Germline cancer susceptibility in individuals with melanoma.

BACKGROUND: Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers. OBJECTIVE: To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma. METHODS: Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets. RESULTS: Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study. LIMITATIONS: Cohorts with varying degrees of selection, some retrospective. CONCLUSION: Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants.

BACKGROUND: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. METHODS: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. RESULTS: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. CONCLUSIONS: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.

Oral Cancer-related Inherited Cancer Syndromes: A Comprehensive Review.

Oral squamous cell carcinoma is the most common malignancy of the oral cavity, which is usually preceded by a myriad of oral potentially malignant disorders (OPMDs). In the classification of OPMDs, inherited cancer syndromes (ICSs) were proposed as one of the categories. Inherited cancer syndromes are genetic disorders in which inherited genetic mutation in one or more genes predispose the affected individuals to the development of cancer and may also cause its early onset. Many of these syndromes are caused by mutations in tumor suppressor genes, oncogenes, and genes involved in angiogenesis. General dental practitioners frequently come across OPMDs in their day-to-day practice. It becomes of paramount importance to have knowledge about these rare but prognostically important OPMDs. With this view in mind, in this article, efforts have been made to comprehensively discuss about various ICSs that have higher potential of transformation into oral cancer. The ICSs discussed in this article are xeroderma pigmentosum (XP), ataxia telangiectasia (AT), Bloom syndrome (BS), Fanconi's anemia (FA), and Li-Fraumeni syndrome (LFS), with special emphasis on signs, symptoms, and genetic considerations.

Genetic Testing for Successful Cancer Treatment.

Cancer genetic testing is a revolutionary medical approach that involves the assessment of genetic markers in asymptomatic individuals to predict their future susceptibility to cancer. This paradigm shift in early detection and intervention has the potential to profoundly alter our strategies for cancer prevention and treatment. One pivotal area where genetic testing can have a significant impact is among families with a hereditary predisposition to cancer. Recent research has seen a surge in the exploration of how individuals perceive their cancer risk within the realm of cancer genetics. This proactive approach to genetic testing allows healthcare professionals to identify family members who may carry the same cancer-related genetic mutations, empowering them to make informed decisions regarding their healthcare and cancer risk management. Genetic testing for cancer-related disorders has significantly improved in accuracy and affordability, potentially revolutionizing monitoring and treatment methods. The expanding knowledge of genetic mutations associated with cancer susceptibility has driven significant progress in cancer therapy. Identifying numerous major cancer susceptibility genes has propelled predictive genetic testing, providing individuals with valuable insights into their genetic predisposition to cancer. While perceived risk plays a vital role in genetic counseling, it is equally essential to offer comprehensive information about the advantages and potential risks associated with genetic testing. Ensuring that individuals have a clear understanding of the benefits and potential drawbacks of genetic testing is imperative for making informed healthcare decisions. In our comprehensive review, researchers explored several critical aspects of genetic testing in the context of cancer, including awareness and knowledge, the communication of cancer genetic risk, genetic testing for inherited cancer syndromes, and the challenges and limitations linked to genetic testing. Through this examination, we aim to illuminate the transformative potential of genetic testing in cancer prevention and treatment.

Pediatric solid tumors and associated cancer predisposition syndromes: Workup, management, and surveillance. A summary from the APSA Cancer Committee.

BACKGROUND/PURPOSE: Cancer predisposition syndromes (CPS) are a heterogeneous group of inherited disorders that greatly increase the risk of developing malignancies. CPS are particularly relevant to pediatric surgeons since nearly 10% of cancer diagnoses are due to inherited genetic traits, and CPS often contribute to cancer development during childhood. MATERIALS/METHODS: The English language literature was searched for manuscripts, practice guidelines, and society statements on "cancer predisposition syndromes in children". Following review of these manuscripts and cross-referencing of their bibliographies, tables were created to summarize findings of the most common CPS associated with surgically treated pediatric solid malignancies. RESULTS: Pediatric surgeons should be aware of CPS as the identification of one of these syndromes can completely change the management of certain tumors, such as WT. The most common CPS associated with pediatric solid malignancies are outlined, with an emphasis on those most often encountered by pediatric surgeons: neuroblastoma, Wilms' tumor, hepatoblastoma, and medullary thyroid cancer. Frequently associated non-tumor manifestations of these CPS are also included as a guide to increase surgeon awareness. Screening and management guidelines are outlined, and published genetic testing and counseling guidelines are included where available. CONCLUSION: Pediatric surgeons play an important role as surgical oncologists and are often the first point of contact for children with solid tumors. In their role of delivering a diagnosis and developing a follow-up and treatment plan as part of a multidisciplinary team, familiarity with common CPS will ensure evidence-based practices are followed, including important principles such as organ preservation and intensified surveillance plans. This review defines and summarizes the CPS associated with common childhood solid tumors encountered by the pediatric surgeon, as well as common non-cancerous disease stigmata that may help guide diagnosis. TYPE OF STUDY: Summary paper. LEVEL OF EVIDENCE: 5.

Case Report: Male Lobular Breast Cancer in Hereditary Cancer Syndromes.

Background: Lobular breast carcinoma (LBC) is considered an exceptionally rare disease in men, including only 1% of all male breast malignancies. The majority of LBCs have negative immunohistochemical staining for E-cadherin (CDH1) expression, and the loss of CDH1 function was traditionally implicated in the tumorigenesis of diffuse gastric cancer as well as LBC. It is well recognized that LBC in women could be involved in both hereditary breast and ovarian cancer (HBOC) and hereditary diffuse gastric cancer (HDGC) syndromes; however, there are no data present in literature about the involvement of male LBC in these inherited conditions. Methods: BRCA1, BRCA2, and CDH1 genes were performed on DNA from peripheral blood using next-generation sequencing (NGS), Sanger sequencing, and multiplex ligation-dependent probe amplification analyses. BRCA2 and CDH1 somatic gene analyses were performed on breast tumoral DNA using the NGS sequencing approach. Results and conclusions: Here, we describe two men affected by LBC, the carriers of a pathogenic variant of BRCA2 and CDH1 genes, respectively. Our data, including somatic and germline results, demonstrate a strong relationship between male LBC and HBOC/HDGC syndromes, excluding a sporadic origin of LBC in these two patients. Male LBC could represent a sentinel cancer for inherited syndrome identification, and early identification of cancer susceptibility could improve cancer prevention both for men and women in these families. The history of the LBC patient carrier of the CDH1 variant suggests to include male LBC genetic testing criteria and male breast surveillance in HDGC guidelines.

Inherited predisposition to pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the US by 2030. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of PDAC. Precision treatment, informed by germline genetic testing and molecular tumor analysis, can optimize therapeutic regimens and outcomes for those diagnosed with PDAC. As a result, the National Comprehensive Cancer Network currently recommends genetic testing for all newly diagnosed PDAC patients given the clinical implications for treatment but also for the identification of at-risk family members who can benefit from pancreatic cancer screening and other cancer prevention strategies. This article reviews inherited risk factors for the development of PDAC and current screening strategies for the early detection of PDAC in high-risk populations.

The microbiome in PTEN hamartoma tumor syndrome.

Germline PTEN mutations defining PTEN hamartoma tumor syndrome (PHTS) confer heritable predisposition to breast, endometrial, thyroid and other cancers with known age-related risks, but it remains impossible to predict if any individual will develop cancer. In the general population, gut microbial dysbiosis has been linked to cancer, yet is unclear whether these are associated in PHTS patients. In this pilot study, we aimed to characterize microbial composition of stool, urine, and oral wash from 32 PTEN mutation-positive individuals using 16S rRNA gene sequencing. PCoA revealed clustering of the fecal microbiome by cancer history (P = 0.03, R2 = 0.04). Fecal samples from PHTS cancer patients had relatively more abundant operational taxonomic units (OTUs) from family Rikenellaceae and unclassified members of Clostridia compared to those from non-cancer patients, whereas families Peptostreptococcaceae, Enterobacteriaceae, and Bifidobacteriaceae represented relatively more abundant OTUs among fecal samples from PHTS non-cancer patients. Functional metagenomic prediction revealed enrichment of the folate biosynthesis, genetic information processing and cell growth and death pathways among fecal samples from PHTS cancer patients compared to non-cancer patients. We found no major shifts in overall diversity and no clustering by cancer history among oral wash or urine samples. Our observations suggest the utility of an expanded study to interrogate gut dysbiosis as a potential cancer risk modifier in PHTS patients.

Outcome of genetic evaluation of patients with kidney cancer referred for suspected hereditary cancer syndromes.

OBJECTIVE: To analyze patients with kidney cancer referred for evaluation at a high-volume genetics service at a comprehensive cancer center and identify factors associated with positive tests for hereditary cancer syndromes. METHODS: A retrospective review of patients referred to the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center was performed, and patients with a personal history of kidney cancer were identified. Patient and disease characteristics were reviewed. In all, 4 variables including age at diagnosis of kidney tumor, presence of syndromic manifestations, family history of kidney cancer, and number of primary malignancies were evaluated for association with positive test results in 2 groups: patients tested for renal cell carcinoma syndromes and Lynch syndrome. Guidance for genetic testing strategy in patients with kidney cancer is provided. RESULTS: Between 1999 and 2012, 120 patients with a history of kidney cancer were evaluated by the Clinical Genetics Service. The mean age at kidney cancer diagnosis was 52 years (interquartile range: 42-63), with 57% being women. A family history of kidney cancer was reported by 39 patients (33%). Time between diagnosis of first cancer and genetic consultation was <1 year in 54%, 2 to 5 years in 23%, and>5 years in the remaining 23%. Overall, 95 patients were tested for genetic abnormalities with 27 (28%) testing positive. Testing for renal cell carcinoma (RCC)-related syndromes was performed on 43 patients, with 13 testing positive (30%). Lynch syndrome testing was positive in 9 patients (32%) after 28 were tested. In RCC-associated syndromes, young age of diagnosis was associated with positive test results. Conversely, syndromic manifestations and increasing number of primary malignancies were associated with positive Lynch testing. CONCLUSIONS: The discovery of inherited kidney cancer syndromes has provided a unique opportunity to identify patients at increased risk for cancer. Factors associated with positive genetic testing are unique to different syndromes. These data suggest that in kidney cancer patients evaluated for hereditary cancer syndromes, young age is associated with diagnosis of RCC syndromes, whereas syndromic manifestations and multiple primaries are found in Lynch syndrome. These results, along with clinical awareness, may be useful for practicing urologists to select patients with kidney cancer to refer for genetic counseling.