively, approximately 6.1% of CRC patients carried pathogenic germline variants, and additional somatic second hit increases the genomic instability in CRC, whereas the more clinical significance warrants further study.

Keywords: Colorectal cancer; DNA damage repair; germline mutation; somatic second hit
Eur J Med Genet. 2021 Dec 03. pii: S1769-7212(21)00267-6. [Epub ahead of print] 104401

Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes.

José Garcia-Pelaez, Rita Barbosa-Matos, Celina São José, Sónia Sousa, Irene Gullo, Nicoline Hoogerbrugge, Fátima Carneiro, Carla Oliveira.

  Tumour risk syndromes (TRS) are characterized by increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes, allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support, if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting a GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS.

Keywords:  CDH1; Candidate genes; Familial intestinal gastric cancer (FIGC); Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS); Hereditary diffuse gastric cancer (HDGC)

DOI:  https://doi.org/10.1016/j.ejmg.2021.104401
J Pathol Clin Res. 2021 Dec 06.

Mismatch repair deficiency in early-onset duodenal, ampullary, and pancreatic carcinomas is a strong indicator for a hereditary defect.

Valentyna Kryklyva, Lodewijk Aa Brosens, Monica Aj Marijnissen-van Zanten, Marjolijn Jl Ligtenberg, Iris D Nagtegaal.

  Mismatch repair deficiency (dMMR) is a hallmark of Lynch syndrome (LS), but its prevalence in early-onset (diagnosed under the age of 50 years) duodenal, ampullary, and pancreatic carcinomas (DC, AC, and PC, respectively) is largely unknown. We explored the prevalence of dMMR and the underlying molecular mechanisms in a retrospectively collected cohort of 90 early-onset carcinomas of duodenal, ampullary, and pancreatic origin. dMMR was most prevalent in early-onset DCs (47.8%); more than half of those were associated with hereditary cancer syndromes (LS or constitutional mismatch repair deficiency syndrome). All dMMR AC and PC were due to LS. Concordance of dMMR with underlying hereditary condition warrants ubiquitous dMMR testing in all early-onset DC, AC, and PC.

Keywords:  Lynch syndrome; constitutional mismatch repair deficiency syndrome; early-onset ampullary carcinoma; early-onset duodenal carcinoma; early-onset pancreatic carcinoma; germline variants; microsatellite instability; mismatch repair deficiency

DOI:  https://doi.org/10.1002/cjp2.252
Hematology Am Soc Hematol Educ Program. 2021 Dec 10. 2021(1): 390-398

Mechanisms of somatic transformation in inherited bone marrow failure syndromes.

Haruna Batzorig Choijilsuren, Yeji Park, Moonjung Jung.

Inherited bone marrow failure syndromes (IBMFS) cause hematopoietic stem progenitor cell (HSPC) failure due to germline mutations. Germline mutations influence the number and fitness of HSPC by various mechanisms, for example, abnormal ribosome biogenesis in Shwachman-Diamond syndrome and Diamond-Blackfan anemia, unresolved DNA cross-links in Fanconi anemia, neutrophil maturation arrest in severe congenital neutropenia, and telomere shortening in short telomere syndrome. To compensate for HSPC attrition, HSPCs are under increased replication stress to meet the need for mature blood cells. Somatic alterations that provide full or partial recovery of functional deficit implicated in IBMFS can confer a growth advantage. This review discusses results of recent genomic studies and illustrates our new understanding of mechanisms of clonal evolution in IBMFS.

DOI: https://doi.org/10.1182/hematology.2021000271