bims-lifras 2022-03-27 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–03–27
thirteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Differential gain-of-function activity of three p53 hotspot mutants in vivo.
Aspirin Colorectal Cancer Prevention in Lynch Syndrome: Recommendations in the Era of Precision Medicine.
Evolution of germline TP53 variant classification in children with cancer.
Real-World Data on Detection of Germline and Somatic Pathogenic/Likely Pathogenic Variants in BRCA1/2 and Other Susceptibility Genes in Ovarian Cancer Patients Using Next Generation Sequencing.
Cancer Predisposition Genes in Adolescents and Young Adults (AYAs): a Review Paper from the Italian AYA Working Group.
CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma.
Lynch Syndrome-Associated Endometrial Cancer With Combined EPCAM-MSH2 Deletion: A Case Report.
Patient navigation for hereditary colorectal cancer: Design of a randomized controlled trial to determine the effectiveness of pathways to genetic counseling.
MEN4, the MEN1 mimicker; a case series of 3 phenotypically heterogenous patients with unique CDKN1B mutations.
Universal Screening for Lynch Syndrome Compared with Pedigree-Based Screening: 10-Year Experience in a Tertiary Hospital.
Review article: Lynch Syndrome-a mechanistic and clinical management update.
Laboratory-related outcomes from integrating an accessible delivery model for hereditary cancer risk assessment and genetic testing in populations with barriers to access.
Hereditary evaluation and genetic counselling in young individuals with colorectal cancer in a population-based cohort.

Cancer Res. 2022 Mar 23. pii: canres.3376.2021. [Epub ahead of print]

Differential gain-of-function activity of three p53 hotspot mutants in vivo.

Shunbin Xiong, Dhruv Chachad, Yun Zhang, Jovanka Gencel-Augusto, Mario Sirito, Vinod Pant, Peirong Yang, Chang Sun, Gilda Chau, Yuan Qi, Xiaoping Su, Elizabeth M Whitley, Adel K El-Naggar, Guillermina Lozano.

The majority of TP53 missense mutations identified in cancer patients are in the DNA-binding domain and are characterized as either structural or contact mutations. These missense mutations exhibit inhibitory effects on wild-type p53 activity. More importantly, these mutations also demonstrate gain-of-function (GOF) activities characterized by increased metastasis, poor prognosis, and drug resistance. To better understand the activities by which TP53 mutations, identified in Li-Fraumeni syndrome, contribute to tumorigenesis, we generated mice harboring a novel germline Trp53R245W allele (contact mutation) and compared them to existing models with Trp53R172H (structural mutation) and Trp53R270H (contact mutation) alleles. Thymocytes from heterozygous mice showed that all three hotspot mutations exhibited similar inhibitory effects on wild-type Trp53 transcription in vivo, and tumors from these mice had similar levels of loss of heterozygosity. However, the overall survival of Trp53R245W/+ and Trp53R270H/+ mice, but not Trp53R172H/+ mice, was significantly shorter than that of Trp53+/- mice, providing strong evidence for p53 mutant-specific GOF contributions to tumor development. Furthermore, Trp53R245W/+ and Trp53R270H/+ mice had more osteosarcoma metastases than Trp53R172H/+ mice, suggesting that these two contact mutants have stronger GOF in driving osteosarcoma metastasis. Transcriptomic analyses using RNA-sequencing data from Trp53R172H/+, Trp53R245W/+, and Trp53R270H/+ primary osteosarcomas in comparison to Trp53+/- indicated that GOF of the three mutants was mediated by distinct pathways. Thus, both the inhibitory effect of mutant over WT p53 and GOF activities of mutant p53 contributed to tumorigenesis in vivo. Targeting p53 mutant-specific pathways may be important for therapeutic outcomes in osteosarcoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3376
Genes (Basel). 2022 Mar 03. pii: 460. [Epub ahead of print]13(3):

Aspirin Colorectal Cancer Prevention in Lynch Syndrome: Recommendations in the Era of Precision Medicine.

Davide Serrano, Paola Patrignani, Vittoria Stigliano, Daniela Turchetti, Stefania Sciallero, Franco Roviello, Alessandro D'Arpino, Ignazio Grattagliano, Salvo Testa, Cristina Oliani, Lucio Bertario, Bernardo Bonanni.

  Cancer prevention in the era of precision medicine has to consider integrated therapeutic approaches. Therapeutic cancer prevention should be offered to selected cohorts with increased cancer risk. Undoubtedly, carriers of hereditary cancer syndromes have a well-defined high cancer risk. Lynch Syndrome is one of the most frequent hereditary syndromes; it is mainly associated with colorectal cancer (CRC). Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies, initially with contradictory results; however, longer follow-up confirmed a reduced CRC incidence and mortality. The CAPP2 study recruited 861 Lynch syndrome participants randomly assigned to 600 mg of aspirin versus placebo. Like sporadic CRCs, a significant CRC risk reduction was seen after an extended follow-up, with a median treatment time that was relatively short (2 years). The ongoing CAPP3 will address whether lower doses are equally effective. Based on pharmacology and clinical data on sporadic CRCs, the preventive effect should also be obtained with low-dose aspirin. The leading international guidelines suggest discussing with Lynch syndrome carriers the possibility of using low-dose aspirin for CRC prevention. We aim systematically promote this intervention with all Lynch syndrome carriers.

Keywords:  aspirin; colorectal cancer; lynch syndrome

DOI:  https://doi.org/10.3390/genes13030460
Cancer Genet. 2022 Mar 03. pii: S2210-7762(22)00023-0. [Epub ahead of print]264-265 29-32

Evolution of germline TP53 variant classification in children with cancer.

E Tallis, S Scollon, D I Ritter, S E Plon.

  Li-Fraumeni syndrome, caused by germline pathogenic variants in TP53, results in susceptibility to multiple cancers. Variants of uncertain significance (VUS) and reclassification of variants over time pose management concerns given improved survival with cancer surveillance for LFS patients. We describe the experience of TP53 variant reclassification at a pediatric cancer center.
METHODS: We reviewed medical records (2010-2019) of 756 patients seen in Texas Children's Cancer Genetics Clinic. We noted initial TP53 classification and any reclassifications. We then classified TP53 variants following ClinGen TP53 variant curation expert panel recommendations using data from ClinVar, medical literature and IARC database.
RESULTS: Of 234 patients tested for TP53, 27 (11.5%) reports contained pathogenic/likely pathogenic (P/LP) variants and 7 (3)% contained VUS. By January 2022, 4 of 6 unique VUS and 2 of 16 unique P/LP variants changed interpretations in ClinVar. Reinterpretation of these 4 VUS in ClinVar matched clinical decision at the time of initial report. Applying TP53 VCEP specifications classified 3 VUS to P/LP/benign, and one pathogenic variant to likely benign.
CONCLUSIONS: Planned review of variant significance is essential, especially for patients with high probability of LFS.

Keywords:  LFS; Pediatric cancer predisposition syndrome; TP53; VUS; Variant reclassification

DOI:  https://doi.org/10.1016/j.cancergen.2022.02.011
Cancers (Basel). 2022 Mar 10. pii: 1434. [Epub ahead of print]14(6):

Real-World Data on Detection of Germline and Somatic Pathogenic/Likely Pathogenic Variants in BRCA1/2 and Other Susceptibility Genes in Ovarian Cancer Patients Using Next Generation Sequencing.

Vida Stegel, Ana Blatnik, Erik Škof, Vita Šetrajčič Dragoš, Mateja Krajc, Brigita Gregorič, Petra Škerl, Ksenija Strojnik, Gašper Klančar, Marta Banjac, Janez Žgajnar, Maja Ravnik, Srdjan Novaković.

  Detection of germline and somatic pathogenic/likely pathogenic variants (PV/LPV) in BRCA genes is at the moment a prerequisite for use of PARP inhibitors in different treatment settings of different tumors. The aim of our study was to determine the most appropriate testing workflow in epithelial ovarian cancer (EOC) patients using germline and tumor genotyping of BRCA and other hereditary breast and/or ovarian cancer (HBOC) susceptibility genes. Consecutive patients with advanced non-mucinous EOC, who responded to platinum-based chemotherapy, were included in the study. DNA extracted from blood and FFPE tumor tissue were genotyped using NGS panels TruSightCancer/Hereditary and TruSight Tumor 170. Among 170 EOC patients, 21.8% had BRCA germline or somatic PV/LPV, and additionally 6.4% had PV/LPV in other HBOC genes. Sensitivity of tumor genotyping for detection of germline PV/LPV was 96.2% for BRCA genes and 93.3% for HBOC genes. With germline genotyping-only strategy, 58.8% of HBOC PV/LPV and 68.4% of BRCA PV/LPV were detected. By tumor genotyping-only strategy, 96.1% of HBOC PV/LPV and 97.4% of BRCA PV/LPV were detected. Genotyping of tumor first, followed by germline genotyping seems to be a reasonable approach for detection of PV/LPV in breast and/or ovarian cancer susceptibility genes in non-mucinous EOC patients.

Keywords:  BRCA; HBOC; PARP inhibitors; germline genotyping; ovarian cancer; reverse mutation; tumor genotyping

DOI:  https://doi.org/10.3390/cancers14061434
Curr Oncol Rep. 2022 Mar 23.

Cancer Predisposition Genes in Adolescents and Young Adults (AYAs): a Review Paper from the Italian AYA Working Group.

Angela Toss, Paola Quarello, Maurizio Mascarin, Giuseppe Luigi Banna, Marco Zecca, Saverio Cinieri, Fedro Alessandro Peccatori, Andrea Ferrari.

   PURPOSE OF REVIEW: The present narrative systematic review summarizes current knowledge on germline gene mutations predisposing to solid tumors in adolescents and young adults (AYAs).
RECENT FINDINGS: AYAs with cancer represent a particular group of patients with specific challenging characteristics and yet unmet needs. A significant percentage of AYA patients carry pathogenic or likely pathogenic variants (PV/LPVs) in cancer predisposition genes. Nevertheless, knowledge on spectrum, frequency, and clinical implications of germline variants in AYAs with solid tumors is limited. The identification of PV/LPV in AYA is especially critical given the need for appropriate communicative strategies, risk of second primary cancers, need for personalized long-term surveillance, potential reproductive implications, and cascade testing of at-risk family members. Moreover, these gene alterations may potentially provide novel biomarkers and therapeutic targets that are lacking in AYA patients. Among young adults with early-onset phenotypes of malignancies typically presenting at later ages, the increased prevalence of germline PV/LPVs supports a role for genetic counseling and testing irrespective of tumor type.

Keywords:  Adolescents; Cancer; Predisposition genes; Young adults

DOI:  https://doi.org/10.1007/s11912-022-01213-3
Genes (Basel). 2022 Feb 23. pii: 400. [Epub ahead of print]13(3):

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma.

Jihenne Ben Aissa-Haj, Maria Kabbage, Houcemeddine Othmen, Patrick Saulnier, Haifa Tounsi Kettiti, Amira Jaballah-Gabteni, Azer Ferah, Mouna Medhioub, Amal Khsiba, Moufida Mahmoudi, Afifa Maaloul, Sonia Ben Nasr, Emna Chelbi, Sonia Abdelhak, M Samir Boubaker, Mohamed Mousaddak Azzouz, Etienne Rouleau.

  Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G > A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.

Keywords:  CDH1; CTNNA1; Tunisian patients; germline variants; hereditary diffuse gastric cancer; large rearrangements

DOI:  https://doi.org/10.3390/genes13030400
Front Oncol. 2022 ;12 856452

Lynch Syndrome-Associated Endometrial Cancer With Combined EPCAM-MSH2 Deletion: A Case Report.

Rong Huang, Xiangyu Deng, Zhenhua Zhang, Qinglian Wen, Dan Li.

   Background: Lynch syndrome (LS), an autosomal dominant disorder, is characterized by germline pathogenic variants in DNA mismatch repair (MMR) genes like MSH2. EPCAM deletions cause a minority (3%) of LS cases. However, there are only a few reports of LS-associated endometrial cancer (LS-EC) induced by the inactivation of the MSH2 gene due to EPCAM deletions.
Case Presentation: We present the case of a 45-years old woman diagnosed with endometrial cancer (EC). Definitive surgery revealed meso-differentiated endometrioid adenocarcinoma, stage IA without lymph-vascular space invasion. Four months later, she received radiation therapy (125I radioactive seeds implantation), and platinum-containing regimen combined chemotherapy because of vaginal stump metastasis of EC. After five years, we performed immunohistochemistry (IHC) on pelvic mass because of presacral metastatic lymph node. IHC showed the absence of MSH2 and MSH6 protein expression in the pelvic mass tissue. Peripheral blood was used for genetic testing based on her cancer diagnosis and family history of cancer in close relatives. Genetic testing revealed deletions of exon 8 and 9 in EPCAM and deletions of exon 1 and 8 in MSH2; thus, we diagnosed the presence of LS. The patient underwent interstitial brachytherapy (BT) of the presacral metastatic lymph node.
Conclusion: This case highlights that patients with LS-EC who are carriers of combined EPCAM-MSH2 deletion might experience better oncologic outcomes even with early recurrence.

Keywords:  EPCAM; MSH2; case; endometrial carcinoma; lynch syndrome

DOI:  https://doi.org/10.3389/fonc.2022.856452
Contemp Clin Trials. 2022 Mar 21. pii: S1551-7144(22)00061-1. [Epub ahead of print] 106735

Patient navigation for hereditary colorectal cancer: Design of a randomized controlled trial to determine the effectiveness of pathways to genetic counseling.

Alyssa K Reed, Marlana J Kohn, Sarah Stayman, Allison M Cole, Cynthia W Ko, Eric Q Konnick, Paul E Swanson, Ying Zhang, Sarah Knerr.

   BACKGROUND: Diagnosis of Lynch and other hereditary colorectal cancer (CRC) syndromes through germline genetic testing has important implications for treatment and risk-management, yet guideline-recommended genetic counseling referral and attendance is suboptimal.
METHODS: Our team developed an adapted patient navigation program-Pathways to Genetic Counseling-to address multilevel barriers to genetic counseling referral and receipt. This paper describes the methods of a randomized controlled trial (RCT) testing Pathways to Genetic Counseling's effectiveness at increasing genetic counseling attendance in the University of Washington Medicine health system. We will identify CRC patients eligible for genetic counseling (diagnosed before age 50 or at any age with evidence of inherited mismatch repair deficiency) through a combination of structured electronic health record queries and manual chart review. Patients will be randomized 1:1 prior to consent and receive either care as usual (no contact) or be invited to participate in patient navigation. We will use chart review to compare rates of genetic counseling referral and attendance within six months of randomization, regardless of patients' engagement with navigation. We plan to identify and randomize 161 eligible CRC patients over a nine-month period beginning in late 2021.
DISCUSSION: Our pragmatic RCT design will provide real-world data on the potential for patient navigation to address longstanding care gaps in preventive genomic medicine. If effective, we hope to pilot Pathways to Genetic Counseling in additional settings with a long-term goal of improving appropriate diagnosis of hereditary CRC syndromes and subsequent cascade screening of eligible family members.

Keywords:  Genetic counseling; Genetic testing; Hereditary colorectal cancer; Implementation; Patient navigation

DOI:  https://doi.org/10.1016/j.cct.2022.106735
J Clin Endocrinol Metab. 2022 Mar 22. pii: dgac162. [Epub ahead of print]

MEN4, the MEN1 mimicker; a case series of 3 phenotypically heterogenous patients with unique CDKN1B mutations.

Amanda Seabrook, Ayanthi Wijewardene, Sunita De Sousa, Tang Wong, Nisa Sheriff, Anthony J Gill, Rakesh Iyer, Michael Field, Catherine Luxford, Roderick Clifton-Bligh, Ann McCormack, Katherine Tucker.

   CONTEXT: Germline CDKN1B pathogenic variants result in Multiple Endocrine Neoplasia type 4, an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma and duodenopancreatic neuroendocrine tumors.
OBJECTIVE: To report the phenotype of three unrelated cases each with a unique germline CDKN1B variant (of which two are novel) and compare these cases to those described in the current literature.
DESIGN/METHODS: Three case studies, including clinical presentation, germline and tumor genetic analysis and family history.
SETTING: Two tertiary University Hospitals in Sydney, NSW, and one tertiary University Hospital in Canberra, ACT, Australia.
OUTCOME: Phenotype of the three cases and their kindred; molecular analysis and tumor p27 kip1 immunohistochemistry.
RESULTS: Family A: the proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal non-functioning duodenopancreatic neuroendocrine tumor (DP-NET). Family B: the proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: the proband was diagnosed with a non-functioning pituitary microadenoma and ectopic Cushing's syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, two of which are novel (c.179G>A, p.Trp60*; c.475G>A, p.Asp159Asn;) and one previously reported (c.374_375delCT, p.Ser125*).
CONCLUSIONS: Germline CDKN1B pathogenic variants cause the syndrome Multiple Endocrine Neoplasia type 4. The phenotype resulting from the three pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.

Keywords:   CDKN1B germline mutation; MEN4; Multiple Endocrine Neoplasia type 4; atypical carcinoid tumor; pancreatic neuroendocrine tumor; pituitary adenoma; primary hyperparathyroidism

DOI:  https://doi.org/10.1210/clinem/dgac162
Cancer Res Treat. 2022 Mar 21.

Universal Screening for Lynch Syndrome Compared with Pedigree-Based Screening: 10-Year Experience in a Tertiary Hospital.

Min Hyun Kim, Duck-Woo Kim, Hye Seung Lee, Su Kyung Bang, Soo Hyun Seo, Kyung Un Park, Heung-Kwon Oh, Sung-Bum Kang.

   Purpose: Universal screening for Lynch Syndrome (LS) refers to routine tumor testing for microsatellite instability (MSI) among all patients with colorectal cancer (CRC). Despite its widespread adoption, real-world data on the yield is lacking in Korean population. We studied the yield of adopting universal screening for LS in comparison with pedigree-based screening in a tertiary center.
Materials and Methods: CRC patients from 2007-2018 were reviewed. Family histories were obtained and were evaluated for hereditary nonpolyposis colorectal cancer (HNPCC) using Amsterdam II criteria. Tumor testing for MSI began in 2007 and genetic testing was offered using all available clinicopathologic data. Yield of genetic testing for LS was compared for each approach and step.
Results: Of the 5,520 patients, tumor testing was performed in 4,701 patients (85.2%) and family histories were obtained from 4,241 patients (76.8%). Hereditary CRC (LS or HNPCC) was present in 69 patients (1.3%). MSI-high was present in 6.9%, and 25 patients had confirmed LS. Genetic testing was performed in 41.2% (47/114) of MSI-high patients, out of which 40.4% (19/47) were diagnosed with LS. There were 6 additional LS patients found outside of tumor testing. For pedigree-based screening, Amsterdam II criteria diagnosed 55 patients with HNPCC. Fifteen of these patients underwent genetic testing, and 11 (73.3%) were diagnosed with LS. Two patients without prior family history were diagnosed with LS and relied solely on tumor testing results.
Conclusion: Despite widespread adoption of routine tumor testing for MSI, this is not a fail-safe approach to screen all LS patients. Obtaining a thorough family history in combination with universal screening provides a more comprehensive 'universal' screening method for LS.

Keywords:  Colorectal neoplasms; Family history; Hereditary nonpolyposis colorectal cancer; Lynch syndrome; Pedigree; Universal screening

DOI:  https://doi.org/10.4143/crt.2021.1512
Aliment Pharmacol Ther. 2022 Mar 21.

Review article: Lynch Syndrome-a mechanistic and clinical management update.

Kit Curtius, Samir Gupta, C Richard Boland.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to various cancers.
AIM: To review the pathogenesis, clinical presentation, differential diagnosis and clinical strategies for detection and management of LS.
METHODS: A narrative review synthesising knowledge from published literature, as well as current National Comprehensive Cancer Network guidelines for management of LS was conducted.
RESULTS: LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. LS is one of the most common hereditary causes of cancer, and about 1 in 279 individuals carry a PV in an LS gene that predisposes to associated cancers. Individuals with LS have increased risks for colorectal, endometrial and other cancers, with significant variation in lifetime risk by LS-associated gene.
CONCLUSIONS: As genetic testing becomes more widespread, the number of individuals identified with LS is expected to increase in the population. Understanding the pathogenesis of LS informs current strategies for detection and clinical management, and also guides future areas for clinical innovation. Unravelling the mechanisms by which these tumours evolve may help to more precisely tailor management by the gene involved.

DOI: https://doi.org/10.1111/apt.16826
Genet Med. 2022 Mar 16. pii: S1098-3600(22)00652-9. [Epub ahead of print]

Laboratory-related outcomes from integrating an accessible delivery model for hereditary cancer risk assessment and genetic testing in populations with barriers to access.

CHARM Study

   PURPOSE: This study aimed to evaluate the laboratory-related outcomes of participants who were offered genomic testing based on cancer family history risk assessment tools.
METHODS: Patients from clinics that serve populations with access barriers, who are screened at risk for a hereditary cancer syndrome based on adapted family history collection tools (the Breast Cancer Genetics Referral Screening Tool and PREMM5), were offered exome-based panel testing for cancer risk and medically actionable secondary findings. We used descriptive statistics, electronic health record review, and inferential statistics to explore participant characteristics and results, consultations and actions related to pathogenic/likely pathogenic variants identified, and variables predicting category of findings, respectively.
RESULTS: Of all the participants, 87% successfully returned a saliva kit. Overall, 5% had a pathogenic/likely pathogenic cancer risk variant and 1% had a secondary finding. Almost all (14/15, 93%) participants completed recommended consultations with nongenetics providers after an average of 17 months. The recommended actions (eg, breast magnetic resonance imaging) were completed by 17 of 25 participants. Participant personal history of cancer and PREMM5 score were each associated with the category of findings (history and colon cancer finding, Fisher's exact P = .02; history and breast cancer finding, Fisher's exact P = .01; PREMM5TM score; and colon cancer finding, Fisher's exact P < .001).
CONCLUSION: This accessible model of hereditary cancer risk assessment and genetic testing yielded results that were often acted upon by patients and physicians.

Keywords:  Barriers to access; Genomic sequencing; Hereditary cancer risk; Service delivery models

DOI:  https://doi.org/10.1016/j.gim.2022.02.006
Surg Oncol. 2022 Mar 17. pii: S0960-7404(22)00034-2. [Epub ahead of print]41 101741

Hereditary evaluation and genetic counselling in young individuals with colorectal cancer in a population-based cohort.

Erik Lundqvist, Ekaterina Kuchinskaya, Kalle Landerholm, Jeanette Assarsson, Anna Benckert, Pär Myrelid, Staffan Haapaniemi.

AIM: Early-onset colorectal cancer should raise suspicions of a hereditary colorectal cancer (CRC) syndrome, including Lynch syndrome (LS) and Familial Adenomatous Polyposis (FAP). Collection of family history and genetic counselling (GC) is mandatory but previous studies have revealed low awareness of hereditary CRC among clinicians why there has been an incentive to implement universal LS screening. In this population-based cohort study, we aimed to observe the uptake of GC in the Swedish South-Eastern medical care region for young CRC patients and to investigate the frequency of patients diagnosed with LS.
METHODS: Patients below 50 years of age diagnosed with CRC between 2008 and 2017 were identified from the national Swedish Colorectal Cancer Registry. Medical records were reviewed regarding family history, co-morbidity and referral for GC, with a follow-up time of at least three years.
RESULTS: The analysis included 278 patients with 287 tumours, 108 (38%) located in rectum and 179 (62%) in colon. One hundred sixteen (42%) individuals were referred to the Regional Clinical Genetics service, whereof 74 (27%) underwent complete investigation. Thirteen (18%) patients were identified with a mutation, eleven (15%) had LS and two (3%) FAP. The remaining 61 (82%), without proven mutation, were considered as familial CRC. Younger age correlated with a higher chance of referral for GC.
CONCLUSION: The study found that only a minority of young CRC patients underwent genetic counselling, contrary to clinical guidelines. Hereditary CRC is therefore probably underdiagnosed even among young individuals.

DOI: https://doi.org/10.1016/j.suronc.2022.101741