bims-lifras 2020-05-17 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2020–05–17
ten papers selected by
Joanna Zawacka-Pankau

Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden.
Variability in retinoblastoma genome stability is driven by age and not heritability.
Double mutation of APC and BRCA1 in an Italian family.
Clinicopathological characteristics of BRCA-associated breast cancer in Asian patients.
Genetic Variants in the 3'UTR of BRCA1 and BRCA2 Genes and their Putative Effects on the microRNA Mechanism in Hereditary Breast and Ovarian Cancer.
Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.
Efficacy of platinum in advanced triple-negative breast cancer with germline BRCA mutation determined by next generation sequencing.
A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.
Cancer Genetics.
Long-Term Outcomes of Pancreas-Sparing Duodenectomy for Duodenal Polyposis in Familial Adenomatous Polyposis Syndrome.

Nat Commun. 2020 May 15. 11(1): 2438

Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden.

Tao Qing, Hussein Mohsen, Michal Marczyk, Yixuan Ye, Tess O'Meara, Hongyu Zhao, Jeffrey P Townsend, Mark Gerstein, Christos Hatzis, Yuval Kluger, Lajos Pusztai.

Cancers harbor many somatic mutations and germline variants, we hypothesized that the combined effect of germline variants that alter the structure, expression, or function of protein-coding regions of cancer-biology related genes (gHFI) determines which and how many somatic mutations (sM) must occur for malignant transformation. We show that gHFI and sM affect overlapping genes and the average number of gHFI in cancer hallmark genes is higher in patients who develop cancer at a younger age (r = -0.77, P = 0.0051), while the average number of sM increases in increasing age groups (r = 0.92, P = 0.000073). A strong negative correlation exists between average gHFI and average sM burden in increasing age groups (r = -0.70, P = 0.017). In early-onset cancers, the larger gHFI burden in cancer genes suggests a greater contribution of germline alterations to the transformation process while late-onset cancers are more driven by somatic mutations.

DOI: https://doi.org/10.1038/s41467-020-16293-7
Genes Chromosomes Cancer. 2020 May 11.

Variability in retinoblastoma genome stability is driven by age and not heritability.

Ashley Polski, Liya Xu, Rishvanth K Prabakar, Xiaowu Gai, Jonathan W Kim, Rachana Shah, Rima Jubran, Peter Kuhn, David Cobrinik, James Hicks, Jesse L Berry.

  Retinoblastoma (RB) is a childhood intraocular cancer initiated by biallelic inactivation of the retinoblastoma tumor suppressor gene (RB1-/- ). RB can be hereditary (germline RB1 pathogenic allele is present) or non-hereditary. Somatic copy number alterations (SCNAs) contribute to subsequent tumorigenesis. Previous studies of only enucleated RB eyes have reported associations between heritability status and the prevalence of SCNAs. Herein, we use an aqueous humor (AH) liquid biopsy to investigate RB genomic profiles in the context of germline RB1 status, age, and International Intraocular Retinoblastoma Classification (IIRC) clinical grouping for both enucleated and salvaged eyes. Between 2014 and 2019, AH was sampled from a total of 54 eyes of 50 patients. Germline RB1 status was determined from clinical blood testing, and cell-free DNA from AH was analyzed for SCNAs. Of the 50 patients, 23 (46.0%; 27 eyes) had hereditary RB, and 27 (54.0%, 27 eyes) had non-hereditary RB. Median age at diagnosis was comparable between hereditary (13 ± 10 months) and non-hereditary (13 ± 8 months) eyes (P = 0.818). There was no significant difference in the prevalence or number of SCNAs based on 1) hereditary status (P > 0.56) or 2) IIRC grouping (P > 0.47). There was, however, a significant correlation between patient age at diagnosis and 1) number of total SCNAs (r[52] = 0.672, P < 0.00001) and 2) number of highly-recurrent RB SCNAs (r[52] = 0.616, P < 0.00001). This evidence does not support the theory that specific molecular or genomic subtypes exist between hereditary and non-hereditary RB; rather, the prevalence of genomic alterations in RB eyes is strongly related to patient age at diagnosis.

Keywords:  Retinoblastoma; Somatic copy number alterations; aqueous humor; hereditary; liquid biopsy

DOI:  https://doi.org/10.1002/gcc.22859
Cancer Genet. 2020 Apr 28. pii: S2210-7762(20)30224-6. [Epub ahead of print]244 32-35

Double mutation of APC and BRCA1 in an Italian family.

Maria Teresa Vietri, Giovanna D'Elia, Gemma Caliendo, Amelia Casamassimi, Marianna Resse, Luana Passariello, Michele Cioffi, Anna Maria Molinari.

Familial adenomatous polyposis (FAP) is a rare genetic disorder caused mainly by monoallelic mutations of APC gene. The hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers as a result of germline mutations in BRCA1 or BRCA2 genes. In a family, mutations in two cancer susceptibility genes are extremely rare. We studied a family with a case of a 46 years-old woman affected with FAP and ovarian cancer. The patient was affected with profuse FAP since the age of 18 years and a serous ovarian cancer was diagnosed at the age of 45 years. She reported other FAP cases and one case of breast cancer in maternal family. Initially, she was tested for FAP predisposition with mutational analysis of APC gene that revealed the presence of a frameshift mutation, c.3927_3931delAAAGA (p.Glu1309AspfsX4). The presence of ovarian cancer in the patient and of a breast cancer case in the maternal family, suggested an extended analysis to HBOC susceptibility genes that led to the detection of a frameshift mutation, c.3756_3759delGTCT (p.Ser1253Argfs), in BRCA1 gene. The genetic analysis was extended also to family members. The occurrence of the double mutation in APC and BRCA1 genes in the patient was responsible for the onset of FAP and ovarian cancer respectively. The genetic counselling in hereditary cancer with a careful analysis of the pedigree allows identifying the gene to be analyzed. The development of multi-gene panels testing for cancer predisposition, with next generation sequencing (NGS), may reveal mutations in genes of high and moderate penetrance for cancer, although at a low frequency and allows diagnosing a possible double heterozygosity. This enables an adjusted treatment for the affected patient and is critical as it allows initiation of early risk-reducing measures for identified mutation carriers among family members.

DOI: https://doi.org/10.1016/j.cancergen.2020.04.074
J Pathol Transl Med. 2020 May 14.

Clinicopathological characteristics of BRCA-associated breast cancer in Asian patients.

Eun-Kyu Kim, So Yeon Park, Sung-Won Kim.

  BRCA1/2 germline mutations account for the majority of hereditary breast cancers. Since the identification of the BRCA genes, several attempts have been made to define the clinicopathological characteristics of BRCA-associated breast cancer in comparison with sporadic breast cancer. Asians constitute 60% of the world population, and although the incidence of breast cancer in Asia remains low compared to the West, breast cancer is the most prevalent female cancer in the region. The epidemiological aspects of breast cancer are different between Asians and Caucasians. Asian patients present with breast cancer at a younger age than Western patients. The contributions of BRCA1/2 mutations to breast cancer incidence are expected to differ between Asians and Caucasians, and the different genetic backgrounds among races are likely to influence the breast cancer phenotypes. However, most large-scale studies on the clinicopathological characteristics of BRCA-associated breast cancer have been on Western patients, while studies on Asian populations were small and sporadic. In this review, we provide an overview of the clinical and pathological characteristics of BRCA-associated breast cancer, incorporating findings on Asian patients.

Keywords:  Asian Continental Ancestry Group; Breast neoplasms; Genes, BRCA1; Genes, BRCA2

DOI:  https://doi.org/10.4132/jptm.2020.04.07
Diagnostics (Basel). 2020 May 13. pii: E298. [Epub ahead of print]10(5):

Genetic Variants in the 3'UTR of BRCA1 and BRCA2 Genes and their Putative Effects on the microRNA Mechanism in Hereditary Breast and Ovarian Cancer.

María Marisela Sánchez-Chaparro, Idalia Garza-Veloz, Omar Alejandro Zayas-Villanueva, Margarita L Martinez-Fierro, Iván Delgado-Enciso, Mayra Alejandra Gomez-Govea, Laura Elia Martínez-de-Villarreal, Diana Reséndez-Pérez, Iram Pablo Rodríguez-Sánchez.

  Hereditary breast and ovarian cancer (HBOC) syndrome is mainly caused by mutations in the BRCA1 and BRCA2 genes. The 3'UTR region allows for the binding of microRNAs, which are involved in genetic tune regulation. We aimed to identify allelic variants on 3'UTR miRNA-binding sites in the BRCA1 and BRCA2 genes in HBOC patients. Blood samples were obtained from 50 patients with HBOC and from 50 controls. The 3'UTR regions of BRCA1 and BRCA2 were amplified by PCR and sequenced to identify genetic variants using bioinformatics tools. We detected nine polymorphisms in 3'UTR, namely: four in BRCA1 (rs3092995 (C/G), rs8176318 (C/T), rs111791349 (G/A), and rs12516 (C/T)) and five in BRCA2 (rs15869 (A/C), rs7334543 (A/G), rs1157836 (A/G), and rs75353978 (TT/del TT)). A new variant in position c.*457 (A/C) on 3'UTR of BRCA2 was also identified. The following three variants increased the risk of HBOC in the study population: rs111791349-A, rs15869-C, and c.*457-C (odds ratio (OR) range 3.7-15.4; p < 0.05). Genetic variants into the 3'UTR of BRCA1 and BRCA2 increased the risk of HBOC between 3.7-15.4 times in the study population. The presence/absence of these polymorphisms may influence the loss/creation of miRNA binding sites, such as hsa-miR-1248 in BRCA1 3'UTR or the hsa-miR-548 family binding site in BRCA2. Our results add new evidence of miRNA participation in the pathogenesis of HBOC.

Keywords:  3’UTR region; BRCA1; BRCA2; hereditary breast and ovarian cancer; miRNA; polymorphism

DOI:  https://doi.org/10.3390/diagnostics10050298
Cancer. 2020 May 15.

Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer.

Brian Shuch, Shantao Li, Harvey Risch, Ranjit S Bindra, Patrick D McGillivray, Mark Gerstein.

   BACKGROUND: Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (FH). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the FH carrier frequency and kidney cancer penetrance.
METHODS: Data sets containing sequencing data for the FH gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the FH gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss-of-function alterations, and 3) highly impactful missense alterations. The cumulative incidence of FH alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence.
RESULTS: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10-3 (1 in 393) and 1.20 × 10-3 (1 in 835), respectively. There were differences in the allele frequencies of FH alterations between world populations. Based on various estimates of the percentage of kidney cancers with FH alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7% to 5.8%.
CONCLUSIONS: FH alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.

Keywords:  fumarate hydratase (FH); hereditary; hereditary leiomyomatosis and renal cancer (HLRCC); renal cell carcinoma

DOI:  https://doi.org/10.1002/cncr.32914
Chin J Cancer Res. 2020 Apr;32(2): 149-162

Efficacy of platinum in advanced triple-negative breast cancer with germline BRCA mutation determined by next generation sequencing.

Nan Wang, Kun Li, Wenfa Huang, Weiyao Kong, Xiaoran Liu, Weijie Shi, Feng Xie, Hanfang Jiang, Guohong Song, Lijun Di, Quanren Wang, Jianjun Yu, Huiping Li.

   Objective: To compare the efficacy of platinum- and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer (TNBC) and analyze the relationship between their efficacy and BRCA gene status.
Methods: Retrospectively analyze clinical data of 220 patients diagnosed pathologically with advanced TNBC and treated at the Department of Breast Oncology, Peking University Cancer Hospital from 2013 to 2018 and evaluate the efficacy of chemotherapy. A total of 114 patients had BRCA1/2 gene tested by next generation sequencing (NGS) using peripheral blood, and we analyzed the correlation between their efficacy and BRCA1/2 gene status.
Results: Non-platinum-based chemotherapy (NPCT) was administered to 129 and platinum-based chemotherapy (PBCT) to 91 study patients. The clinical benefit rate (CBR) and median progression-free survival (PFS) were not statistically different between NPCT and PBCT groups. The median overall survival (OS) was 30.0 and 22.5 months for PBCT and NPCT group, respectively [P=0.090, hazard ratios (HR)=0.703]. BRCA status was assessed in 114 patients, 14 of whom had deleterious germline BRCA1/2 (gBRCA) mutations (seven in each group). In PBCT group, the CBR was 85.7% and 35.1% for patients with and without deleterious gBRCA mutations, respectively (P=0.039). The median PFS were 14.9 and 5.3 months and median OS were 26.5 and 15.5 months for patients with and without deleterious gBRCA mutations, respectively (P=0.001, P=0.161, respectively). Patients in PBCT group had significantly greater rates of grade 3-4 anemia (5.5%vs. 0%) and thrombocytopenia (8.8% vs. 0%), whereas palmar-plantar erythrodysesthesia (12.4% vs. 0%) and peripheral neuropathy (8.6% vs. 1.1%) occurred more frequently in NPCT group.
Conclusions: Platinum-based regimens are more effective in patients with deleterious gBRCA mutations, but no difference in patients without BRCA gene mutations, so non-platinum is an option in patients without BRCA gene mutations considering the toxicity and side effect. And we recommend that patients with advanced TNBC should have BRCA gene test.

Keywords:  Advanced breast cancer; BRCA mutation ; efficacy; next-generation sequencing; platinum; triple negative

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2020.02.03
Eur Urol. 2020 May 11. pii: S0302-2838(20)30328-6. [Epub ahead of print]

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Burcu F Darst, Peggy Wan, Xin Sheng, Jeannette T Bensen, Sue A Ingles, Benjamin A Rybicki, Barbara Nemesure, Esther M John, Jay H Fowke, Victoria L Stevens, Sonja I Berndt, Chad D Huff, Sara S Strom, Jong Y Park, Wei Zheng, Elaine A Ostrander, Patrick C Walsh, Shiv Srivastava, John Carpten, Thomas A Sellers, Kosj Yamoah, Adam B Murphy, Maureen Sanderson, Dana C Crawford, Susan M Gapstur, William S Bush, Melinda C Aldrich, Olivier Cussenot, Meredith Yeager, Gyorgy Petrovics, Jennifer Cullen, Christine Neslund-Dudas, Rick A Kittles, Jianfeng Xu, Mariana C Stern, Zsofia Kote-Jarai, Koveela Govindasami, Anand P Chokkalingam, Luc Multigner, Marie-Elise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Adam S Kibel, Eric A Klein, Phyllis J Goodman, Bettina F Drake, Jennifer J Hu, Peter E Clark, Pascal Blanchet, Graham Casey, Anselm J M Hennis, Alexander Lubwama, Ian M Thompson, Robin Leach, Susan M Gundell, Loreall Pooler, Lucy Xia, James L Mohler, Elizabeth T H Fontham, Gary J Smith, Jack A Taylor, Rosalind A Eeles, Laurent Brureau, Stephen J Chanock, Stephen Watya, Janet L Stanford, Diptasri Mandal, William B Isaacs, Kathleen Cooney, William J Blot, David V Conti, Christopher A Haiman.

  Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

Keywords:  8q24; African ancestry; Familial prostate cancer; Family history; Genetic variant; Genetics; Health disparities; Prostate cancer

DOI:  https://doi.org/10.1016/j.eururo.2020.04.060
Surg Clin North Am. 2020 Jun;pii: S0039-6109(20)30025-6. [Epub ahead of print]100(3): 483-498

Cancer Genetics.

Christine Van Cott.

  For most individuals, cancer development is multifactorial; however, up to 10% of all cancers are related to an inherited genetic mutation. As health care shifts to having a greater emphasis on prevention, care providers, including general surgeons, will need to play a role in identifying patients at high risk for cancer development. Genetic testing provides a tool to determine those patients with a genetic mutation and to whom appropriate preventive care and treatment may be offered. It is imperative for general surgeons to understand the role genetics plays in the care of individual patients and their relatives.

Keywords:  BRCA; Familial adenomatous polyposis; Genetic testing; Hereditary cancer syndromes; Lynch syndrome

DOI:  https://doi.org/10.1016/j.suc.2020.02.012
J Gastrointest Surg. 2020 May 14.

Long-Term Outcomes of Pancreas-Sparing Duodenectomy for Duodenal Polyposis in Familial Adenomatous Polyposis Syndrome.

Robert Naples, Robert Simon, Maitham Moslim, Toms Augustin, James Church, Carol A Burke, Amit Bhatt, Matthew Kalady, R Matthew Walsh.

   BACKGROUND: Pancreas-sparing duodenectomy (PSD) offers definitive therapy for duodenal polyposis associated with familial adenomatous polyposis (FAP). We reviewed the long-term complications of PSD and evaluated the incidence of high-grade dysplasia (HGD) and cancer in the remaining upper gastrointestinal tract.
METHODS: Forty-seven FAP patients with duodenal polyposis undergoing PSD from 1992 to 2019 were reviewed. Long-term was defined as > 30 days from PSD.
RESULTS: All patients were treated with an open technique, and 43 (91.5%) had Spigelman stage III or IV duodenal polyposis. Median follow-up was 107 months (IQR, 26-147). There was no 90-day mortality. Seven patients died at a median of 10.5 years (IQR, 5.4-13.3) after PSD, with one attributed to gastric cancer. Pancreatitis occurred in 10 patients (21.3%), and two required surgical intervention. Seven patients (14.9%) developed an incisional hernia, and all underwent definitive repair. Forty-one patients (87.2%) had postoperative surveillance endoscopy over a median follow-up of 111 months (IQR, 42-138). Three patients (6.4%) developed adenocarcinoma (two gastric, one jejunal), and four (8.5%) had adenomas with HGD (two gastric, two jejunal) with a median of 15 years (IQR, 9-16) from PSD. One patient with gastric adenocarcinoma and all patients with HGD or adenocarcinoma of the jejunum required surgical intervention.
CONCLUSION: PSD can be performed with a low but definable risk of long-term morbidity. Risk of gastric and jejunal carcinoma rarely occurs and was diagnosed decades after PSD. This demonstrates the need for lifelong endoscopic surveillance and educates us on the risk of carcinoma in the remaining gastrointestinal tract.

Keywords:  Duodenal adenoma; Duodenal polyposis; Familial adenomatous polyposis; Pancreas-sparing duodenectomy; Polyp

DOI:  https://doi.org/10.1007/s11605-020-04621-7