bims-lifras 2022-04-10 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–04–10
eight papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Considerations for Germline Testing in Melanoma: Updates in Behavioral Change and Pancreatic Surveillance for Carriers of CDKN2A Pathogenic Variants.
How a woman's myomectomy saved her father's life: evidence of fumarate hydratase-deficient uterine leiomyoma and early detection of germline variants in fumarate hydratase.
Global distribution of prophylactic total gastrectomy in E-cadherin (CDH1) mutations.
Identification of Germline Mutations in Upper Tract Urothelial Carcinoma With Suspected Lynch Syndrome.
Breast Cancer Phenotype Associated With Li-Fraumeni Syndrome: A Brazilian Cohort Enriched by TP53 p.R337H Carriers.
Familial Lynch syndrome with early age of onset and confirmed splice site mutation in MSH2: A case report.
A Case Report of CHEK2 and MUTYH Germline Mutations Associated With Cholangiocarcinoma in a Young Patient.
Embodied risk for families with Li-Fraumeni syndrome: Like electricity through my body.

Front Oncol. 2022 ;12 837057

Considerations for Germline Testing in Melanoma: Updates in Behavioral Change and Pancreatic Surveillance for Carriers of CDKN2A Pathogenic Variants.

Kristen Pauley, Ambreen Khan, Wendy Kohlmann, Joanne Jeter.

  The largest proportion of hereditary melanoma cases are due to pathogenic variants (PVs) in the CDKN2A/p16 gene, which account for 20%-40% of familial melanomas and confer up to a 30%-70% lifetime risk for melanoma in individuals with these variants. In addition, PVs in the CDKN2A gene also increase risk for pancreatic cancer (~5-24% lifetime risk). Individuals with PVs in the CDKN2A gene also tend to have an earlier onset of cancer. Despite these known risks, uptake of germline testing has been limited in the past, largely due to perceptions of limited benefit for patients. Prevention recommendations have been developed for individuals with CDKN2A PVs as well the providers who care for them. On the patient level, behavioral modifications regarding melanoma prevention such as wearing sunscreen, limiting prolonged sun exposure and practicing general sun safety can help reduce risks. Germline testing can provide motivation for some individuals to adhere to these lifestyle changes. On the provider level, pancreatic cancer surveillance for individuals with CDKN2A PVs has been increasingly endorsed by expert consensus, although the efficacy of these surveillance methods remains under study. This review summarizes the updated surveillance guidelines for individuals with CDKN2A PVs and explores the impact of genetic counseling and testing in influencing behavioral changes in these individuals.

Keywords:  CDKN2A; behavior change; hereditary cancer syndromes; melanoma; pancreatic cancer; surveillance

DOI:  https://doi.org/10.3389/fonc.2022.837057
F S Rep. 2022 Mar;3(1): 26-31

How a woman's myomectomy saved her father's life: evidence of fumarate hydratase-deficient uterine leiomyoma and early detection of germline variants in fumarate hydratase.

Greysha Rivera-Cruz, Baris Boyraz, John C Petrozza.

   Objective: To describe a case of a personal and family history of early uterine leiomyomatosis that revealed a pathogenic variant in the FH gene encoding fumarate hydratase. After the patient's diagnosis, a first-degree relative was detected with early-stage renal cell carcinoma. The patient decided to undergo preimplantation genetic testing to reduce the risk to her future children.
Design: A case report of autosomal dominant hereditary leiomyomatosis and renal cell cancer syndrome where the patient underwent 2 cycles of in vitro fertilization with preimplantation genetic testing for monogenic disease/aneuploidy (PGT-MA) that resulted in 3 unaffected, euploid embryos.
Setting: Large academic single-center hospital.
Patients: A 35-year-old nulligravida woman with a personal history of an early-onset uterine leiomyomatosis and a family history of renal cell carcinoma and uterine leiomyomas, who is heterozygous for a pathogenic variant in FH and diagnosed with hereditary leiomyomatosis and renal cell cancer syndrome. Informed consent was obtained.
Interventions: Two laparoscopic myomectomies were performed, and tissue was sent for histopathology and immunostaining. Hereditary leiomyomatosis and renal cell cancer syndrome was confirmed by germline testing, and 2 cycles of PGT-MA were performed.
Main Outcome Measures: Through PGT-MA, the patient was able to mitigate the risk of passing a known familial variant to her future children.
Results: After 2 cycles of in vitro fertilization with PGT-MA, 3 unaffected embryos were available for transfer. An unaffected, euploid embryo was transferred for pregnancy, and the patient is currently pregnant in her second trimester.
Conclusions: Pathogenic variants in FH should be suspected in patients with early-onset uterine leiomyomas and a family history of cutaneous and/or uterine leiomyomas. Familial variant testing is crucial in identifying relatives at risk to start early screening.

Keywords:  Fumarate hydratase; preimplantation genetic testing; renal cell carcinoma; uterine leiomyoma

DOI:  https://doi.org/10.1016/j.xfre.2021.10.002
Semin Oncol. 2022 Mar 18. pii: S0093-7754(22)00022-7. [Epub ahead of print]

Global distribution of prophylactic total gastrectomy in E-cadherin (CDH1) mutations.

Giovanni Corso, Francesca Magnoni, Vincenzo Nicastro, Vincenzo Bagnardi, Cristina Maria Trovato, Paolo Veronesi.

  Individuals with germline E-cadherin (CDH1) mutations are at high risk of developing diffuse gastric cancer (GC) and prophylactic total gastrectomy (PTG) represents the only life-saving treatment. We reviewed all PTGs reported in literature associated with CDH1 germline mutations. A total of 224 PTGs were reported. The majority were described in the United States of America (50%), the Netherlands (17.8%), and Canada (12.5%). GC was identified in 85.4% of cases after PTG, with a high rate of "no cancer" at histopathology identified in the United States of America (19.6%). Considering the mutation type, a total of 61 different germline mutations was reported, primarily non-missense versus missense alterations (86.9% v 13.1%). Twenty-one PTGs were performed in individuals with no family history of GC, and tumor was detected in 33.3% of investigated cases; regarding individuals with a family history of GC, tumor was identified in 85% of cases. PTG remains the best treatment for individuals harboring germline CDH1 mutations and fulfilling specific clinical criteria; in other CDH1-associated conditions, PTG should be suggested, but not strongly recommended. Additional studies are required to assess the cancer risk in those conditions.

Keywords:  CDH1 mutations; E-cadherin mutations; Hereditary diffuse gastric cancer; Prophylactic total gastrectomy

DOI:  https://doi.org/10.1053/j.seminoncol.2022.03.001
Front Oncol. 2022 ;12 774202

Identification of Germline Mutations in Upper Tract Urothelial Carcinoma With Suspected Lynch Syndrome.

Bao Guan, Jie Wang, Xuesong Li, Lin Lin, Dong Fang, Wenwen Kong, Chuangyu Tian, Juan Li, Kunlin Yang, Guanpeng Han, Yucai Wu, Yuhui He, Yiji Peng, Yanfei Yu, Qun He, Shiming He, Yanqing Gong, Liqun Zhou, Qi Tang.

   Objective: Whole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients.
Methods: In total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations.
Results: Of 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER.
Conclusions: We identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.

Keywords:  DNA mismatch repair; Lynch syndrome; inherited cancer; upper tract urothelial carcinoma; whole-exon sequence

DOI:  https://doi.org/10.3389/fonc.2022.774202
Front Oncol. 2022 ;12 836937

Breast Cancer Phenotype Associated With Li-Fraumeni Syndrome: A Brazilian Cohort Enriched by TP53 p.R337H Carriers.

Renata Lazari Sandoval, Natalia Polidorio, Ana Carolina Rathsam Leite, Mariana Cartaxo, Janina Pontes Pisani, Carla Vanessa Quirino, Loureno Cezana, Natálya Gonçalves Pereira, Allan Andresson Lima Pereira, Benedito Mauro Rossi, Maria Isabel Achatz.

  Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. A TP53 founder pathogenic variant (c.1010G>A; p.R337H) is responsible for the higher prevalence of this syndrome among women of Brazilian ancestry.
Purpose: The aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and other TP53 germline pathogenic/likely pathogenic variants (non-p.R337H carriers).
Methods: We searched for cases of TP53 germline pathogenic/likely pathogenic variant carriers affected by BC included between 2015 and 2020 in the BLiSS (Brazilian Li-Fraumeni Study) registry at the Sírio-Libanês Hospital.
Results: Among 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5% <31 years; 66.7% 31-45 years; 21.8% >45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20-69 years) compared to 34 years (range 21-63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductal in situ carcinomas and 2 soft-tissue sarcomas. Overall, 90.5% of invasive breast carcinomas were hormone receptor (HR)-positive, 39.5% were human epidermal growth factor receptor 2 (HER2)-positive, and 32.8% showed HR and HER2 co-expression. In addition, 55.4% of patients opted for contralateral prophylactic mastectomy after a first BC diagnosis. There were no significant differences in the risk of developing contralateral BC or in the immunohistochemical profile between p.R337H and non-p.R337H groups.
Conclusions: The expressed phenotype of p.R337H is similar to that of other TP53 pathogenic/likely pathogenic variants, except for an average older age at the onset of disease; however, this is still younger than the general population.

Keywords:  Li-Fraumeni syndrome; R337H; TP53; early-onset breast cancer; hereditary breast cancer

DOI:  https://doi.org/10.3389/fonc.2022.836937
Biomed Rep. 2022 May;16(5): 39

Familial Lynch syndrome with early age of onset and confirmed splice site mutation in MSH2: A case report.

Zornitsa Bogomilova Kamburova, Savelina Lubenova Popovska, Katya Stefanova Kovacheva, Krasimir Todorov Petrov, Slavena Enkova Nikolova.

  Lynch syndrome (LS) is an autosomal dominant cancer syndrome. It can be caused by mutations of several genes, including MLH1, MSH2, MSH6, PMS2, MLH3 and MSH3, which are responsible for DNA mismatch repair, and LS affects 3-5% of patients with colorectal cancer (CRC). LS is associated with a high risk of cancer in several different locations, although the most commonly affected regions are the colon (20-70% risk), endometrium (15-70% risk), stomach (6-13% risk) and ovaries (4-12% risk). In the present report, the familial case of LS with a detected pathogenic variant in the MSH2 gene is described. The proband was a male who was diagnosed with CRC at the age of 25 years. Genealogy analysis revealed a total of seven affected relatives (including the proband), one of whom (I degree relative, mother) had synchronous cancers (endometrial and ovarian) and five others (of II and III degree relation) had ovarian cancer. Genetic analysis using next generation sequencing detected a heterozygous germline mutation in the MSH2 gene (c.1386 + 1G >A) in the proband and his mother, confirming the diagnosis of LS. The results of the recommended genetic test in an asymptomatic relative of the proband (II degree relative, uncle), found the same familial mutation. Subsequent prophylactic colonoscopy of this relative revealed early stage CRC. The presented case confirms the need for specific genetic analysis, alongside genetic counseling, in hereditary cancer syndromes. Active genetic prophylaxis in patients with LS allows early detection of primary cancers in other locations, and pre-symptomatic genetic analysis of relatives is an option for early diagnosis.

Keywords:  Lynch syndrome; colorectal cancer; endometrial cancer; genetic counseling; mismatch repair deficiency; ovarian cancer; pathogenic variant; splice site

DOI:  https://doi.org/10.3892/br.2022.1522
Cureus. 2022 Feb;14(2): e22631

A Case Report of CHEK2 and MUTYH Germline Mutations Associated With Cholangiocarcinoma in a Young Patient.

Obaid Rehman, Bradley Sackfield, Viveksandeep Thoguluva Chandrasekar, Jorge Oliver, Ganesh Aswath.

  Cholangiocarcinoma (CCA) is a major cause of primary liver carcinoma and has been associated with the penetrance of several germline mutations. We present a 31-year-old female evaluated for left upper quadrant pain and abnormal liver function tests. Ultrasound revealed a nodule in the liver, and biopsy showed intrahepatic adenocarcinoma. Germline testing was positive for two mutations: c.1100delC and c.1227_1228dupGG on the CHEK2 gene and the MUTYH gene, respectively. The patient was started on chemotherapy and tolerated it well. We aimed to demonstrate an association between CHEK2 and MUTYH mutations with CCA and highlight the importance of genetic testing for at-risk patients.

Keywords:  chek2 mutation; cholangiocarcinoma; extrahepatic; intrahepatic; mutyh mutation

DOI:  https://doi.org/10.7759/cureus.22631
Soc Sci Med. 2022 Mar 17. pii: S0277-9536(22)00211-8. [Epub ahead of print]301 114905

Embodied risk for families with Li-Fraumeni syndrome: Like electricity through my body.

Allison Werner-Lin, Rowan Forbes Shepherd, Jennifer L Young, Catherine Wilsnack, Shana L Merrill, Mark H Greene, Payal P Khincha.

   INTRODUCTION: Experiences of illness change the physical body and embodiments, or the ways in which the world and the self are known through the body. When illness is anticipated, such as with inherited cancer predisposition syndromes, risk becomes embodied and shared in family groups. Embodied risk is experienced whether or not symptoms have manifested. To examine how individuals and families with genetic risk experience the world and understand their disease through their bodies, we employ Li-Fraumeni syndrome (LFS) as an exemplar. LFS is a rare, genetic, cancer predisposition syndrome with nearly 100% lifetime cancer risk starting from birth, limited opportunities for prevention, rigorous screening protocols, and early mortality.
METHODS: Forty-five families, including 117 individuals aged 13-81 years, enrolled in the National Cancer Insitute's LFS study (NCT01443468) completed 66 open-ended interviews regarding LFS experiences. An interdisciplinary team used modified grounded theory to explore physical aspects of living with LFS in psychosocial contexts.
FINDINGS: The physicality of living with LFS included constant monitoring of LFS bodies across the family to identify physical change that might indicate carcinogenesis. Cancer screening, risk reduction, and treatment acted as dually protective and invasive, and as an unavoidable features of LFS. Connections between family members with similar embodiments normalized aesthetic changes and supported coping with visible markers of difference. In some circumstances, participants objectified the body to preserve the self and important relationships. In others, intense pain or loss created thresholds beyond which the self could no longer be separated from the body to support coping.
DISCUSSION: This paper focuses on Li-Fraumeni syndrome, a familial condition with a well-established genetic identity in which the body-self is experienced in relation to important others, to medical imaging, and to historical experiences with cancer. We expand on theories of embodied risk and inter-embodiment to describe experiences across disease trajectories, with attention to division and union between body, self, and other.

Keywords:  Cancer; Dis-embodiment; Embodiment; Family; Hereditary cancer; Li-Fraumeni syndrome; TP53

DOI:  https://doi.org/10.1016/j.socscimed.2022.114905