bims-lifras 2021-03-28 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–03–28
fiveteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes.
A novel germline GATA2 frameshift mutation with a premature stop codon in a family with congenital sensory hearing loss and myelodysplastic syndrome.
Molecular alterations governing predisposition to myelodysplastic syndromes: Insights from Shwachman-Diamond syndrome.
Extended gene panel testing in lobular breast cancer.
Clinical implementation of an oncology-specific family health history risk assessment tool.
Prevalence of BRCA1 and BRCA2 mutations in Japanese patients with triple-negative breast cancer: A single institute retrospective study.
Interpreting Sequence Variation in PDAC-Predisposing Genes Using a Multi-Tier Annotation Approach Performed at the Gene, Patient, and Cohort Level.
Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients.
Breast cancer risk and hormone replacement therapy among BRCA carriers after risk-reducing salpingo-oophorectomy.
PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer.
Germline evaluation of patients undergoing tumor genomic profiling: An academic cancer center's experience with implementing a germline review protocol.
Adaptation and early implementation of the PREdiction model for gene mutations (PREMM5™) for lynch syndrome risk assessment in a diverse population.
Interval between the First Cancer and the Genetic Diagnosis in Lynch Syndrome Probands.
CDKN2A germline alterations and the relevance of genotype-phenotype associations in cancer predisposition.
Laboratory and Clinical Implications of Incidental and Secondary Germline Findings During Tumor Testing.

J Natl Cancer Inst. 2021 Mar 23. pii: djab038. [Epub ahead of print]

Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes.

Anna M Varghese, Isha Singh, Rituraj Singh, Siddharth Kunte, Joanne F Chou, Marinela Capanu, Winston Wong, Maeve A Lowery, Zsofia K Stadler, Erin Salo-Mullen, Lily V Saadat, Alice C Wei, Marsha Reyngold, Olca Basturk, Ryma Benayed, Diana Mandelker, Christine A Iacobuzio-Donahue, David P Kelsen, Wungki Park, Kenneth H Yu, Eileen M O'Reilly.

BACKGROUND: Recent evidence suggests a rising incidence of cancer in younger individuals. Herein, we report the epidemiologic, pathologic, and molecular characteristics of a patient cohort with early-onset pancreas cancer (EOPC).
METHODS: Institutional databases were queried for demographics, treatment history, genomic results and outcomes. Overall survival (OS) from date of diagnosis was estimated using Kaplan-Meier method.
RESULTS: Four hundred and fifty patients with EOPC were identified at Memorial Sloan Kettering between 2008 and 2018. Median OS was 16.3 months (95% confidence interval [CI] = 14.6 to 17.7 months) in the entire cohort and 11.3 months (95% CI = 10.2 to 12.2 months) for patients with stage IV disease at diagnosis. One hundred and thirty-two (29.3% of the cohort) underwent somatic testing; 21 of 132 (15.9%) had RAS wild-type cancers with identification of several actionable alterations, including ETV6-NTRK3, TPR-NTRK1, SCLA5-NRG1 and ATP1B1-NRG1 fusions, IDH1 R132C mutation, and mismatch repair deficiency. One hundred and thirty-eight (30.7% of the cohort) underwent germline testing; 44 of 138 (31.9%) had a pathogenic germline variant (PGV) and 27.5% harbored alterations in cancer susceptibility genes. Of patients seen between 2015 and 2018, 30 of 193 (15.5%) had a pathogenic germline variant. Among 138 who underwent germline testing, those with a PGV had a reduced all-cause mortality compared to patients without a PGV controlling for stage and year of diagnosis (hazard ratio = 0.42, 95%CI = 0.26 to 0.69).
CONCLUSIONS: PGVs are present in a substantial minority of patients with EOPC. Actionable somatic alterations were identified frequently in EOPC, enriched in the RAS wild-type subgroup. These observations underpin the recent guidelines for universal germline testing and somatic profiling in pancreatic ductal adenocarcinoma.

DOI: https://doi.org/10.1093/jnci/djab038
Int J Hematol. 2021 Mar 23.

A novel germline GATA2 frameshift mutation with a premature stop codon in a family with congenital sensory hearing loss and myelodysplastic syndrome.

Hideyuki Nakazawa, Tomomi Yamaguchi, Hitoshi Sakai, Masae Maruyama, Toru Kawakami, Fumihiro Kawakami, Sayaka Nishina, Masumi Ishikawa, Tomoki Kosho, Fumihiro Ishida.

  GATA2 is a zinc-finger transcription factor regulating early hematopoiesis and developmental processes. Heterozygous germline mutations in GATA2 underlie a pleiotropic autosomal dominant disorder, GATA2 deficiency syndrome. The wide spectrum of its clinical features involves familial predisposition to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) and multiorgan dysfunction, including congenital sensorineural hearing loss (CSHL). We herein report a pedigree with a novel germline frameshift mutation presenting as CSHL and familial MDS. The proband was a 46-year-old man, and his daughter also presented with an identical set of clinical syndromes. Target DNA sequencing identified a novel eight-nucleotide duplicative insertion at exon 5 (NM_032638.4:c.1126_1133dup:p.Lys378Asnfs*12)　of the GATA2 gene. RT-PCR and subcloning analysis showed that the frameshift might result in a truncated mutation with an early stop codon without interfering with the predicted splice site. The predicted mutant protein had 388 amino acids and in silico analysis showed the variant was considered deleterious. This mutation was not detected in unaffected family members. Its deleterious effect is highly likely to have portended the familial MDS and CSHL in this pedigree. Genetic testing among suspected individuals may be warranted for adequate management, including timely transplantation.

Keywords:  Congenital sensory hearing loss; Familial MDS; GATA2; Germline mutation

DOI:  https://doi.org/10.1007/s12185-021-03130-w
Best Pract Res Clin Haematol. 2021 Mar;pii: S1521-6926(21)00017-7. [Epub ahead of print]34(1): 101252

Molecular alterations governing predisposition to myelodysplastic syndromes: Insights from Shwachman-Diamond syndrome.

Akiko Shimamura.

  Identifying germline mutations responsible for genetic predisposition to myeloid malignancies would be useful in creating opportunities for early intervention. Recent genomic and functional studies in Shwachman-Diamond syndrome (SDS) have deciphered distinct roles for heterozygous mutations in EIF6 and TP53 in alleviating germline genetic stress and a role for biallelic TP53 mutations in malignant progression. This review has summarized evidence for a mechanistic framework underlying SDS that can potentially be applied to the study of other germline myelodysplastic syndromes (MDS) predisposition disorders.

Keywords:  AML; Acute myeloid leukemia; EIF6; MDS Shwachman-diamond syndrome; Myelodysplastic syndromes; SDS; TP53

DOI:  https://doi.org/10.1016/j.beha.2021.101252
Fam Cancer. 2021 Mar 25.

Extended gene panel testing in lobular breast cancer.

Elke M van Veen, D Gareth Evans, Elaine F Harkness, Helen J Byers, Jamie M Ellingford, Emma R Woodward, Naomi L Bowers, Andrew J Wallace, Sacha J Howell, Anthony Howell, Fiona Lalloo, William G Newman, Miriam J Smith.

   PURPOSE: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC.
METHODS: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.
RESULTS: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83-66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58-23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52-29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2.
CONCLUSION: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

Keywords:  ATM; Genetics; Lobular breast cancer; Panel testing

DOI:  https://doi.org/10.1007/s10689-021-00241-5
Hered Cancer Clin Pract. 2021 Mar 20. 19(1): 20

Clinical implementation of an oncology-specific family health history risk assessment tool.

Si Ming Fung, R Ryanne Wu, Rachel A Myers, Jasper Goh, Geoffrey S Ginsburg, David Matchar, Lori A Orlando, Joanne Ngeow.

   BACKGROUND: The presence of hereditary cancer syndromes in cancer patients can have an impact on current clinical care and post-treatment prevention and surveillance measures. Several barriers inhibit identification of hereditary cancer syndromes in routine practice. This paper describes the impact of using a patient-facing family health history risk assessment platform on the identification and referral of breast cancer patients to genetic counselling services.
METHODS: This was a hybrid implementation-effectiveness study completed in breast cancer clinics. English-literate patients not previously referred for genetic counselling and/or gone through genetic testing were offered enrollment. Consented participants were provided educational materials on family health history collection, entered their family health history into the platform and completed a satisfaction survey. Upon completion, participants and their clinicians were given personalized risk reports. Chart abstraction was done to identify actions taken by patients, providers and genetic counsellors.
RESULTS: Of 195 patients approached, 102 consented and completed the study (mean age 55.7, 100 % women). Sixty-six (65 %) met guideline criteria for genetic counseling of which 24 (36 %) were referred for genetic counseling. Of those referred, 13 (54 %) participants attended and eight (33 %) completed genetic testing. On multivariate logistic regression, referral was not associated with age, cancer stage, or race but was associated with clinical provider (p = 0.041). Most providers (71 %) had higher referral rates during the study compared to prior. The majority of participants found the experience useful (84 %), were more aware of their health risks (83 %), and were likely to recommend using a patient-facing platform to others (69 %).
CONCLUSIONS: 65 % of patients attending breast cancer clinics in this study are at-risk for hereditary conditions based on current guidelines. Using a patient-facing risk assessment platform enhances the ability to identify these patients systematically and with widespread acceptability and recognized value by patients. As only a third of at-risk participants received referrals for genetic counseling, further understanding barriers to referral is needed to optimize hereditary risk assessment in oncology practices.
TRIAL REGISTRATION: NIH Clinical Trials registry, NCT04639934 . Registered Nov 23, 2020 -- Retrospectively registered.

Keywords:  Family history; Genetic counselling; Hereditary cancer syndromes; Referral; Risk assessment

DOI:  https://doi.org/10.1186/s13053-021-00177-y
Mol Clin Oncol. 2021 May;14(5): 96

Prevalence of BRCA1 and BRCA2 mutations in Japanese patients with triple-negative breast cancer: A single institute retrospective study.

Fumie Fujisawa, Yasuhiro Tamaki, Tazuko Inoue, Takahiro Nakayama, Toshinari Yagi, Nobuyoshi Kittaka, Tetsuhiro Yoshinami, Minako Nishio, Saki Matsui, Hiroki Kusama, Shoji Kamiura.

  Numerous databases for risk assessment of BRCA1/2 gene mutations contain insufficient data about Asians. Furthermore, few studies have reported the prevalence of germline BRCA1/2 mutations in Japanese patients, particularly those with triple-negative breast cancer (TNBC). The present study was a retrospective analysis of data from patients with TNBC who underwent BRCA1/2 mutation testing at Osaka International Cancer Institute (Osaka, Japan) between October 2014 and March 2020. A total of 65 patients with TNBC underwent a test for BRCA1/2 mutations, and 13 (20.0%) had deleterious mutations in the BRCA1 or BRCA2 genes. Furthermore, 12 out of 29 patients with a family history of breast or ovarian cancer had deleterious BRCA1/2 mutations, and only 1 of 34 without a family history had a mutation (41.4 vs. 2.9%; P=0.014). No patients aged >60 years had BRCA1/2 mutations; however, the age of diagnosis was not a significant risk factor for BRCA1/2 mutations (P=0.60). The prevalence of BRCA1/2 mutations in the present cohort of Japanese patients with TNBC was slightly higher than those reported in other larger studies from Europe and North America. Further data from large prospective studies are required to more precisely define the prevalence of BRCA1/2 mutations.

Keywords:  BRCA1; BRCA2; triple-negative breast cancer

DOI:  https://doi.org/10.3892/mco.2021.2258
Front Oncol. 2021 ;11 606820

Interpreting Sequence Variation in PDAC-Predisposing Genes Using a Multi-Tier Annotation Approach Performed at the Gene, Patient, and Cohort Level.

Michael T Zimmermann, Angela J Mathison, Tim Stodola, Douglas B Evans, Jenica L Abrudan, Wendy Demos, Michael Tschannen, Mohammed Aldakkak, Jennifer Geurts, Gwen Lomberk, Susan Tsai, Raul Urrutia.

  We investigated germline variation in pancreatic ductal adenocarcinoma (PDAC) predisposition genes in 535 patients, using a custom-built panel and a new complementary bioinformatic approach. Our panel assessed genes belonging to DNA repair, cell cycle checkpoints, migration, and preneoplastic pancreatic conditions. Our bioinformatics approach integrated annotations of variants by using data derived from both germline and somatic references. This integrated approach with expanded evidence enabled us to consider patterns even among private mutations, supporting a functional role for certain alleles, which we believe enhances individualized medicine beyond classic gene-centric approaches. Concurrent evaluation of three levels of evidence, at the gene, sample, and cohort level, has not been previously done. Overall, we identified in PDAC patient germline samples, 12% with mutations previously observed in pancreatic cancers, 23% with mutations previously discovered by sequencing other human tumors, and 46% with mutations with germline associations to cancer. Non-polymorphic protein-coding pathogenic variants were found in 18.4% of patient samples. Moreover, among patients with metastatic PDAC, 16% carried at least one pathogenic variant, and this subgroup was found to have an improved overall survival (22.0 months versus 9.8; p=0.008) despite a higher pre-treatment CA19-9 level (p=0.02). Genetic alterations in DNA damage repair genes were associated with longer overall survival among patients who underwent resection surgery (92 months vs. 46; p=0.06). ATM alterations were associated with more frequent metastatic stage (p = 0.04) while patients with BRCA1 or BRCA2 alterations had improved overall survival (79 months vs. 39; p=0.05). We found that mutations in genes associated with chronic pancreatitis were more common in non-white patients (p<0.001) and associated with longer overall survival (52 months vs. 26; p=0.004), indicating the need for greater study of the relationship among these factors. More than 90% of patients were found to have variants of uncertain significance, which is higher than previously reported. Furthermore, we generated 3D models for selected mutant proteins, which suggested distinct mechanisms underlying their dysfunction, likely caused by genetic alterations. Notably, this type of information is not predictable from sequence alone, underscoring the value of structural bioinformatics to improve genomic interpretation. In conclusion, the variation in PDAC predisposition genes appears to be more extensive than anticipated. This information adds to the growing body of literature on the genomic landscape of PDAC and brings us closer to a more widespread use of precision medicine for this challenging disease.

Keywords:  genetic predisposition; genomic data interpretation; medical oncology; pancreatic cancer; precision oncology; structural bioinformatics; survival analysis

DOI:  https://doi.org/10.3389/fonc.2021.606820
Prostate. 2021 Mar 24.

Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients.

Rachel A Sabol, Elisa M Ledet, Ellen Jaeger, Whitley Hatton, Marcus Moses, Anjali Lankford, Alexa Zaheria, Pedro Barata, Jodi L Layton, Brian E Lewis, Oliver Sartor.

   BACKGROUND: Recent literature highlights the importance of germline genetic testing in prostate cancer (PCa) patients. Surprisingly, a literature review indicates that family history (FH) records are incomplete in the major published studies from prostate cancer patients.
METHODS: Prospective family history data were gathered from 496 men in a single institution with a personal history of PCa who underwent germline genetic testing using a panel of at least 79 genes. Comprehensive first degree FH were obtained in all PCa of patients and analysis of prevalent FH was assessed at the time of sample collection.
RESULTS: Pathogenic/likely pathogenic variants (PV/LPVs) were not associated with age at diagnosis, race, or presence of metastasis. One or more first degree relatives (FDR) with any cancer was not predictive for germline PV/LPVs for men with PCa (p = .96). Separate analysis of patients with one or more FDR with breast, prostate, ovarian, or pancreatic cancer revealed that only FDR with breast or ovarian cancer was predictive for PV/LPVs (p = .028, p = .015 respectively). Patients with a FDR with breast cancer had 1.8 increased risk of PV/LPVs, and patients with a FDR with ovarian cancer had 2.9 increased risk of PV/LPV.
CONCLUSION: In men with a personal history of PCa, germline PV/LPVs were associated with a FDR with breast or ovarian cancer. Notably having FDRs with PCa does not predict for PV/LPVs. These data emphasize the contribution of FH in a data set with complete ascertainment of FH.

Keywords:  family history; pathogenic germline variants; prostate cancer

DOI:  https://doi.org/10.1002/pros.24120
Eur J Cancer. 2021 Mar 16. pii: S0959-8049(21)00089-7. [Epub ahead of print]148 95-102

Breast cancer risk and hormone replacement therapy among BRCA carriers after risk-reducing salpingo-oophorectomy.

Rachel Michaelson-Cohen, Shira Gabizon-Peretz, Shunit Armon, Naama Srebnik-Moshe, Pnina Mor, Ariela Tomer, Ephrat Levy-Lahad, Shani Paluch-Shimon.

   INTRODUCTION: BRCA1/BRCA2 mutation carriers often undergo risk-reducing salpingo-oophorectomy (RRSO) before natural menopause, raising the issue of hormonal replacement treatment (HRT) use. There is conflicting evidence on the effect of HRT on breast cancer (BC) risk, and there are limited data on risk based on age at exposure. In the general population, HRT users have an increased BC risk (hazard ratio = 1.34). We assessed the impact of short-term HRT use on BC risk among healthy BRCA1/2 mutation carriers, with emphasis on age at exposure to HRT.
METHODS: A retrospective cohort of 306 consecutive healthy BRCA1/2 mutation carriers who had undergone RRSO was followed up for a mean of 7.26 years. We compared BC incidence over time in carriers who received HRT with that in those who did not receive.
RESULTS: Thirty-six of the carriers were diagnosed with BC, 20 of 148 patients (13.5%) in the HRT group compared with 16 of 155 (10.3%) in the non-HRT group (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 0.7-2.7). In women who were aged 45 years or younger at RRSO, HRT did not affect BC rates. However, in those older than 45 years at RRSO, BC rates were significantly higher in HRT users than in non-users (OR = 3.43, p < 0.05, 95% CI = 1.2-9.8).
CONCLUSIONS: In BRCA1/BRCA2 carriers in this study, short-term post-RRSO HRT use was associated with a threefold risk of BC in carriers older than 45 years. These results suggest that risk may be related to time of exposure to HRT around the natural age of menopause, even among BRCA1/2 carriers. Further studies are needed for validation and to guide future recommendations.

Keywords:  BRCA mutation carriers; Cancer risk; Combined oestrogen and progesterone; Ductal carcinoma in situ (DCIS); Hereditary cancer; Hormone replacement therapy; Invasive breast cancer; Menopause; Oestrogen replacement therapy; Risk-reducing salpingo-oophorectomy

DOI:  https://doi.org/10.1016/j.ejca.2021.02.007
JCI Insight. 2021 Mar 25. pii: 141532. [Epub ahead of print]

PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer.

Lucia Liotta, Sebastian Lange, H Carlo Maurer, Kenneth P Olive, Rickmer Braren, Nicole Pfarr, Alexander Muckenhuber, Moritz Jesinghaus, Wilko Weichert, Katja Steiger, Sebastian Burger, Helmut Friess, Roland M Schmid, Hana Alguel, Philipp Jost, Juliane Ramser, Christine Fischer, Anne S Quante, Maximilian Reichert, Michael Quante.

   BACKGROUND AND AIMS: Pancreatic cancer is one of the deadliest cancers, still with low long term survival rates. Despite recent advances in treatment, it is extremely important to screen high-risk individuals in order to establish preventive and early detection measures and, in some cases, molecular driven therapeutic options. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are known to be related with an increased risk and might offer novel screening and therapy options. In this study, our goal was to discover the identity of a familial pancreatic cancer gene in two members of a family with FPC.
METHODS: Whole exome sequencing and PCR confirmation was performed on the surgical specimen and peripheral blood of an index patient and her sister in a family with high incidence of pancreatic cancer, to identify somatic and germline mutations associated with familial pancreatic cancer. Compartment-specific gene expression data and immunohistochemistry was used to characterize PALLD expression.
RESULTS: A germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer. The identical PALLD mutation was identified in the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the two sisters. Apart from the PALLD mutation, commonly mutated genes that characterize PDAC (KRAS and CDKN2A) were found in both tumor samples. However, the two patients harbored different somatic KRAS mutations (respectively G12D in the index patient and G12V in the index patient's sister). Analysis for PALLD mutation in the healthy siblings of the two sisters was negative, indicating that the identified PALLD mutation might have a disease specific impact. Of note, compartment-specific gene expression data and IHC suggested a predominant role in cancer associated fibroblasts (CAFs).
CONCLUSION: We identified a germline mutation of the palladin (PALLD) gene in two siblings in Europe, affected by familial pancreatic cancer, with a predominant function in the tumor stroma.

Keywords:  Cancer; Gastroenterology; Molecular genetics; Oncology

DOI:  https://doi.org/10.1172/jci.insight.141532
J Genet Couns. 2021 Mar 22.

Germline evaluation of patients undergoing tumor genomic profiling: An academic cancer center's experience with implementing a germline review protocol.

Samantha Stachowiak, Amanda Jacquart, Michael T Zimmermann, Ben George, Huaying Dong, Jennifer L Geurts.

  Tumor genomic profiling (TGP) has the potential to identify germline variants in addition to its primary use of informing cancer treatment based on genetic alterations within the tumor. However, there are no formal consensus guidelines to identify patients who would be eligible for genetic counseling (GC) and germline testing (GT) testing in patients undergoing TGP. The purpose of this study is to describe an institutionally developed Germline Review Protocol (GRP) to evaluate adult cancer patient cases already undergoing TGP to determine GC referral eligibility. We report on our retrospective experience implementing this protocol into practice wherein 172 patients out of 638 patients reviewed (27%) were recommended for a GC referral over a 17-month time period. Of those 172 patients recommended for a GC referral, only 34 patients (20%) completed GC and GT. Among patients who received GT, 15 (44%) were positive for at least one pathogenic or likely pathogenic (P/LP) variant, seven patients (21%) were negative and 12 patients (35%) had at least 1 variant of uncertain significance (VUS). The primary reason GC and GT was not completed was because the patient moved to hospice care or was deceased. This is one of the first studies outlining the process and results of a formalized institutional protocol to facilitate patient referrals for GC and GT based on TGP results.

Keywords:  cancer genetics; genetic counseling; genetic counselor; genetic testing; tumor genomic profiling

DOI:  https://doi.org/10.1002/jgc4.1392
Fam Cancer. 2021 Mar 23.

Adaptation and early implementation of the PREdiction model for gene mutations (PREMM5™) for lynch syndrome risk assessment in a diverse population.

Kathleen F Mittendorf, Chinedu Ukaegbu, Marian J Gilmore, Nangel M Lindberg, Tia L Kauffman, Donna J Eubanks, Elizabeth Shuster, Jake Allen, Carmit McMullen, Heather Spencer Feigelson, Katherine P Anderson, Michael C Leo, Jessica Ezzell Hunter, Sonia Okuyama Sasaki, Jamilyn M Zepp, Sapna Syngal, Benjamin S Wilfond, Katrina A B Goddard.

  Lynch syndrome (LS) is the most common inherited cause of colorectal and endometrial cancers. Identifying individuals at risk for LS without personal cancer history requires detailed collection and assessment of family health history. However, barriers exist to family health history collection, especially in historically underserved populations. To improve LS risk assessment in historically underserved populations, we adapted the provider-facing PREdiction Model for gene Mutations (PREMM5™ model), a validated LS risk assessment model, into a patient-facing electronic application through an iterative development process involving expert and patient stakeholders. We report on preliminary findings based on the first 500 individuals exposed to the adapted application in a primary care population enriched for low-literacy and low-resource patients. Major adaptations to the PREMM5™ provider module included reduction in reading level, addition of interactive literacy aids, incorporation of family history assessment for both maternal and paternal sides of the family, and inclusion of questions about individual relatives or small groups of relatives to reduce cognitive burden. In the first 500 individuals, 90% completed the PREMM5™ independently; of those, 94% did so in 5 min or less (ranged from 0.2 to 48.8 min). The patient-facing application was able to accurately classify 84% of patients as having clinically significant or not clinically significant LS risk. Our preliminary results suggest that in this diverse study population, most participants were able to rapidly, accurately, and independently complete an interactive application collecting family health history assessment that accurately assessed for Lynch syndrome risk.

Keywords:  Family history; Hereditary cancer; Lynch syndrome; Risk assessment; Underserved

DOI:  https://doi.org/10.1007/s10689-021-00243-3
Intern Med. 2021 Mar 22.

Interval between the First Cancer and the Genetic Diagnosis in Lynch Syndrome Probands.

Kentaro Yamashita, Hisayo Fukushima, Mizue Teramoto, Kenji Okita, Aki Ishikawa, Akihiro Sakurai, Kiwamu Akagi, Hiroshi Nakase.

  Objective Little is known about the time from developing a first cancer to confirming the presence of a mismatch repair (MMR) gene mutation for Lynch syndrome (LS) probands. Methods This was a retrospective single center study. LS probands, who have an MMR gene mutation that was confirmed first in a pedigree and thereafter developed at least one cancer, were included in this study. Results There were 21 LS probands who had developed at least one cancer; 6 with MLH1 mutations, 9 with MSH2 mutations, 4 with MSH6 mutations, and 2 with EPCAM deletions. The median ages at the first cancer and the genetic diagnosis were 47 (34-71) and 62 (38-84) years old, respectively. The mean interval between the first cancer and the genetic diagnosis was 11.0 (0-25) years, and 20 years or longer interval was required for the 5 probands. Six (28.6%) probands were older than 70 years, and 3 (14.3%) were in their 80s when they were diagnosed to have LS. The genetic diagnosis was confirmed at the first, second, third, and fourth cancer or later in 5, 5, 6, and 5 probands, respectively. Of the 16 cancers examined, 2 (12.5%) were microsatellite stable (MSS), both of whom had germline MSH6 mutations. All 17 LS probands who developed colorectal cancer met the revised Bethesda guidelines at the genetic diagnosis, but only 7 of 11 (63.6%) met them at the first cancer. Twelve out of 21 (57.1%) met the revised Amsterdam criteria. Conclusion It took 11 years for the LS probands from the first cancer to the diagnostic confirmation by genetic tests. A quarter of the probands were in their 70s or 80s at genetic diagnosis.

Keywords:  Lynch syndrome; colorectal cancer; microsatellite instability; mismatch repair genes; probands

DOI:  https://doi.org/10.2169/internalmedicine.6603-20
Hered Cancer Clin Pract. 2021 Mar 25. 19(1): 21

CDKN2A germline alterations and the relevance of genotype-phenotype associations in cancer predisposition.

Sock Hoai Chan, Jianbang Chiang, Joanne Ngeow.

  Although CDKN2A is well-known as a susceptibility gene for melanoma and pancreatic cancer, germline variants have also been anecdotally associated with a broader range of neoplasms including neural system tumors, head and neck squamous cell carcinomas, breast carcinomas, as well as sarcomas. The CDKN2A gene encodes for two distinct tumor suppressor proteins, p16INK4A and p14ARF, however, the independent association of germline alterations affecting these two proteins with cancer is under-appreciated. Here, we reviewed CDKN2A germline alterations reported among individuals and families with cancer in the literature, specifically addressing the cancer phenotypes in relation to the molecular consequence on p16INK4A and p14ARF. While melanoma is observed to associate with variants affecting both p16INK4A and p14ARF transcripts, it is noted that variants affecting p14ARF are more frequently observed with a heterogenous range of cancers. Finally, we reflected on the implications of this inferred genotype-phenotype association in clinical practice and proposed that clinical management of CDKN2A germline variant carriers should involve dedicated cancer genetics services, with multidisciplinary input from various healthcare professionals.

Keywords:  CDKN2A; Cancer predisposition; p14ARF; p16INK4A

DOI:  https://doi.org/10.1186/s13053-021-00178-x
Arch Pathol Lab Med. 2021 Mar 26.

Laboratory and Clinical Implications of Incidental and Secondary Germline Findings During Tumor Testing.

Allison Cushman-Vokoun, Josh Lauring, John Pfeifer, Damon R Olson, Anna Berry, John Thorson, Karl Voelkerding, Jonathan Myles, James Barbeau, Pranil Chandra, Marilyn Li, Gail H Vance, Brad W Jensen, Molly Y Hansen, Sophia Yohe.

CONTEXT.—: Next-generation sequencing is a powerful clinical tool for cancer management but can produce incidental/secondary findings that require special consideration.
OBJECTIVE.—: To discuss clinical and laboratory issues related to incidental or secondary germline findings in the clinical setting of tumor testing and inform future guidelines in this area.
DESIGN.—: A College of American Pathologists workgroup including representation from the American Society of Clinical Oncology, the Association for Molecular Pathology, and the American College of Medical Genetics and Genomics created a review of items that should be considered when developing guidelines for incidental or secondary findings when performing clinical tumor testing.
RESULTS.—: Testing recommendations should be cognizant of the differences among anticipated incidental, unanticipated incidental, and secondary findings, and whether normal tissue is also tested. In addition to defining which variants will be reported, robust recommendations must also take into account test design and validation, reimbursement, cost, infrastructure, impact on reflex testing, and maintenance of proficiency. Care providers need to consider the potential of a test to uncover incidental or secondary findings, the recommendation of upfront counseling, the need for consent, the timing of testing and counseling, and that the exact significance of a finding may not be clear.
CONCLUSIONS.—: As clinical oncology testing panels have become a mainstay of clinical cancer care, guidelines addressing the unique aspects of incidental and secondary findings in oncology testing are needed. This paper highlights clinical and laboratory considerations with regard to incidental/secondary findings and is a clarion call to create recommendations.

DOI: https://doi.org/10.5858/arpa.2020-0025-CP