MCM9 is associated with germline predisposition to early-onset cancer—clinical evidence

Mutated MCM9 has been associated with primary ovarian insufficiency. Although MCM9 plays a role in genome maintenance and has been reported as a candidate gene in a few patients with inherited colorectal cancer (CRC), it has not been clearly established as a cancer predisposition gene. We re-evaluated family members with MCM9-associated fertility problems. The heterozygote parents had a few colonic polys. Three siblings had early-onset cancer: one had metastatic cervical cancer and two had early-onset CRC. Moreover, a review of the literature on MCM9 carriers revealed that of nine bi-allelic carriers reported, eight had early-onset cancer. We provide clinical evidence for MCM9 as a cancer germline predisposition gene associated with early-onset cancer and polyposis, mainly in a recessive inheritance pattern. These observations, coupled with the phenotype in knockout mice, suggest that diagnostic testing for polyposis, CRC, and infertility should include MCM9 analysis. Early screening protocols may be beneficial for carriers.

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

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.

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Familial juvenile polyposis syndrome with a de novo germline missense variant in BMPR1A gene: a case report

Background Juvenile polyposis syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract with an increased risk of colorectal cancer. Germline mutations in two genes, SMAD4 and BMPR1A, have been identified to cause JPS. Case presentation Here, we report a germline heterozygous missense variant (c.299G > A) in exon 3 BMPR1A gene in a family with juvenile polyposis. This variant was absent from the population database, and concluded as de novo compared with the parental sequencing. Further sequencing of the proband’s children confirmed the segregation of this variant with the disease, while the variant was also predicted to have damaging effect based on online prediction tools. Therefore, this variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Conclusions Germline genetic testing revealed a de novo germline missense variant in BMPR1A gene in a family with juvenile polyposis. Identification of the pathogenic variant facilitates the cancer risk management of at-risk family members, and endoscopic surveillance is recommended for mutation carriers.

Integrating Genetic and Genomic Testing Into Oncology Practice

Genetic information, both germline and somatic, is an increasingly important consideration in therapeutic decision-making in cancer. Germline mutations in genes associated with increased cancer risk can identify those individuals without cancer who may benefit from enhanced screening and prevention strategies. In individuals with cancer, germline and somatic mutations may help to guide local and systemic management decisions. Here, we review considerations of these issues in selected cancer types.