Lancet Oncology: Important new discovery! Shen Hongbing/Hu Zhibin of Nanjing Medical University discovered new endogenous indicators of lung cancer risk to optimize the individualized risk stratification of lung cancer

Lung cancer is one of the most common cancers worldwide and the leading cause of
cancer death worldwide.
Population screening has benefits in reducing lung cancer morbidity and mortality, with risk-stratified screening methods potentially further improving screening outcomes
.
Therefore, a better understanding of risk factors for lung cancer is needed to help optimize risk stratification assessments and identify individuals
at high risk for this disease.

On October 17, 2022, Shen Hongbing and Hu Zhibin of Nanjing Medical University jointly published a joint communication paper entitled "Association of the interaction between mosaic chromosomal alterations and polygenic risk score with the risk of lung cancer" online in Lancet Oncology (IF=54): an array-based case-control association and prospective cohort study", which found that mCAs, as a new endogenous indicator of lung cancer risk, may be used in combination with PRS to optimize the individualized risk stratification
of lung cancer.

Both genetic and non-genetic factors contribute to the development and progression
of lung cancer.
Genome-wide association studies have identified many inherited genetic loci in
lung cancer.
Polygenic risk scores (PRS) constructed by combining these susceptibility sites have also been shown to be effective in quantifying individual risk
of lung cancer.
However, the predictive performance of PRS varies between individuals, depending on their lifestyle and environmental exposure, suggesting that the influence of genetic factors can be modified
by non-genetic risk factors.
Combining PRS with other non-genetic factors may improve individualized risk stratification
of lung cancer.

Proportion of individuals with mCA detected by age group (Figure from Lancet Oncology)

Chimeric chromosomal changes (mCAs), detected from blood-derived DNA, are a group of somatic changes that occur after fertilization, from early embryonic development to later in a person's life, including the acquisition and loss of heterozygosity
.
Aging is a recognized risk factor for mCAs, and several other mutagenic factors have also been reported to help shape the landscape of mCAs, such as exposure to dangerous chemicals and radiation, suggesting that mCAs may be internal genomic signatures that
accumulate DNA damage.
In addition, considering that this type of structural genome alteration spans tens to hundreds or even thousands of genes simultaneously, their important role in hematological malignancies and mortality has long been recognized
.

A large number of population-based studies have suggested that mCAs may also be a possible source of unexplained susceptibility to solid cancers; However, little
is known about the type, frequency, and impact of acquired sex chromosome abnormalities on the development of lung cancer, as well as their interaction with genetic factors.
In this study, detectable autosomal mCAs were systematically investigated in relation to lung cancer risk and their interactions
with genetic factors (i.
e.
, PRS) were examined.

The relationship between mCAs and lung cancer risk in Nanjing Lung Cancer Cohort (A) and UK Biobank (B) study (Figure from Lancet Oncology)

The aim of the study was to investigate whether mCAs contribute to lung cancer risk and change the role of
polygenic risk scores (PRS) in lung cancer risk prediction.
Blood-derived DNA from lung cancer patients of Chinese descent and cancer-free controls in the Nanjing Lung Cancer Cohort (NJLCC) study was genotyped using a screening array and mCAs
were detected using a chimeric chromosomal alteration (MoChA) pipeline.
The mCA call set for individuals with European ancestry was from the UK Biobank (UKB) prospective cohort study, including documented lung cancer events
.

All lung cancer patients in the NJLCC study (age 15 years or older at diagnosis) were histopathologically confirmed by at least two pathologists as new-onset cases of lung cancer and had not received chemotherapy or radiation prior
to diagnosis.
Participants diagnosed with lung cancer after being recruited to UKB (aged 37-73 at the time of assessment) were identified
by contact with the National Cancer Registry.
In NJLCC (Logistic Regression) and UKB (Cox Proportional Risk Model) studies, Logistic regression and Cox proportional hazard models were applied to evaluate the relationship between
mCAs and lung cancer risk.

The NJLCC study included 10 248 people (6445 [62.
89%] male, 3803 [37.
11%]) female; The median age was 60·0 years [IQR value 53·0 - 66·0]), and there were 9298 lung cancer patients (5871 males [66.
3·14%], 3427 females [36·86%]; Patients without lung cancer
recruited from the northern, central and southern regions of the country (mean age 60·0 years [52·0 - 65·0]) between April 15, 2003 and August 18, 2017 。 UKB recruited 450821 participants from 22 UK centres between 13 March 2006 and 1 November 2010, including 2088 lung cancer patients (1075 men [51.
48%], 1013 women [48.
52%]; median age 63.
0 years [IQR 59·0 - 66·0]), 448733 participants without lung cancer (204713 [45·62%] men, 244,020 [54.
38%] women; Median age 58·0 years [IQR 50·0 - 63·0]).

Risk of lung cancer based on chimeric chromosome loss and genetic classification in Nanjing lung cancer cohort study (Figure from Lancet Oncology)

Compared with non-carriers with chimeric deletion, carriers were represented in NJLCC (odds ratio [OR] 1.
81, 95% CI 1.
43 to 2·28; p= 6.
69 × 10−7) and UKB (hazard ratio [HR] 1.
40, 95% CI 1.
00 - 1.
95; p = 0·048) significantly increased
the risk of developing lung cancer in the study.
In NJLCC, the risk of this increased increase was even higher in patients with dilated mCAs cell fraction (i.
e.
, cell fraction ≥ 10% vs.
cell fraction <10%) (OR 1.
61 [95% CI 1.
26 to 2.
08] vs 1.
03 [0.
83 to 1·26]; Heterogeneity test P = 6·41 × 10−3).

In both NJLCC and UKB, PRS and chimeric loss had significant multiplier interactions on lung cancer risk (interaction p-value = 0.
030).

。 In the NJLCC study, participants with enlarged chimeric deletions (cell fraction ≥10%) and high genetic risk had an approximately six-fold increased risk of lung cancer compared to non-carriers with low genetic risk of chimeric deletions (OR 6·40 [95% CI 3.
22 to 12.
69]), while in the UKB study, the risk of lung cancer increased almost fourfold (HR 3.
75 [95% CI 1.
86 to 7.
55]).

。 In the NJLCC study, additive interactions also resulted in a relative additional risk of 3.
67 (95% CI 0.
49 to 6.
85), compared with a relative additional risk of 2.
15 (0.
12 to 4.
19)
in the UKB study.

In conclusion, the study found that mCAs, as a new endogenous indicator of lung cancer risk, may be used in combination with PRS to optimize the individualized risk stratification
of lung cancer.

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