bims-lifras Biomed News
on Li-Fraumeni Syndrome
Issue of 2019‒11‒10
sixteen papers selected by
Joanna Zawacka-Pankau



  1. Clin Transl Oncol. 2019 Nov 05.
    Gargallo P, Yáñez Y, Segura V, Juan A, Torres B, Balaguer J, Oltra S, Castel V, Cañete A.
      Clinical variability is commonly seen in Li-Fraumeni syndrome. Phenotypic heterogeneity is present among different families affected by the same pathogenic variant in TP53 gene and among members of the same family. However, causes of this huge clinical spectrum have not been studied in depth. TP53 type mutation, polymorphic variants in TP53 gene or in TP53-related genes, copy number variations in particular regions, and/or epigenetic deregulation of TP53 expression might be responsible for clinical heterogeneity. In this review, recent advances in the understanding of genetic and epigenetic aspects influencing Li-Fraumeni phenotype are discussed.
    Keywords:  Epigenome; Genotype; Li–Fraumeni syndrome; Pediatrics; Phenotype
    DOI:  https://doi.org/10.1007/s12094-019-02236-2
  2. Crit Rev Oncog. 2019 ;24(2): 149-156
    Rahman AU, Zahid E, Khan MT, Naeem A, Ali S, Rashid MU, Ahmad S.
      Up to 20% of patients with pancreatic cancer have a family history of the disease. Familial pancreatic cancer is defined as at least two first-degree relatives with pancreatic cancer that occurs without being part of a cancer syndrome. Although this does not follow a specific Mendelian pattern of inheritance, research is underway to better understand this cohort of patients. Recent expert opinion/recommendations encourage physicians treating patients with pancreatic cancer to ask them to consider having germline testing. Herein, we summarize the current peer-reviewed literature on the most common syndromes associated with pancreatic cancer, associated genetic mutations, and recommendations from various consortia regarding screening strategies. Lastly, we describe the economic impact of pancreatic cancer and the impact of screening tools in high-risk populations.
    DOI:  https://doi.org/10.1615/CritRevOncog.2019031637
  3. Diagnostics (Basel). 2019 Oct 31. pii: E169. [Epub ahead of print]9(4):
    Matsubayashi H, Kiyozumi Y, Ishiwatari H, Uesaka K, Kikuyama M, Ono H.
      A family history of pancreatic cancer (PC) is a risk factor of PC, and risk levels increase as affected families grow in number and/or develop PC at younger ages. Familial pancreatic cancer (FPC) is defined as a client having at least two PC cases in a first degree relatives. In the narrow sense, FPC does not include some inherited cancer syndromes that are known to increase the risks of PC, such as Peutz-Jeghers syndrome (PJS), hereditary pancreatitis (HP), hereditary breast ovarian cancer syndrome (HBOC), and so on. FPC accounts for 5%-10% of total PC diagnoses and is marked by several features in genetic, epidemiological, and clinicopathological findings that are similar to or distinct from conventional PC. Recent advances in genetic medicine have led to an increased ability to identify germline variants of cancer-associated genes. To date, high-risk individuals (HRIs) in many developed countries, including FPC kindreds and inherited cancer syndromes, are screened clinically to detect and treat early-stage PC. This article highlights the concept of FPC and the most recent data on its detection.
    Keywords:  familial pancreatic cancer; genetic; high risk; surveillance; treatment
    DOI:  https://doi.org/10.3390/diagnostics9040169
  4. J Obstet Gynaecol Can. 2019 Oct 31. pii: S1701-2163(19)30671-1. [Epub ahead of print]
    Cameron A, Chiarella-Redfern H, Chu P, Perrier R, Duggan MA.
      BACKGROUND: Lynch syndrome (LS) is an autosomal dominant cancer syndrome caused by a germline mutation in the mismatch repair (MMR) genes. Protocols based on immunohistochemical expression of MMR proteins in cancer are used to identify patients with LS.METHODS: The universal LS screening protocol of the Tom Baker Cancer Centre (Calgary, AB) of all patients diagnosed between April 1, 2013 and April 1, 2015 with endometrioid carcinoma of the endometrium was audited through a retrospective chart review. LS status and frequency of protocol compliance at each of the key steps were calculated (Canadian Task Force Classification II-2).
    RESULTS: The cohort consisted of 375 patients. MMR immunohistochemical testing was requested for 321 (85.6%). Expression of at least one protein was lost in 86 (26.8%). Twenty-one (6.5%) patients were eligible for genetic counselling because PMS2, MSH2, or MSH6 protein expression was lost in 19, and two patients had a family history of LS. Eleven (91.7%) of 12 (57.1%) who attended had germline testing, and six (54.5%) showed a mutation diagnostic of LS. LS status among the cohort of 375 patients was positive in six (1.6%), negative in 294 (78.4%), and unknown in 75 (20%) because of protocol non-compliance. LS was confirmed in six (2%) of the 321 women who completed the protocol.
    CONCLUSION: This is the first audit of a Canadian-based universal LS screening protocol of patients with endometrial cancer. The success of the protocol is endorsed by the 80% compliance and by the 2% prevalence of LS, which is within the published range.
    Keywords:  DNA mismatch repair; Hereditary cancer syndrome; Lynch syndrome; endometrial carcinoma
    DOI:  https://doi.org/10.1016/j.jogc.2019.06.018
  5. Curr Treat Options Gastroenterol. 2019 Nov 08.
    Kidambi TD, Kohli DR, Samadder NJ, Singh A.
      PURPOSE OF REVIEW: Colorectal cancer (CRC) is the third most common cancer in the USA and inherited cancer syndromes are responsible for approximately 3-5% of all CRCs. Genetic testing costs have plummeted in recent years; however, awareness and referral of high-risk patients for testing is still very low. We review the salient clinical features, genetics, and management of well-defined gastrointestinal (GI) hereditary polyposis syndromes including familial adenomatous polyposis, MUTYH-associated polyposis, and the hamartomatous polyposis syndromes.RECENT FINDINGS: Comprehensive endoscopic surveillance has the potential to prevent the development of GI cancer and to identify early-stage cancer; newer developments like high-definition endoscopes, chromoendoscopy, and the use of cap-assisted endoscopy have shown promise for enhanced lesion detection rates. Several chemoprevention trials have yielded promising results but safety and efficacy data for long-term use is still awaited. Several new polyposis genes have also been identified in the recent years. Multiple societies have recently published updated surveillance guidelines to aid clinicians in the detection and management of patients with hereditary GI polyposis syndromes. Although these syndromes are rare, it is crucial for the clinicians to recognize these in a timely manner, for the appropriate management plans for both the patient and their at risk family members.
    Keywords:  Cowden syndrome; Familial adenomatous polyposis; Hereditary colon cancer; Juvenile polyposis; Peutz-Jeghers syndrome; Polyposis
    DOI:  https://doi.org/10.1007/s11938-019-00251-4
  6. DNA Repair (Amst). 2019 Oct 17. pii: S1568-7864(19)30170-3. [Epub ahead of print]85 102733
    Goellner EM.
      DNA mismatch repair (MMR) increases replication fidelity and genome stability by correcting DNA polymerase errors that remain after replication. Defects in MMR result in the accumulation of mutations and lead to human tumor development. Germline mutations in MMR cause the hereditary cancer syndrome, Lynch syndrome. After replication, DNA is reorganized into its chromatin structure and wrapped around histone octamers. DNA MMR is thought to be less efficient in recognizing and repairing mispairs packaged in chromatin, in which case MMR must either compete for access to naked DNA before histone deposition or actively move nucleosomes to access the mispair. This article reviews studies into the mechanistic and physical interactions between MMR and various chromatin-associated factors, including the histone deposition complex CAF1. Recent Xenopus and Saccharomyces cerevisiae studies describe a physical interaction between Msh2 and chromatin-remodeling ATPase Fun30/SMARCAD1, with potential mechanistic roles for SMARCAD1 in moving histones for both mispair access and excision tract elongation. The RSC complex, another histone remodeling complex, also potentially influences excision tract length. Deletion mutations of RSC2 point to mechanistic interactions with the MMR pathways. Together, these studies paint a picture of complex interactions between MMR and the chromatin environment that will require numerous additional genetic, biochemical, and cell biology experiments to fully understand. Understanding how these pathways interconnect is essential in fully understanding eukaryotic MMR and has numerous implications in human tumor formation and treatment.
    Keywords:  CAF1; Chromatin; Fun30; Genome instability; Mismatch repair; SMARCAD1
    DOI:  https://doi.org/10.1016/j.dnarep.2019.102733
  7. Semin Cancer Biol. 2019 Nov 02. pii: S1044-579X(19)30271-8. [Epub ahead of print]
    Ooi A.
      Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant hereditary cancer syndrome with incomplete penetrance. It is caused by a germline amorphic allele of the FH gene, which encodes the TCA cycle enzyme, fumarate hydratase (FH). HLRCC patients are genetically predisposed to develop skin leiomyomas, uterine fibroids, and the aggressive kidney cancer of type 2 papillary morphology. Loss-of-heterozygocity at the FH locus that cause a complete loss of FH enzymatic function is always detected in these tumor tissues. Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH-/- tumor cells. These treatment strategies include ferroptosis induction, oxidative stress promotion, and metabolic alteration. As the fundamental biology of HLRCC continues to be uncovered, these treatment strategies continue to be refined and may one day lead to a strategy to prevent disease onset among HLRCC patients. With a more complete picture of HLRCC biology, the safe translation of experimental treatment strategies into clinical practice is achievable in the foreseeable future.
    DOI:  https://doi.org/10.1016/j.semcancer.2019.10.016
  8. Nat Commun. 2019 Nov 07. 10(1): 5061
    Deng Q, Hu H, Yu X, Liu S, Wang L, Chen W, Zhang C, Zeng Z, Cao Y, Xu-Monette ZY, Li L, Zhang M, Rosenfeld S, Bao S, Hsi E, Young KH, Lu Z, Li Y.
      A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.
    DOI:  https://doi.org/10.1038/s41467-019-13002-x
  9. Cancer. 2019 Nov 04.
    Vysotskaia V, Kaseniit KE, Bucheit L, Ready K, Price K, Johansen Taber K.
      BACKGROUND: Although management guidelines exist for several genes associated with a 2-fold to 5-fold increase in the relative risk for certain cancers, the value of testing for them remains controversial.METHODS: De-identified personal and family history data for 654 individuals with pathogenic variants (PVs) in PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and/or RAD51D were analyzed for pretest and post-test candidacy for guideline-recommended management of cancer risk. These individuals were invited to complete a survey about provider recommendations and their adherence.
    RESULTS: Twenty-four percent of CHEK2, ATM, PALB2, or NBN PV carriers were appropriate for consideration of annual breast magnetic resonance imaging screening before genetic testing, with the remaining 76% appropriate only after testing. No BRIP1, RAD51C, or RAD51D PV carriers were appropriate for consideration of risk-reducing salpingo-oophorectomy before genetic testing; 100% were appropriate only after testing. Seventeen percent of CHEK2 PV carriers were appropriate for earlier and more frequent colonoscopy before genetic testing, with the remaining 83% appropriate only after testing. Provider recommendations for annual breast magnetic resonance imaging, consideration of risk-reducing salpingo-oophorectomy, and earlier and more frequent colonoscopy were reported by 42%, 26%, and 66% of breast, ovarian, and colorectal cancer risk PV carriers, respectively, before genetic testing, versus 82%, 79%, and 81%, respectively, after testing. Nearly all respondents had planned or undertaken provider-recommended management.
    CONCLUSIONS: Testing for PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D changed management for those carrying PVs. Provider recommendations were aligned with guidelines, and patients adhered to recommendations, both of which are critical for reducing both long-term cancer morbidity and mortality.
    Keywords:  breast cancer; cancer risk; colorectal cancer; hereditary cancer; ovarian cancer
    DOI:  https://doi.org/10.1002/cncr.32572
  10. Int J Gynecol Cancer. 2019 Nov 07. pii: ijgc-2019-000540. [Epub ahead of print]
    Dowson CB, Stewart C, O'Sullivan S, Pachter N, Schofield L, Cohen PA.
      OBJECTIVE: To compare the germline BRCA1 and BRCA2 mutation (gBRCA) status in women with high-grade serous tubo-ovarian and primary peritoneal carcinoma with and without serous tubal intra-epithelial carcinomas (serous tubal intra-epithelial carcinoma-positive vs serous tubal intra-epithelial carcinoma-negative).MATERIALS AND METHODS: A retrospective study was performed of patients in Western Australia diagnosed with high-grade serous tubo-ovarian and primary peritoneal carcinoma and referred for genetic counseling and gBRCA testing from July 1, 2014 to June 30, 2017. Histopathology reports were reviewed to ascertain whether serous tubal intra-epithelial carcinoma was present. Personal or family gBRCA status, family history, age at diagnosis, mode of treatment (neoadjuvant chemotherapy vs primary surgery), and stage were also recorded.
    RESULTS: A total of 269 women with high-grade serous tubo-ovarian and primary peritoneal carcinoma were referred for genetic counseling and testing. 114 patients were excluded because the serous tubal intra-epithelial carcinoma status was not assessable or because patients did not attend for genetic assessment. 155 patients (55 serous tubal intra-epithelial carcinoma-positive and 100 serous tubal intra-epithelial carcinoma-negative) underwent genetic testing. gBRCA mutations were found in 27.8% of serous tubal intra-epithelial carcinoma-positive patients compared with 14.0% of serous tubal intra-epithelial carcinoma-negative patients (p=0.094). Of those found to have a gBRCA mutation, 89.7% reported a positive personal or family history of BRCA-related cancers.
    CONCLUSIONS: The gBRCA mutation detection rate in serous tubal intra-epithelial carcinoma-positive patients was nearly double that of serous tubal intra-epithelial carcinoma-negative patients. Factors such as a positive family history of BRCA-related cancers were seen at a higher proportion in the mutation positive women.
    Keywords:  cystadenocarcinoma; fallopian tube neoplasms; ovarian cancer; ovarian neoplasms; serous
    DOI:  https://doi.org/10.1136/ijgc-2019-000540
  11. Cancers (Basel). 2019 Nov 01. pii: E1708. [Epub ahead of print]11(11):
    Dubrova Y.
      The analysis of mutation induction in human families exposed to mutagens provides the only source of reliable estimates of factors contributing to the genetic risk of human exposure to mutagens. In this paper, I briefly summarize the results of recent studies on the pattern of mutation induction in the human and mouse germline. The results of recent studies on the genome-wide effects of exposure to mutagens on mutation induction in the mammalian germline are presented and discussed. Lastly, this review also addresses the issue of transgenerational effects of parental exposure to mutagens on mutation rates in their non-exposed offspring, which are known as transgenerational instability. The possible contribution of transgenerational instability to the genetic risk of human exposure to mutagens is discussed.
    Keywords:  germline; ionizing radiation; mutagens; mutation
    DOI:  https://doi.org/10.3390/cancers11111708
  12. Medicine (Baltimore). 2019 Nov;98(45): e17872
    Xiong J, Zhu K, Mao J, Cai J, He M, Li L, Wang J, Wang L.
      RATIONALE: Ewing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) is a rare type of soft tissue sarcomas (STS), especially in infants, with poor prognosis. It is a so-called "small round cell" sarcoma, and has many features of Ewing sarcoma, but lacks rearrangements in EWSR1. The diagnosis and treatment of this kind of STS remains challenging. BCOR genetic abnormalities have been found in some Ewing-like sarcomas.PATIENT CONCERNS: This report presents an ELS case of a female infant, who was 2 months old when initially diagnosed, with the clinical stage of IIIA (G2T2N0M0). Histologic findings revealed an undifferentiated neoplasm composed of small round tumor cells with round, open chromatic nuclei, and scant cytoplasm in a sheet growth pattern. Fluorescence in situ hybridization (FISH) analysis showed absence of EWSR1 and ETV6 gene rearrangement. Molecular genetic testing found no established variants of clinical significance but variants of unknown significance in APC, KMT2D, and MSH6 were detected. Immunostaining revealed that the tumor cells were positive for TLE1 and BCOR, and negative for cytokeratin (AE1/AE3), Desmin, CD45, S100, CD31, HMB45, and SATB2. INI-1 was retained.
    DIAGNOSIS: Ewing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) INTERVENTIONS:: After initial diagnosis, the patient received 4 cycles of combination chemotherapy for 2 months. Radical amputation of left upper extremity was performed 3 months after diagnosis. Postoperative chemotherapy was continued for 6 cycles.
    OUTCOMES: The patient died of intracranial metastasis with hemorrhage in 13 months after initial diagnosis, 5 months after the last cycle of chemotherapy.
    LESSONS: ELS in infancy is extremely rare and has a poorer prognosis than Ewing sarcoma or infantile fibrosarcoma. APC and MSH6 variation might be related with the disease progression and predict a poorer prognosis. This rare case promotes better understanding of the disease and suggests a promising role for the combination chemotherapy regimen in treating infantile ELS. Importantly, it brings to light the possibility of intracranial metastasis, which requires proactive screening for timely detection.
    DOI:  https://doi.org/10.1097/MD.0000000000017872
  13. Genes (Basel). 2019 Nov 01. pii: E882. [Epub ahead of print]10(11):
    Arason A, Agnarsson BA, Johannesdottir G, Johannsson OT, Hilmarsdottir B, Reynisdottir I, Barkardottir RB.
      Mutations in BRCA1 result in predisposal to breast and ovarian cancers, but many variants exist with unknown clinical significance (VUS). One is BRCA1 c.4096+3A>G, which affects production of the full-length BRCA1 transcript, while augmenting transcripts lacking most or all of exon 11. Nonetheless, homozygosity of this variant has been reported in a healthy woman. We saw this variant cosegregate with breast and ovarian cancer in several family branches of four Icelandic pedigrees, with instances of phenocopies and a homozygous woman with lung cancer. We found eight heterozygous carriers (0.44%) in 1820 unselected breast cancer cases, and three (0.15%) in 1968 controls (p = 0.13). Seeking conclusive evidence, we studied tumors from carriers in the pedigrees for wild-type-loss of heterozygosity (wtLOH) and BRCA1-characteristic prevalence of estrogen receptor (ER) negativity. Of 15 breast and six ovarian tumors, wtLOH occurred in nine breast and all six ovarian tumours, and six of the nine breast tumors with wtLOH were ER-negative. These data accord with a pathogenic BRCA1-mutation. Our findings add to the current knowledge of BRCA1, and the role of its exon 11 in cancer pathogenicity, and will be of use in clinical genetic counselling.
    Keywords:  BRCA1; Knudson's two-hit model; LOH; VUS; breast cancer; cancer risk; homozygous lethality; ovarian cancer; tumorigenesis
    DOI:  https://doi.org/10.3390/genes10110882
  14. Pharmacogenomics. 2019 Nov 08.
    Labriet A, Lévesque É, Mattia E, Cecchin E, Jonker D, Couture F, Simonyan D, Buonadonna A, D'Andrea M, Villeneuve L, Toffoli G, Guillemette C.
      Aim: Germline variants could modify survival of metastatic colorectal cancer patients (mCRC). Patients & methods: The association of 285 haplotype-tagging single nucleotide polymorphisms in 11 candidate genes and overall survival (OS) was tested in two cohorts totalizing 417 FOLFIRI-treated mCRC. Gene expression was investigated in vitro and in public datasets. Results: In the combined cohort, CES1 rs9921399T>C was associated with prolonged OS (hazard ratio [HR] = 0.40) whereas ABCC1 rs17501011G>A (HR = 2.08) and UGT1 rs1113193G>A (HR = 2.12) were associated with shorter OS (p ≤ 0.005). A combined effect of these polymorphisms was observed with HR of 1.98-2.97 (p < 0.05). The ABCC1 rs17501011A variant reduced reporter-gene activity (p < 0.05) whereas ABCC1 tumor expression was associated with shorter survival (p ≤ 0.013). Conclusion: We identified a combination of genetic determinants that could predict mCRC survival.
    Keywords:  biomarkers; irinotecan; metastatic colorectal cancer; pharmacogenomics; polymorphisms
    DOI:  https://doi.org/10.2217/pgs-2019-0091
  15. J Surg Res. 2019 Nov 01. pii: S0022-4804(19)30707-3. [Epub ahead of print]
    DiBrito SR, Blair AB, Prasath V, Habibi M, Harmon JW, Duncan MD.
      BACKGROUND: Gastric cancer is a leading cause of cancer-related death across the world. A subset of gastric cancers demonstrates an inherited genetic predisposition. Individuals with germline mutations in the CDH1 gene incur a lifetime risk for diffuse gastric cancer and benefit from prophylactic gastrectomy. The results for this operative intervention remain relatively undescribed in the literature, despite guidelines supporting its use.METHODS: We present a single-institution series of patients with confirmed CDH1 mutations who underwent gastrectomy. We describe their presenting symptoms, preoperative screening, clinicopathologic features, and outcomes. Focal outcomes of interest are weight loss and postoperative morbidity.
    RESULTS: Between 2010 and 2018, ten patients with a confirmed CDH1 mutation underwent total gastrectomy with intestinal pouch reconstruction at our institution. Two patients had clinical gastric cancer at the time of their operation at 21 and 60 y of age. Eight patients had prophylactic gastrectomy. All prophylactic patients had undergone prior endoscopic screening without detection of cancer; however, three had occult gastric cancer on pathological examination. Median weight loss after gastrectomy was 10 kg at 6 mo and 11 kg at 1 y. Postoperative morbidity was limited to one anastomotic leak, one hematoma, and one case of pneumonia. All patients remain disease-free with median follow-up of 19 mo.
    CONCLUSIONS: Total gastrectomy for patients with a CDH1 mutation is a cancer-preventing operation for a high-risk population. For this series, jejunal pouch reconstruction was performed with encouragingly low postoperative morbidity, weight loss, and good subjective function.
    Keywords:  CDH1; Familial gastric cancer; Hereditary diffuse gastric cancer; Prophylactic gastrectomy
    DOI:  https://doi.org/10.1016/j.jss.2019.09.062