bims-lifras 2021-11-21 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021‒11‒21
twenty papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study.
Reproduction and Genetic Responsibility: An Interpretive Description of Reproductive Decision-Making for Young People With Li-Fraumeni Syndrome.
Germline Hereditary Risk: Common Side Effects.
Genetic Syndromes Associated with Gastric Cancer.
Identification of Lynch Syndrome.
Germline cancer susceptibility gene testing in unselected patients with hepatobiliary cancers: A multi-center prospective study.
Familial Predisposition and Genetic Risk Factors Associated with Pancreatic Cancer.
Pancreatic Cancer Surveillance and Novel Strategies for Screening.
Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer.
Early Detection of Pancreatic Cancer: Risk Factors and the Current State of Screening Modalities.
Surveillance and Surgical Considerations in Hereditary Diffuse Gastric Cancer.
Parental age and retinoblastoma-a retrospective study of demographic data and genetic analysis.
Chemoprevention Considerations in Patients with Hereditary Colorectal Cancer Syndromes.
Implication and Influence of Multigene Panel Testing with Genetic Counseling in Korean Patients with BRCA1/2 Mutation-Negative Breast Cancer.
Disparities in germline testing among racial minorities with prostate cancer.
Disparities in Genetic Testing for Heritable Solid-Tumor Malignancies.
Germline PALB2 Variants and PARP Inhibitors in Endometrial Cancer.
Lynch Syndrome-Associated Cancers Beyond Colorectal Cancer.
Systemic Barriers to Risk-Reducing Interventions for Hereditary Cancer Syndromes: Implications for Health Care Inequities.
DNMT3A Overgrowth Syndrome is associated with the development of hematopoietic malignancies in children and young adults.

Lancet Oncol. 2021 Nov 12. pii: S1470-2045(21)00580-5. [Epub ahead of print]

Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study.

Kelvin César de Andrade, Payal P Khincha, Jessica N Hatton, Megan N Frone, Talia Wegman-Ostrosky, Phuong L Mai, Ana F Best, Sharon A Savage.

BACKGROUND: Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants.METHODS: This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975-2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov, NCT01443468.
FINDINGS: Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9-26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9-13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% [95% CI 19·6-30·5] vs 50·4% [43·5-56·5] by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence.
INTERPRETATION: This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals.
FUNDING: Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health.

DOI: https://doi.org/10.1016/S1470-2045(21)00580-5
Qual Health Res. 2021 Nov 15. 10497323211046240

Reproduction and Genetic Responsibility: An Interpretive Description of Reproductive Decision-Making for Young People With Li-Fraumeni Syndrome.

Rowan Forbes Shepherd, Allison Werner-Lin, Louise A Keogh, Martin B Delatycki, Laura E Forrest.

  The reproductive decision-making of young people (aged 15-39 years) with Li-Fraumeni syndrome (LFS), an early onset inherited cancer syndrome, has not been studied in depth. Using interpretive description methodology, we conducted semi-structured interviews with 30 young Australians (mean age 25.5 years) diagnosed with LFS or at 50% genetic risk. With reflexive thematic analysis, we show how young people's reproductive decision-making and ideals for family formation were shaped by a sense of genetic responsibility to ensure the health of future biological kin. Reproductive technology provided choices for family formation in the context of LFS and also complicated reproductive decisions, as these choices were difficult to understand, make, or carry out. We uphold that reproductive decision-making when living with LFS is a profoundly moral practice that may pose significant challenges for young people navigating their formative years. We offer genetic counseling practice recommendations to support individuals with LFS when making reproductive decisions.

Keywords:  Li-Fraumeni syndrome; TP53; adolescent and young adult; family formation; interpretive description; psychosocial; reproductive decision-making; young people

DOI:  https://doi.org/10.1177/10497323211046240
Clin J Oncol Nurs. 2021 Dec 01. 25(6): 21-22

Germline Hereditary Risk: Common Side Effects.

Mary L Schmitt.

  For germline (hereditary) risk, standards of care are based on emerging evidence-based practice. Cancer may affect any individual, but some people are at higher risk than others. The majority of cancer cases are sporadic, caused by DNA damage that may occur in one cell (not an egg or sperm) and accumulate over a lifetime. Hereditary predisposition to cancer is caused by pathogenic variants in certain genes passed from parent to offspring through the egg or sperm and referred to as germline. In hereditary cancer syndromes, higher incidence, earlier age at onset, and patterns of cancer may be seen within families.

Keywords:  cancer; germline variant; hereditary; survivorship care

DOI:  https://doi.org/10.1188/21.CJON.S2.21-22
Gastrointest Endosc Clin N Am. 2022 Jan;pii: S1052-5157(21)00086-6. [Epub ahead of print]32(1): 147-162

Genetic Syndromes Associated with Gastric Cancer.

Woojin Kim, Trilokesh Kidambi, James Lin, Gregory Idos.

  Although environmental factors such as Helicobacter pylori, tobacco, and diet are major contributors to the development of gastric cancer (GC) worldwide, it is estimated that up to 5% to 10% of GC cases are due to an underlying hereditary susceptibility caused by germline pathogenic variants. Hereditary diffuse gastric cancer (HDGC) caused by germline pathogenic variants in the CDH1 gene is the principal familial GC syndrome. However, other well-established hereditary gastrointestinal syndromes have been associated with an increased risk of GC. In this review, we will discuss the latest insights and advances in our understanding of GC associated with Lynch syndrome (LS), familial adenomatous polyposis (FAP), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS). We will also discuss the emergence of new associations of the homologous recombination pathway genes (BRCA1, BRCA2) with GC.

Keywords:  Familial polyposis; GAPPS; Gastric cancer; Juvenile polyposis syndrome; Li-Fraumeni syndrome; Lynch syndrome; Peutz–Jeghers syndrome

DOI:  https://doi.org/10.1016/j.giec.2021.08.004
Gastrointest Endosc Clin N Am. 2022 Jan;pii: S1052-5157(21)00095-7. [Epub ahead of print]32(1): 45-58

Identification of Lynch Syndrome.

Jennifer K Maratt, Elena Stoffel.

  Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic germline variants (PGV) in any of the 4 DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, or deletions in EPCAM. LS leads to an increased risk of intestinal and extraintestinal cancers, of which colorectal and endometrial cancers are the most common. Individuals at risk for LS can be identified by using clinical criteria, prediction models, and universal tumor testing. Understanding each of these tools, including limitations and mimics of LS, is essential to the early identification of at-risk individuals.

Keywords:  Hereditary colorectal cancer syndrome; Hereditary nonpolyposis colorectal cancer; Lynch syndrome; Mismatch repair

DOI:  https://doi.org/10.1016/j.giec.2021.09.002
Cancer Prev Res (Phila). 2021 Nov 15. pii: canprevres.0189.2021. [Epub ahead of print]

Germline cancer susceptibility gene testing in unselected patients with hepatobiliary cancers: A multi-center prospective study.

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

Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in hepatobiliary cancer patients we undertook a prospective multi-site study of germline sequencing using a >80 gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected based on stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were white, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n=32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer and 33% in carcinoma of ampulla of Vater. Based on these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers.

DOI: https://doi.org/10.1158/1940-6207.CAPR-21-0189
Gastrointest Endosc Clin N Am. 2022 Jan;pii: S1052-5157(21)00092-1. [Epub ahead of print]32(1): 1-12

Familial Predisposition and Genetic Risk Factors Associated with Pancreatic Cancer.

Sheila D Rustgi, Kimberly J Hilfrank, Fay Kastrinos.

  Pancreatic cancer (PC) is a highly lethal cancer and projected to be the second leading cause of cancer death by 2030. Multigene panel testing has facilitated the identification of germline variants associated with an increased risk of PC. Precision treatment has led to improved outcomes for patients with these findings. Because of these improved outcomes as well as the implications for at-risk family members who may benefit from additional cancer screening, the NCCN recommends universal genetic testing for newly diagnosed PC patients. This review describes the most common heritable conditions associated with PC and those who may benefit from screening.

Keywords:  Familial pancreatic cancer; Genetic risk assessment; Genetic testing; Hereditary pancreatic cancer; Pancreatic cancer screening

DOI:  https://doi.org/10.1016/j.giec.2021.09.001
Gastrointest Endosc Clin N Am. 2022 Jan;pii: S1052-5157(21)00090-8. [Epub ahead of print]32(1): 13-25

Pancreatic Cancer Surveillance and Novel Strategies for Screening.

Beth Dudley, Randall E Brand.

  Individuals with a genetic susceptibility to pancreatic ductal adenocarcinoma (PDAC) may benefit from surveillance to increase the likelihood of early detection. Currently, candidates for surveillance are identified based on genetic test results and family history of PDAC, and surveillance is accomplished through imaging of the pancreas (endoscopic ultrasound or MRI). Novel methods that incorporate personalized risk, biomarkers, and radiomics are being investigated in an attempt to improve identification of at-risk individuals and to increase detection of precursor and early-stage lesions.

Keywords:  Familial pancreatic cancer; Hereditary pancreatic cancer; Pancreatic cancer screening; Pancreatic cancer surveillance

DOI:  https://doi.org/10.1016/j.giec.2021.08.008
ESMO Open. 2021 Nov 11. pii: S2059-7029(21)00262-3. [Epub ahead of print]6(6): 100300

Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer.

M Condorelli, M Bruzzone, M Ceppi, A Ferrari, A Grinshpun, A S Hamy, E de Azambuja, E Carrasco, F A Peccatori, A Di Meglio, S Paluch-Shimon, P D Poorvu, M Venturelli, C Rousset-Jablonski, C Senechal, L Livraghi, R Ponzone, L De Marchis, K Pogoda, A Sonnenblick, C Villarreal-Garza, O Córdoba, L Teixeira, F Clatot, K Punie, R Graffeo, M V Dieci, J A Pérez-Fidalgo, F P Duhoux, F Puglisi, A R Ferreira, E Blondeaux, T Peretz-Yablonski, O Caron, C Saule, L Ameye, J Balmaña, A H Partridge, H A Azim, I Demeestere, M Lambertini.

  BACKGROUND: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants.PATIENTS AND METHODS: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy.
RESULTS: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group.
CONCLUSION: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing.

Keywords:  ART; BRCA; breast cancer; fertility; pregnancy; survival

DOI:  https://doi.org/10.1016/j.esmoop.2021.100300
Gastroenterol Hepatol (N Y). 2021 Jun;17(6): 254-262

Early Detection of Pancreatic Cancer: Risk Factors and the Current State of Screening Modalities.

Tara Keihanian, Jodie A Barkin, Enrico O Souto.

Pancreatic cancer (PC) is expected to become the second leading cause of cancer-related mortality in the United States within the next decade. Patients often present at late stages of the disease, when they become symptomatic; in many cases, these patients have unresectable disease that is associated with a poor prognosis. Considering the low incidence of PC in the general population, routine screening of average-risk individuals is not feasible and not recommended. Individuals with familial germline mutations or familial PC are at higher risk of developing PC. Improving detection of PC at an earlier stage entails the recognition of high-risk individuals who may benefit from a long-term screening program. This article identifies patients who may be at increased risk of developing PC, discusses PC screening recommendations, and compares imaging-based modalities and biomarkers for early detection of PC.

Keywords: Pancreatic cancer; biomarker; endoscopic ultrasound; familial pancreatic cancer; screening
Gastrointest Endosc Clin N Am. 2022 Jan;pii: S1052-5157(21)00091-X. [Epub ahead of print]32(1): 163-175

Surveillance and Surgical Considerations in Hereditary Diffuse Gastric Cancer.

Lauren A Gamble, Jeremy L Davis.

  Inactivating germline variants in the CDH1 tumor suppressor gene cause the hereditary diffuse gastric cancer syndrome. Total gastrectomy is recommended for prevention, although it is associated with adverse outcomes and chronic health risks. Gastric cancer surveillance is an alternative to surgery; however, upper gastrointestinal endoscopy is limited by poor sensitivity. Cancer surveillance requires accurate detection of early carcinoma and patient-specific disease penetrance estimates. Current clinical care should incorporate up-to-date information on variable disease penetrance, which does not seem to correlate with CDH1 genotype. Affected patients and families warrant a balanced presentation of options for cancer surveillance and prophylaxis.

Keywords:  CDH1; Cancer screening; Endoscopic surveillance; Hereditary diffuse gastric cancer; Prophylactic total gastrectomy; Signet ring cells

DOI:  https://doi.org/10.1016/j.giec.2021.08.009
Eye (Lond). 2021 Nov 19.

Parental age and retinoblastoma-a retrospective study of demographic data and genetic analysis.

Meghana Tanwar, Sekaran Balaji, Ayyasamy Vanniarajan, Usha Kim, Gunja Chowdhury.

OBJECTIVE: To determine the association between the parental age gap and the absolute parental age with the risk of retinoblastoma (RB) development in an offspring.METHODS: RB individuals diagnosed between March 2013 and December 2019 in a single tertiary eye care centre were included. We recorded the demographic data, parental age and RB1 gene mutation status in the patient's tumour, blood and the parental blood. We categorised RB1 mutation inheritance as sporadic RB with somatic mutations (only present in tumour), heritable RB with de novo (present in patient's blood) and familial (present in patient and parents' blood) germline mutations. The statistical significance was confirmed by Fisher's exact/Chi-square test.
RESULTS: Out of 259 RB patients, 247 were included in our study. Heritable RB with de novo germline mutations was significantly less common (p value: 0.0387; 95% CI: 0.2676-0.9329) and sporadic RB with somatic mutations was more common (p value: 0.0545; 95% CI: 1.025-3.39), if the parental age gap was <10 years. There were increased odds of a heritable RB with de novo germline mutation with an increase in paternal age and this was more intensified when combined with parental age gap of more than ≥10 years. The heritable RB with de novo germline mutations significantly increased as maternal age progressed, only when it was adjusted to ≥10 years parental age gap (p value: 0.0262; 95% CI: 1.26-17.91).
CONCLUSIONS: An increased parental age gap and increased paternal age are independent risk factors for the development of heritable RB with de novo germline mutation.

DOI: https://doi.org/10.1038/s41433-021-01771-z
Gastrointest Endosc Clin N Am. 2022 Jan;pii: S1052-5157(21)00087-8. [Epub ahead of print]32(1): 131-146

Chemoprevention Considerations in Patients with Hereditary Colorectal Cancer Syndromes.

Carole Macaron, Gautam N Mankaney, Mahnur Haider, Mohamad Mouchli, Karen Hurley, Carol A Burke.

  Secondary prevention of colorectal neoplasia with chemoprevention is long-studied area of research and clinical use in patients with the 2 most common hereditary colorectal cancer syndromes including Lynch syndrome and familial adenomatous polyposis. No medication is currently approved for use for the prevention of colorectal polyps or cancer in either the general population or individuals with the hereditary colorectal cancer syndromes. Emerging data in animal models and limited data in humans suggest vaccines may be the next breakthrough for neoplasia prevention in patients with hereditary colorectal cancer. Clinicians must acknowledge chemoprevention is an adjunct and does not supplant endoscopic surveillance.

Keywords:  Chemoprevention; Familial adenomatous polyposis; Hamartomatous polyposis syndromes; Hereditary colon cancer syndromes; Lynch syndrome

DOI:  https://doi.org/10.1016/j.giec.2021.08.005
Cancer Res Treat. 2021 Nov 17.

Implication and Influence of Multigene Panel Testing with Genetic Counseling in Korean Patients with BRCA1/2 Mutation-Negative Breast Cancer.

Ji Soo Park, Saeam Shin, Yoon Jung Lee, Seung-Tae Lee, Eun Ji Nam, Jung Woo Han, Sun Hwa Lee, Tae Il Kim, Hyung Seok Park.

  Purpose: The aim of the study was to evaluate the clinical implication of multigene panel testing of beyond BRCA genes in Korean patients with BRCA1/2 mutation-negative breast cancer.Materials and Methods: Between 2016 and 2019, a total of 700 BRCA1/2 mutation-negative breast cancer patients received comprehensive multigene panel testing and genetic counseling. Among them, 347 patients completed a questionnaire about cancer worry, genetic knowledge, and preference for the method of genetic tests during pre- and post-genetic test counseling. The frequency of pathogenic and likely pathogenic variants (PV/LPV) were analyzed.
Results: At least one PV/LPV of 26 genes were found in 76 out of 700 patients (10.9 %). The rate for PV/LPV was 3.4% for high-risk genes (17 PALB2, 6 TP53, and 1 PTEN). PV/LPVs of clinical actionable genes for breast cancer management, such as ATM, BARD1, BRIP, CHEK2, NF1, and RAD51D, were observed in 7.4%. Patients who completed the questionnaire showed decreased concerns about the risk of additional cancer development (average score, 4.21 to 3.94; p<0.001), influence on mood (3.27 to 3.13; p<0.001), influence on daily functioning (3.03 to 2.94; p=0.006); and increased knowledge about hereditary cancer syndrome (66.9 to 68.8; p=0.025) in post-test genetic counseling. High cancer worry scales (CWSs) were associated with age≤40 years and the identification of PV/LPV. Low CWSs were related to the satisfaction of the counselee.
Conclusion: Comprehensive multigene panel test with genetic counseling is clinically applicable. It should be based on interpretable genetic information, consideration of potential psychological consequences, and proper preventive strategies.

Keywords:  Beyond BRCA; Breast neoplasms; Cancer worry; Genetic testing; Multigene panels

DOI:  https://doi.org/10.4143/crt.2021.978
Prostate Cancer Prostatic Dis. 2021 Nov 13.

Disparities in germline testing among racial minorities with prostate cancer.

Nicole Weise, Justin Shaya, Juan Javier-Desloges, Heather H Cheng, Lisa Madlensky, Rana R McKay.

Germline testing is becoming increasingly relevant in prostate cancer (PCa) screening, prognosis, and management. A subset of patients with PCa harbor pathogenic/likely pathogenic variants (P/LPVs) in genes mediating DNA-repair processes, and these P/LPVs have implications for cancer screening, treatment, and cascade testing. As a result, it is recommended that all men with high-risk localized and metastatic PCa undergo routine germline testing. As more PCa patients undergo germline testing, it is important that clinicians and genetics experts recognize current disparities in germline testing rates among racial/ethnic minorities in the United States. The reasons for these disparities are multiple and require similarly manifold consideration to close the germline testing gap and reduce inequities in PCa screening, management, and treatment.

DOI: https://doi.org/10.1038/s41391-021-00469-3
Surg Oncol Clin N Am. 2022 Jan;pii: S1055-3207(21)00074-0. [Epub ahead of print]31(1): 109-126

Disparities in Genetic Testing for Heritable Solid-Tumor Malignancies.

Jacquelyn Dillon, Foluso O Ademuyiwa, Megan Barrett, Haley A Moss, Elizabeth Wignall, Carolyn Menendez, Kevin S Hughes, Jennifer K Plichta.

  Genetic testing offers providers a potentially life saving tool for identifying and intervening in high-risk individuals. However, disparities in receipt of genetic testing have been consistently demonstrated and undoubtedly have significant implications for the populations not receiving the standard of care. If correctly used, there is the potential for genetic testing to play a role in decreasing health disparities among individuals of different races and ethnicities. However, if genetic testing continues to revolutionize cancer care while being disproportionately distributed, it also has the potential to widen the existing mortality gap between various racial and ethnic populations.

Keywords:  Disparities; Genetic testing; Germline genetic testing; Hereditary cancer

DOI:  https://doi.org/10.1016/j.soc.2021.08.004
J Natl Compr Canc Netw. 2021 11;pii: jnccn21021. [Epub ahead of print]19(11): 1212-1217

Germline PALB2 Variants and PARP Inhibitors in Endometrial Cancer.

Michael A Cilento, Nicola K Poplawski, Sellvakumaram Paramasivam, David M Thomas, Ganessan Kichenadasse.

PARP inhibitors are orally administered antineoplastic agents that affect the homologous recombination (HR) repair pathway, and are approved by the FDA for the treatment of ovarian, breast, pancreatic, and prostate cancers. This report presents a case of recurrent endometrial carcinoma occurring in a woman with a germline pathogenic PALB2 whole-exon deletion. This uncommon finding in a patient with endometrial carcinoma provided the opportunity to use a management strategy of PARP inhibition with olaparib, resulting in a prolonged response to treatment; however, disease progression eventually occurred. Further studies are required to elucidate the mechanisms underlying resistance to PARP inhibition, and the potential future treatment options in this setting. Current recommendations for risk management of female carriers of PALB2 variants focus on breast and ovarian cancer risk. This case raises the additional question of a potential role for risk-reducing hysterectomy in female carriers of PALB2 variants.

DOI: https://doi.org/10.6004/jnccn.2021.7067
Gastrointest Endosc Clin N Am. 2022 Jan;pii: S1052-5157(21)00084-2. [Epub ahead of print]32(1): 75-93

Lynch Syndrome-Associated Cancers Beyond Colorectal Cancer.

Leah H Biller, Siobhan A Creedon, Margaret Klehm, Matthew B Yurgelun.

  Lynch syndrome (LS) is a common form of inherited cancer susceptibility, which predisposes to colorectal cancer (CRC) along with a wide array of other extracolonic malignancies, including other gastrointestinal cancers, cancers of the gynecologic and genitourinary tracts, and other organ sites. Recent data have provided novel insights into patient-specific factors that can help clinicians understand an individual LS carrier's risk of extracolonic cancers, including sex, specific LS gene, age, family history of cancer, and other factors. This summary seeks to provide an update on extracolonic cancer risks in LS and provide recommendations for surveillance and risk reduction.

Keywords:  Extra-colonic; HNPCC; Screening

DOI:  https://doi.org/10.1016/j.giec.2021.08.002
JCO Precis Oncol. 2021 ;pii: PO.21.00233. [Epub ahead of print]5

Systemic Barriers to Risk-Reducing Interventions for Hereditary Cancer Syndromes: Implications for Health Care Inequities.

Kathleen F Mittendorf, Sarah Knerr, Tia L Kauffman, Nangel M Lindberg, Katherine P Anderson, Heather Spencer Feigelson, Marian J Gilmore, Jessica Ezzell Hunter, Galen Joseph, Stephanie A Kraft, Jamilyn M Zepp, Sapna Syngal, Benjamin S Wilfond, Katrina A B Goddard.

DOI: https://doi.org/10.1200/PO.21.00233
Blood. 2021 Nov 17. pii: blood.2021014052. [Epub ahead of print]

DNMT3A Overgrowth Syndrome is associated with the development of hematopoietic malignancies in children and young adults.

Margaret A Ferris, Amanda M Smith, Sharon E Heath, Eric J Duncavage, Matthew J Oberley, David Freyer, Robert Wynn, Sofia Douzgou, John M Maris, Anne F Reilly, Melinda Wu, Florence Choo, Roel B Fiets, Saskia Koene, David H Spencer, Chrstopher A Miller, Marwan Shinawi, Timothy J Ley.

DNMT3A Overgrowth Syndrome (DOS, also known as Tatton-Brown Rahman Syndrome/TBRS) is one of several overgrowth syndromes with complex phenotypes caused by constitutional mutations in genes encoding epigenetic regulators. The clinical features of DOS are variable but include overgrowth (tall stature and/or obesity) and intellectual disability. DNMT3A is essential for de novo DNA methylation and plays an important role in hematopoiesis. Somatic mutations in DNMT3A are among the most common initiating mutations in normal karyotype acute myeloid leukemia (AML) patients and in elderly people with clonal hematopoiesis. The natural history of DOS has not been fully explored since the first description of this rare condition in 2014. Because of the association of somatic DNMT3A mutations and leukemia development, we assessed information from the ~200 known DOS patients world-wide and were able to document eight with hematologic malignancies. Based on this prevalence, we suggest DOS is a cancer predisposition syndrome, especially for hematologic malignancies. Using recommendations from an expert panel, we suggest DOS patients should be prospectively monitored for hematologic malignancies, which may allow for early intervention and permit its natural history to be better defined.

DOI: https://doi.org/10.1182/blood.2021014052