INTRODUCTION
Advent of next-generation sequencing and large-scale analysis of
mutations in cancer have shown that germline mutations in
cancer-predisposing genes are more common than previously thought and
found in a variable fraction from 5 to 20% of cancer patients, with
different prevalence among cancer types. Germline variants are often
scored also in sporadic cases of cancer with no familial history. To
date, approximately 100 cancer-predisposing genes have been associated
to hereditary syndromes. The PanCancer analysis scored 8% frequency of
pathogenic and likely pathogenic germline mutations in a large cohort of
10,389 patients with 33 different cancer types. Some cancer types show a
significant association with mutations in well-known cancer predisposing
genes, i.e. ovarian cancer in BRCA1/2 , while new associations
were revealed, such as loss of function mutations in BUB1B in
lung cancer and in SDHA in melanoma. These data suggest that a
relevant number of cancer-predisposing genes and their phenotypic
consequences are yet to be identified.
Investigation of an increased risk for cancer development has several
important clinical implications, both for carriers of the pathogenic
variants and their relatives. For cancer patients, identification of a
germline pathogenic variant can yield critical information about
prognosis and direct therapeutic choices, both in terms of efficiency
and toxicity of chemiotherapeutic/radiotherapeutic regimens and of
surgical intervention strategies. Concerning other family members,
identification of pathogenic germline variants in cancer-predisposing
genes may enhance targeted cancer surveillance and improve cancer
prevention.
One of the biggest challenges in this field is the classification of the
identified germline variants, for two main reasons: i) most are
classified as variants of unknown significance (VUS) and, therefore,
have not been assigned a defined biological role nor have they been
attributed to particular disease phenotypes. Consequently, such variants
have no relevance for clinical applications. ii) each
cancer-predisposing gene may confer different cancer risks, ranging from
high to low penetrance (probability) of cancer development, depending
both on cancer type and type of variants affecting the genes.
Acute myeloid leukemia (AML) is among the malignancies with the lowest
frequency of germline variants (4.2% in PanCancer) and traditionally it
has been among the less investigated cancer types from this point of
view. However, germline predisposition of hematological neoplasms is
increasingly assessed and, in recent years, advent of molecular testing
has led to identification of specific hereditary hematological syndromes
. The current guidelines from the European LeukemiaNet (ELN) for
diagnosis and management of AML in adult patients recommend
investigation of germline predisposition. This is particularly critical
for clinical management of AML patients that often receive allogeneic
stem-cell transplantation to consolidate disease remission. Considering
that usually relatives are the best donors, it is critical to exclude
the presence of hematopoietic stem cells harboring pathogenic variants
from the donor before transplantation. The list of cancer predisposing
genes in hematological neoplasms is likely to be largely incomplete and
we are in need for further investigations in order to uncover other
players of hematological hereditability and define the penetrance of the
identified variants.
We designed a comprehensive gene panel for the assessment of germline
pathogenic variants in hematological neoplasms, covering the entire
coding sequence of 256 genes. The employment of large gene panels
enlarges the testing potential compared to genetic screens restricted to
high penetrance genes, allowing discovery of more potential predisposing
variants; however, it also poses the challenge of assigning a specific
functional/phenotypic consequence to newly identified VUS. Variants can
also be reclassified when more information on gene function and/or data
from family history become available over time, based on new studies. We
studied 4 families with two siblings each affected by myeloid neoplasms
in order to exploit the potential of family segregation studies in this
context.