bims-lifras 2021-10-10 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021‒10‒10
seventeen papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

To T or not to B: germline RUNX1 mutation preferences in pediatric ALL predisposition.
Clinical Impact of Pathogenic Germline Variants in Pancreatic Cancer: Results From a Multicenter, Prospective, Universal Genetic Testing Study.
Double Heterozygous Mutations in the BRCA2 and ATM Genes: A Case Report and Review of the Literature.
Overview of hereditary breast and ovarian cancer (HBOC) guidelines across Europe.
Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study.
Family Identity and Roles in the Context of Li-Fraumeni Syndrome: "No One's Like Us Mutants".
Association between 15 known or potential breast cancer susceptibility genes and breast cancer risks in Chinese women.
Lynch syndrome in urological practice: diagnosis, therapeutic strategies, and screening for upper tract urothelial carcinoma.
Outcomes after breast radiotherapy in a diverse patient cohort with a germline BRCA1/2 mutation.
The natural history of ampullary adenomas in familial adenomatous polyposis: a long-term follow-up study.
Successful treatment of refractory lung adenocarcinoma harboring a germline BRCA2 mutation with olaparib: A case report.
Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes.
When guidelines face reality - Lynch syndrome screening in the setting of public health system in a developing country.
Profile of Pathogenic Mutations and Evaluation of Germline Genetic Testing Criteria in Consecutive Breast Cancer Patients Treated at a North Indian Tertiary Care Center.
Genetic Variants of CLPP and M1AP Are Associated With Risk of Non-Small Cell Lung Cancer.
Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis.
Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer.

J Clin Invest. 2021 Sep 01. pii: e152464. [Epub ahead of print]131(17):

To T or not to B: germline RUNX1 mutation preferences in pediatric ALL predisposition.

Serine Avagyan, Anna L Brown.

Germline RUNX1 variants have been identified in relation to myeloid malignancy predisposition, with lymphoid hematological malignancies present at a lower frequency in families. In this issue of the JCI, Li and Yang et al. examined the frequency and type of germline RUNX1 variants in pediatric patients with acute lymphoblastic leukemia (ALL). Patients with T cell ALL (T-ALL) harbored rare, damaging RUNX1 mutations that were not seen in patients with B cell ALL (B-ALL). Further, several of the T-ALL-associated RUNX1 variants had potential dominant-negative activity. RUNX1-mutated T-ALL cases were also associated with somatic JAK3 mutations and enriched for the early T cell precursor (ETP) leukemia subtype, a finding that was validated when RUNX1 and JAK3 mutations were combined in mice. This study confirms germline RUNX1 predisposition beyond myeloid malignancy, demonstrates the importance of examining both germline and somatic mutations in malignancy cohorts, and demarcates the ETP ALL subtype as a flag for germline predisposition in patients.

DOI: https://doi.org/10.1172/JCI152464
Clin Transl Gastroenterol. 2021 Oct 08. 12(10): e00414

Clinical Impact of Pathogenic Germline Variants in Pancreatic Cancer: Results From a Multicenter, Prospective, Universal Genetic Testing Study.

Pedro L S Uson, N Jewel Samadder, Douglas Riegert-Johnson, Lisa Boardman, Mitesh J Borad, Daniel Ahn, Mohamad B Sonbol, Douglas O Faigel, Norio Fukami, Rahul Pannala, Katie Kunze, Michael Golafshar, Margaret Klint, Edward D Esplin, Robert L Nussbaum, A Keith Stewart, Tanios Bekaii-Saab.

INTRODUCTION: To report the prevalence and outcomes of unselected pancreatic cancer (PC) patients with pathogenic/likely pathogenic germline variants (PGVs) detected using a universal testing approach.METHODS: We undertook a prospective, multisite study of germline sequencing using a >80 gene next-generation sequencing platform among 250 patients with PC (not selected for age or family history of cancer) between April 1, 2018, and March 31, 2020. Demographic, tumor characteristics, and clinical outcomes were compared between PGV carriers and noncarriers.
RESULTS: Of 250 patients, the mean age was 65 years (SD 8.7), 56% was male, 83.6% was White, and 65.6% had advanced disease (stages III and IV). PGVs were found in 15.2% (N = 38) of patients, and 2 patients had more than 1 PGV. Variants of uncertain significance were found in 44.4% (N = 111). Family history of cancer (odds ratio: 2.36, 95% confidence interval: 1.14-5.19, P = 0.025) was associated with a higher risk of PGV. In a median follow-up of 16.5 months, the median overall survival was 16.8 months in PGV carriers compared with 16.5 months in noncarriers (hazard ratio: 0.51, 95% confidence interval: 0.25-1.01, P = 0.05). Higher levels of carbohydrate antigen 19-9 and advanced disease stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, and RAD51C.
DISCUSSION: Universal multigene panel testing in PC reveals that 1 in 6 patients are carriers of PGV. Multigene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling.

DOI: https://doi.org/10.14309/ctg.0000000000000414
Breast Care (Basel). 2021 Aug;16(4): 412-417

Double Heterozygous Mutations in the BRCA2 and ATM Genes: A Case Report and Review of the Literature.

Neslihan Duzkale Teker, Nilnur Eyerci.

  Introduction: Germline mutations of the BRCA1 and BRCA2 genes are responsible for about a quarter of hereditary breast cancers (BCs). In this study, we aimed to determine the importance of rare double heterozygous (DH) pathogenic variant carriership in BRCA2and ATM genes in a patient diagnosed with BC and pancreas cancer (PC).Case Report: A 54-year-old female patient was diagnosed with BC at the age of 34 years and with PC at the age of 48 years. The multigene panel and next-generation sequencing technique were used to evaluate the status of the patient's cancer susceptibility genes. Pathogenic variants c.537dup (p.Ile180Tyrfs*3) in the BRCA2 gene and c.5065C>T (p.Gln1689Ter) in the ATM gene were detected as DH in the patient. Co-segregation analysis was performed on the relatives of the patient using Sanger sequencing.
Discussion/Conclusion: Multiple primary malignant neoplasms can be encountered more frequently in DH pathogenic variant carriers, and the diagnosis of malignancies can be made at an earlier age through surveillance guided by genetic testing. In this rare case, more patient studies are needed to determine the contribution of DH in BRCA2 and ATM genes to the phenotype.

Keywords:  ATM; BRCA; Breast cancer; Multiple primary malignant neoplasia; Pancreas cancer

DOI:  https://doi.org/10.1159/000511430
Eur J Med Genet. 2021 Oct 01. pii: S1769-7212(21)00216-0. [Epub ahead of print]64(12): 104350

Overview of hereditary breast and ovarian cancer (HBOC) guidelines across Europe.

extended ERN-GENTURIS Thematic Group 3

  Hereditary breast and ovarian cancer (HBOC) is a syndrome defined by an increased risk of developing breast and/or ovarian cancer most commonly due to germline disease-causing variants in the BRCA1 and BRCA2 genes, but also other causative genes such as PALB2, ATM and CHEK2. As genetic testing becomes more prevalent and new clinical data emerge, updates of national guidelines are required to incorporate these advances in our knowledge. The aim of this work is to review the guidelines for HBOC genetic testing and clinical surveillance across European countries, mostly affiliated to the European Reference Network (ERN) for Genetic Tumor Risk Syndroms (GENTURIS). Young onset breast cancer (BC), triple negative phenotype, or bilateral BC are considered as criteria for genetic testing in all, with differences in age limits. Testing of invasive epithelial non-mucinous ovarian cancer is also universally accepted. While breast magnetic resonance imaging (MRI) is consistently recommended in high-risk individuals, age of onset for mammograms differ between 30 and 40 years. Risk-reducing mastectomy is commonly offered as an option, while risk-reducing salpingo-oophorectomy is universally recommended. The largest differences are observed with respect to ovarian surveillance prior to risk-reducing salpingo-oophorectomy and in breast surveillance for carriers of non-BRCA1/2 genes. These differences in national guidelines reflect the variations in clinical consensus that may be reached in the absence of consistent evidence for some recommendations.

Keywords:  BRCA1; BRCA2; Genetic testing; Guidelines; Hereditary breast ovarian cancer; Surveillance

DOI:  https://doi.org/10.1016/j.ejmg.2021.104350
Cancer Prev Res (Phila). 2021 Oct 08.

Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study.

C Sloane Furniss, Matthew B Yurgelun, Chinedu Ukaegbu, Pamela E Constantinou, Catherine C Lafferty, Eliana R Talcove-Berko, Alison N Schwartz, Jill E Stopfer, Meghan Underhill-Blazey, Barbara Kenner, Scott H Nelson, Sydney Okumura, Sherman Law, Alicia Y Zhou, Tara B Coffin, Nicolette J Rodriguez, Hajime Uno, Allyson J Ocean, Florencia McAllister, Andrew M Lowy, Scott M Lippman, Alison P Klein, Lisa Madlensky, Gloria M Petersen, Judy E Garber, Michael G Goggins, Anirban Maitra, Sapna Syngal.

Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. PREVENTION RELEVANCE: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.

DOI: https://doi.org/10.1158/1940-6207.CAPR-20-0642
Health Soc Work. 2021 Oct 07. pii: hlab032. [Epub ahead of print]

Family Identity and Roles in the Context of Li-Fraumeni Syndrome: "No One's Like Us Mutants".

Catherine Wilsnack, Jennifer L Young, Shana L Merrill, Victoria Groner, Jennifer T Loud, Renee C Bremer, Mark H Greene, Payal P Khincha, Allison Werner-Lin.

  Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome in which individuals have a significantly increased risk of developing multiple cancers throughout the life span. An LFS diagnosis may shift the individual's sense of self and tolerance of cancer risk as they engage in cancer screening and cancer prevention activities. This study examined the impact of family identity on health decision making, communication, and role function. Forty-five families completed one or more interviews during an annual, protocol-specific cancer screening study. An interdisciplinary team analyzed 66 interviews using interpretive description and modified grounding theory. Thematically, identity emerged as an evolving construct regarding self and/or family, embedded in historical and ongoing experiences with LFS. Notions of individual and shared family identities guided decision making related to healthcare and influenced interpersonal communication and role function between supportive networks and families. Alignment between individual, family, and generational identities may shape engagement in genetic testing, risk management, and family life. Medical teams that are unequipped to address the psychosocial challenges that LFS populations face may include mental health professionals on interprofessional care teams to navigate risk management and consequential familial conflict.

Keywords:  Li-Fraumeni syndrome; cancer; decision making; family identity; family roles

DOI:  https://doi.org/10.1093/hsw/hlab032
Cancer Biol Med. 2021 Oct 05. pii: j.issn.2095-3941.2021.0358. [Epub ahead of print]

Association between 15 known or potential breast cancer susceptibility genes and breast cancer risks in Chinese women.

Fenfen Fu, Dongjie Zhang, Li Hu, Senthil Sundaram, Dingge Ying, Ying Zhang, Shuna Fu, Juan Zhang, Lu Yao, Ye Xu, Yuntao Xie.

  OBJECTIVE: There are many hereditary breast cancer patients in China, and multigene panel testing has been a new paradigm of genetic testing for these patients and their relatives. However, the magnitude of breast cancer risks related to multiple breast cancer susceptibility genes are largely unknown in Chinese women.METHODS: We screened pathogenic variants in 15 established or potential breast cancer susceptibility genes from 8,067 consecutive Chinese female breast cancer patients and 13,129 Chinese cancer-free female controls. These breast cancer patients were unselected for age at diagnosis or family history.
RESULTS: We found that pathogenic variants in TP53 [odds ratio (OR): 16.9, 95% confidence interval (CI): 5.2-55.2]; BRCA2 (OR: 10.4, 95% CI: 7.6-14.2); BRCA1 (OR: 9.7, 95% CI: 6.3-14.8); and PALB2 (OR: 5.2, 95% CI: 3.0-8.8) were associated with a high risk of breast cancer. ATM, BARD1, CHEK2, and RAD51D were associated with a moderate risk of breast cancer with ORs ranging from 2-fold to 4-fold. In contrast, pathogenic variants of NBN, RAD50, BRIP1, and RAD51C were not associated with increased risk of breast cancer in Chinese women. The pathogenic variants of PTEN, CDH1, and STK11 were very rare, so they had a limited contribution to Chinese breast cancer. Patients with pathogenic variants of TP53, BRCA1, BRCA2, and PALB2 more often had early-onset breast cancer, bilateral breast cancer, and a family history of breast cancer and/or any cancer.
CONCLUSIONS: This study provided breast cancer risk assessment data for multiple genes in Chinese women, which is useful for genetic testing and clinical management of Chinese hereditary breast cancer.

Keywords:  Multigene panel sequencing; breast cancer risk; case-control study; phenotype; susceptibility genes

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0358
Curr Opin Urol. 2021 Sep 29.

Lynch syndrome in urological practice: diagnosis, therapeutic strategies, and screening for upper tract urothelial carcinoma.

Chiara Lonati, Marco Moschini, Claudio Simeone, Philippe E Spiess, Andrea Necchi.

PURPOSE OF REVIEW: To provide a comprehensive overview of diagnosis, treatment, and screening for upper tract urothelial carcinoma (UTUC) among Lynch syndrome patients.RECENT FINDINGS: Lynch syndrome is an autosomal dominant disorder resulting from the germline mutation in the mismatch repair (MMR) system. The Lynch syndrome predisposes to early onset of a broad spectrum of tumours, among which UTUC represents the third most frequent malignancy. Since up to 10% of UTUC can be attributed to Lynch syndrome, a correct recognition of this disease provides the opportunity for patients and their relatives to be properly treated for UTUC and to be followed up for other Lynch syndrome-related malignancies.
SUMMARY: UTUC patients less than 65 years, or UTUC patients with personal history of Lynch syndrome-related cancer, or with one first-degree relative (FDR) less than 50 years with Lynch syndrome-related cancer, or two FDRs with Lynch syndrome-related cancer regardless of age should be referred to molecular testing and subsequent DNA sequencing to confirm Lynch syndrome diagnosis. Considering the increased risk of metachronous recurrence, treatments other than radical nephroureterectomy, such as ureteroscopic laser ablation may represent valuable therapeutic strategies. As Lynch syndrome patients exhibit an approximate 14-fold increased risk of developing UTUC compared with general population, expert recommendations are urgently required in order to point out appropriate screening protocols.

DOI: https://doi.org/10.1097/MOU.0000000000000936
Int J Radiat Oncol Biol Phys. 2021 Oct 02. pii: S0360-3016(21)02837-6. [Epub ahead of print]

Outcomes after breast radiotherapy in a diverse patient cohort with a germline BRCA1/2 mutation.

Bhavana V Chapman, Diane Liu, Yu Shen, Oluwafikayo O Olamigoke, David S Lakomy, Angelica M Gutierrez Barrera, Shane R Stecklein, Gabriel O Sawakuchi, Scott J Bright, Isabelle Bedrosian, Jennifer K Litton, Benjamin D Smith, Wendy A Woodward, George H Perkins, Karen E Hoffman, Michael C Stauder, Eric A Strom, Banu K Arun, Simona F Shaitelman.

BACKGROUND: BRCA1/2 pathogenic variant (PV) mutations confer radiosensitivity preclinically, but there is limited data regarding breast cancer patient outcomes following radiotherapy (RT) among those with documented BRCA1/2 PV vs. no PV.METHODS: This retrospective cohort study included women with clinical stage I-III breast cancer who received definitive surgery+RT and underwent BRCA1/2 genetic evaluation at the ***. Rates of locoregional recurrence (LRR), disease-specific death (DSD), toxicities, and second cancers were compared by BRCA1/2 PV status.
RESULTS: Of the 2,213 women who underwent BRCA1/2 testing, 63% self-reported as white, 13.6% as Black/African American, 17.6% as Hispanic, and 5.8% as Asian/American Indian/Alaska Native; 124 had BRCA1 and 100 had BRCA2 mutations; 63% (1,394) received regional nodal RT. Median follow-up time for all patients was 7.4 years (95% CI 7.1-7.7 years). No differences were found in 10-year cumulative incidences of LRR or DSD between BRCA1/2 PV and no-mutation groups {(LRR: 11.6% [95% CI 7.0-17.6%] PV vs. 6.6% [95% CI 5.3-8.0%] no-mutation, p=0.466) and (DSD: 12.3% [95% CI 8.0-17.7%] PV vs. 13.8% [95% CI 12.0-15.8%] no-mutation, p=0.716)}. On multivariable analysis, BRCA1/2 status was not associated with LRR or DSD, but Black/African Americans (p=0.036) and Asians/American Indians/Alaska Natives (p=0.002) were at higher risk of LRR as compared to whites, and Black/African Americans were at higher risk of DSD vs. whites (p=0.004). No in-field, non-breast second cancers were observed in the BRCA1/2 PV group. Rates of acute and late grade ≥3 radiation-related toxicity in the BCRA1/2 PV group were 5.4% (n=12) and 0.4% (n=1), respectively.
CONCLUSIONS: Oncologic outcomes in a diverse cohort of breast cancer patients with a germline BRCA1/2 PV mutation treated with RT were similar to those with no mutation, supporting the use of RT according to standard indications in patients with a germline BRCA1/2 PV.

DOI: https://doi.org/10.1016/j.ijrobp.2021.09.033
Gastrointest Endosc. 2021 Oct 05. pii: S0016-5107(21)01693-X. [Epub ahead of print]

The natural history of ampullary adenomas in familial adenomatous polyposis: a long-term follow-up study.

Achintya D Singh, Amit Bhatt, Abel Joseph, Ruishen Lyu, Brandie Heald, Carole Macaron, David Liska, Carol A Burke.

  BACKGROUND AND AIMS: Ampullary adenomas (AAs), common in familial adenomatous polyposis (FAP), are precursors to ampullary carcinoma. We assessed the natural history of AA and factors associated with clinically significant progression (CSP).METHODS: Consecutive FAP patients with AAs and ≥2 esophagogastroduodenoscopies (EGD) were identified from a hereditary gastrointestinal cancer registry. We assessed the incidence of CSP (increase in size to >10 mm, and/or development of advanced histology) of AA. Clinical, endoscopic, and pathologic features between patients with CSP and nonprogressors were compared.
RESULTS: One hundred forty-three patients with AAs were included. Over a median follow-up of 7.8 years (interquartile range: 4.3 to 11.1 years), 41 (28.6%) patients developed CSP for an incidence of 35 per 1000 patient-years. Of 143 patients, 22 (15.6%) progressed to AA >10 mm, 12 (8.5%) progressed to advanced histology, and 7 (4.9%) progressed both in size and histology. Two (1.4%) patients developed ampullary cancer. Male gender, abnormal appearance of papilla at initial AA detection, prior cholecystectomy, and personal history of extracolonic malignancy were associated with CSP. Neither Spigelman stage nor Adenomatous Polyposis Coli gene pathogenic variants were associated with CSP. Intervention specifically for AA and not duodenal polyposis was performed in 24% patients with AAs, including endoscopic papillectomy in 23 patients and duodenectomy in 3 at median observation of 8.2 years.
CONCLUSIONS: Majority of FAP patients with AAs did not experience CSP or require resection over 8 years of surveillance. Ampullary cancer was rare. Male gender, abnormal appearance of the papilla at AA detection, cholecystectomy and history of extracolonic malignancy are associated with CSP. Our findings favor endoscopic surveillance of AAs over expedited resection for most patients with FAP.

Keywords:  Ampullary cancer; ampullary adenoma; duodenal cancer; duodenal polyposis; familial adenomatous polyposis

DOI:  https://doi.org/10.1016/j.gie.2021.09.036
World J Clin Cases. 2021 Sep 06. 9(25): 7498-7503

Successful treatment of refractory lung adenocarcinoma harboring a germline BRCA2 mutation with olaparib: A case report.

Li Zhang, Jing Wang, Ling-Zhi Cui, Kai Wang, Ming-Ming Yuan, Rong-Rong Chen, Li-Jiao Zhang.

  BACKGROUND: In recent years, targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer (NSCLC). However, the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking.CASE SUMMARY: We describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation. He received gefitinib combined with six cycles of vinorelbine, cisplatin, and recombinant human endostatin as the first-line therapy. Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy, resulting in a progression-free survival (PFS) of 14 mo. Chemoradiotherapy was added following progression (enlarged brain metastases) on maintenance treatment. Unfortunately, the brain lesions were highly refractory and progressed again after 15 mo, at which time next-generation sequencing (NGS) of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations. NGS revealed that the patient harbored a BRCA2 germline mutation, the EGFR exon 19 deletion mutation disappeared, and no additional targetable genetic variant was detected. Therefore, the patient received olaparib combined with gefitinib and recombinant human endostatin, with a rapid and long-lasting clinical response (PFS = 13.5 mo).
CONCLUSION: This is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment, suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.

Keywords:  BRCA2 gene; Case report; Next-generation sequencing; Non-small cell lung cancer; Poly (adenosine diphosphate-ribose) polymerase inhibitor

DOI:  https://doi.org/10.12998/wjcc.v9.i25.7498
JAMA Oncol. 2021 Oct 07.

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes.

Catherine Goudie, Leora Witkowski, Noelle Cullinan, Lara Reichman, Ian Schiller, Melissa Tachdjian, Linlea Armstrong, Katherine A Blood, Josée Brossard, Ledia Brunga, Chantel Cacciotti, Kimberly Caswell, Sonia Cellot, Mary Egan Clark, Catherine Clinton, Hallie Coltin, Kathleen Felton, Conrad V Fernandez, Adam J Fleming, Noemi Fuentes-Bolanos, Paul Gibson, Ronald Grant, Rawan Hammad, Lynn W Harrison, Meredith S Irwin, Donna L Johnston, Sarah Kane, Lucie Lafay-Cousin, Irene Lara-Corrales, Valerie Larouche, Natalie Mathews, M Stephen Meyn, Orli Michaeli, Renée Perrier, Meghan Pike, Angela Punnett, Vijay Ramaswamy, Jemma Say, Gino Somers, Uri Tabori, My Linh Thibodeau, Annie-Kim Toupin, Katherine M Tucker, Kalene van Engelen, Stephanie Vairy, Nicolas Waespe, Meera Warby, Jonathan D Wasserman, James A Whitlock, Daniel Sinnett, Nada Jabado, Paul C Nathan, Adam Shlien, Junne Kamihara, Rebecca J Deyell, David S Ziegler, Kim E Nichols, Nandini Dendukuri, David Malkin, Anita Villani, William D Foulkes.

Importance: Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment.Objective: To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS.
Design, Setting, and Participants: In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied.
Exposures: Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results.
Main Outcomes and Measures: The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator.
Results: In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations.
Conclusions and Relevance: In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

DOI: https://doi.org/10.1001/jamaoncol.2021.4536
J Community Genet. 2021 Oct 08.

When guidelines face reality - Lynch syndrome screening in the setting of public health system in a developing country.

Vanessa Nascimento Kozak, Enilze Maria de Souza Fonseca Ribeiro, Milena Massumi Kozonoe, Sergio Ossamu Ioshii, Jose Claudio Casali da Rocha.

  Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC); however, it is still underrecognized and underdiagnosed. While international guidelines gravitate towards universal screening, the underuse of screening methods has been reported in real-world scenarios. This study aims to evaluate screening for LS among patients diagnosed with CRC in a public cancer center in Brazil and evaluate access to genetic counseling and testing for abnormal screens. For that purpose, all patients with CRC registered in our institution from July 2012 to December 2018 had their charts reviewed. Demographic and clinical characteristics were noted, as well as immunohistochemistry and microsatellite instability analysis results, when available. After applying exclusion criteria, a total of 1234 charts were reviewed. Among these, 257 patients were screened for LS, making up a 20.8% screening rate; when considering Jerusalem criteria, screening rate was 24.5%; for Bethesda criteria, it was 35.1%. Almost 80% of patients fulfilling Amsterdam criteria I/II were screened. There were 64 abnormal screens, from which 40 (62.5%) underwent genetic counseling and 12 (18.7%) underwent genetic testing. We concluded that overall screening rates for LS among CRC patients in a public cancer center in Brazil are low, and still very guided by stringent clinical criteria. Referral to genetic counseling and access to testing is limited, calling the whole process into question. Public policies aiming to raise awareness on hereditary cancer and include genetic testing in the public health system could help improve this scenario.

Keywords:  Developing countries; Lynch syndrome; Public health system; Screening rates; Underdiagnosis

DOI:  https://doi.org/10.1007/s12687-021-00549-w
Ann Surg Oncol. 2021 Oct 02.

Profile of Pathogenic Mutations and Evaluation of Germline Genetic Testing Criteria in Consecutive Breast Cancer Patients Treated at a North Indian Tertiary Care Center.

Abhenil Mittal, S V S Deo, Ajay Gogia, Atul Batra, Akash Kumar, Sandeep Bhoriwal, Koushik Sinha Deb, Ekta Dhamija, Sanjay Thulkar, V L Ramprasad, Olufunmilayo Olopade, Raja Pramanik.

BACKGROUND: The burden of hereditary breast cancer in India is not well defined. Moreover, genetic testing criteria (National Comprehensive Cancer Network [NCCN] and Mainstreaming Cancer Genetics [MCG] Plus) have never been validated in the Indian population.METHODS: All new female breast cancer patients from 1st March 2019 to 28th February 2020 were screened. Those providing informed consent and without previous genetic testing were recruited. Multigene panel testing (107 genes) by next-generation sequencing was performed for all patients. The frequency of pathogenic/likely pathogenic (P/LP) mutations between patients qualifying and not qualifying the testing criteria was compared and their sensitivity was computed.
RESULTS: Overall, 275 breast cancer patients were screened and 236 patients were included (median age 45 years); 30 patients did not consent and 9 patients previously underwent genetic testing. Thirty-four (14%) women had a positive family history and 35% had triple-negative breast cancer. P/LP mutations were found in 44/236 (18.64%) women; mutations in BRCA1 (22/47, 46.8%) and BRCA2 (9/47, 19.1%) were the most common, with 34% of mutations present in non-BRCA genes. Patients qualifying the testing criteria had a higher risk of having a P/LP mutation (NCCN: 23.6% vs. 7.04%, p = 0.03; MCG plus: 24.8% vs. 7.2%, p = 0.01). The sensitivity of the NCCN criteria was 88.6% (75.4-96.2) and 86.36% (72.65-94.83) for MCG plus. More than 95% sensitivity was achieved if all women up to 60 years of age were tested. Cascade testing was performed in 31 previous (16/44 families), with 23 testing positive.
CONCLUSIONS: The frequency of P/LP mutations in India is high, with significant contribution of non-BRCA genes. Testing criteria need modification to expand access to testing.

DOI: https://doi.org/10.1245/s10434-021-10870-w
Front Oncol. 2021 ;11 709829

Genetic Variants of CLPP and M1AP Are Associated With Risk of Non-Small Cell Lung Cancer.

Xianghan Li, Yiran Zou, Teng Li, Thomas K F Wong, Ryan T Bushey, Michael J Campa, Elizabeth B Gottlin, Hongliang Liu, Qingyi Wei, Allen Rodrigo, Edward F Patz.

  Background: Single nucleotide polymorphisms (SNPs) are often associated with distinct phenotypes in cancer. The present study investigated associations of cancer risk and outcomes with SNPs discovered by whole exome sequencing of normal lung tissue DNA of 15 non-small cell lung cancer (NSCLC) patients, 10 early stage and 5 advanced stage.Methods: DNA extracted from normal lung tissue of the 15 NSCLC patients was subjected to whole genome amplification and sequencing and analyzed for the occurrence of SNPs. The association of SNPs with the risk of lung cancer and survival was surveyed using the OncoArray study dataset of 85,716 patients (29,266 cases and 56,450 cancer-free controls) and the Prostate, Lung, Colorectal and Ovarian study subset of 1,175 lung cancer patients.
Results: We identified 4 SNPs exclusive to the 5 patients with advanced stage NSCLC: rs10420388 and rs10418574 in the CLPP gene, and rs11126435 and rs2021725 in the M1AP gene. The variant alleles G of SNP rs10420388 and A of SNP rs10418574 in the CLPP gene were associated with increased risk of squamous cell carcinoma (OR = 1.07 and 1.07; P = 0.013 and 0.016, respectively). The variant allele T of SNP rs11126435 in the M1AP gene was associated with decreased risk of adenocarcinoma (OR = 0.95; P = 0.027). There was no significant association of these SNPs with the overall survival of lung cancer patients (P > 0.05).
Conclusions: SNPs identified in the CLPP and M1AP genes may be useful in risk prediction models for lung cancer. The previously established association of the CLPP gene with cancer progression lends relevance to our findings.

Keywords:  CLPP; M1AP; lung cancer risk; non-small cell lung cancer; single nucleotide polymorphism

DOI:  https://doi.org/10.3389/fonc.2021.709829
Sci Rep. 2021 Oct 05. 11(1): 19787

Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis.

kConFab/AOCS Investigators

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

DOI: https://doi.org/10.1038/s41598-021-99409-3
Gynecol Oncol. 2021 Sep 30. pii: S0090-8258(21)01329-9. [Epub ahead of print]

Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer.

Elizabeth M Swisher, Rebecca S Kristeleit, Amit M Oza, Anna V Tinker, Isabelle Ray-Coquard, Ana Oaknin, Robert L Coleman, Howard A Burris, Carol Aghajanian, David M O'Malley, Alexandra Leary, Stephen Welch, Diane Provencher, Geoffrey I Shapiro, Lee-May Chen, Ronnie Shapira-Frommer, Scott H Kaufmann, Sandra Goble, Lara Maloney, Tanya Kwan, Kevin K Lin, Iain A McNeish.

  OBJECTIVE: To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib.METHODS: This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors.
RESULTS: Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10-0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations.
CONCLUSION: Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.

Keywords:  Duration of response; Genomics; Ovarian carcinoma; Rucaparib; Safety

DOI:  https://doi.org/10.1016/j.ygyno.2021.08.030